Clinical trial NCT03583697
Conditions: Achondroplasia
Keywords: Dwarfism Bone Diseases Bone Diseases, Developmental ACH Natriuretic Peptide, C-Type Musculoskeletal Diseases Natriuretic Agents Physiological Effect of Drugs Skeletal Dysplasias Genetic Diseases, Inborn Osteochondrodysplasias
Sponsor: BioMarin Pharmaceutical
Start date: 2018-06-13; Completion date: 2022-01-26
Enrollment: 75 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study 111-206 is a Phase 2 randomized, double-blind, placebo-controlled clinical trial of BMN 111 in infants and young children with a diagnosis of achondroplasia.

Detailed description:

Arms: arm 1: Subcutaneous injection of 15 μg/kg/day and/or 30 μg/kg/day of BMN111 daily. arm 2: Daily subcutaneous injection of placebo
Interventions: intervention 1: BMN 111 intervention 2: Placebo
Intervention descriptions: intervention 1: Subcutaneous injection of 15 μg/kg/day and/or 30 μg/kg/day of BMN 111 daily, subject to adjustment per protocol intervention 2: Subcutaneous injection of 15 μg/kg of placebo daily, Subject to adjustment per protocol

Protocol documents:
Prot_000.pdf: 
 
 
 
 
    
 
 
 
 
 
 
Official Title:  A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial to 
Evaluate the Safety and Efficacy of BMN 111 in Infants and Young Children with 
Achondroplasia, Age 0 to < 60 Months 
 
NCT Number: NCT03583697 
 
Applicant/MAH: BioMarin Pharmaceutical Inc. 
 
Version Date: 08 February 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Proprietary and Confidential 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial 
to Evaluate the Safety and Efficacy of BMN 111 in Infants and Young 
Children with Achondroplasia, Age 0 to < 60 Months 
Protocol Number: 
111-206 
Active Investigational 
Product: 
BMN 111 (modified rhCNP)  
IND 
111299 
European Union Drug 
Regulating Authorities 
Clinical Trials (EudraCT) 
Number: 
2016-003826-18 
Indication: 
Achondroplasia 
Sponsor: 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Development Phase: 
Phase 2 
Sponsor's Responsible 
Medical Monitor: 
, MD, PhD 
  
BioMarin Pharmaceutical Inc. 
10 Bloomsbury Way 
London WC1A 2SL 
Study Design: 
Phase 2 randomized, double-blind, placebo-controlled clinical trial of 
BMN 111 in infants and younger children with a diagnosis of ACH 
Treatment Duration 
52 weeks 
Duration of Subject 
Participation: 
60 weeks for Cohorts 1 and 2 (screening, treatment, follow-up). Subjects 
in Cohort 3 who enter the study for a 12-week observational period will 
participate for approximately 70 weeks (screening, observational period, 
treatment, follow-up) 
Dose: 
15 µg/kg BMN 111 or placebo daily, subject to adjustment per protocol 
Study Population: 
Children 0 to < 60 months old with achondroplasia 
Date of Original Protocol: 
06 December 2017 
Property of BioMarin 
CONFIDENTIAL 
 
May not be divulged, published, or otherwise disclosed to others without prior written approval from BioMarin. 
 
This study will be conducted according to the principles of Good Clinical Practice as described in the U.S. Code of 
Federal Regulations and the International Conference on Harmonisation Guidelines, including the archiving of 
essential documents. 
PI
PI


 
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2 
SYNOPSIS 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
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Dossier: 
 
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TITLE OF STUDY:  A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial to 
Evaluate the Safety and Efficacy of BMN 111 in Infants and Young Children with Achondroplasia, 
Age 0 to < 60 Months 
PROTOCOL NUMBER:  111-206 
STUDY SITES:  Approximately 10-15 sites worldwide 
PHASE OF DEVELOPMENT:  Phase 2 
STUDY RATIONALE: 
BMN 111 is a recombinant CNP analogue that has been engineered to resist degradation by NEP, 
allowing for a longer half-life. 
The pharmacological activity of BMN 111 was explored in two mouse models of ACH, a severe, 
Fgfr3Y367C/+ (TD) model (Lorget, 2012), and a milder [Ach] /+ (Ach) model. These included studies 
in 7-day old TD mice given BMN 111 daily by SC administration for up to 20 days and a study in 
3-week old Ach mice given BMN 111 daily by SC administration for 5 weeks. Partial or complete 
reversion of the ACH phenotype was observed in these mouse models after BMN 111 administration. 
In wild-type mice, and normal rats and monkeys, BMN 111 administration resulted in growth plate 
expansion and dose-dependent skeletal growth at hemodynamically tolerated dose levels 
(Wendt, 2015). Additionally, the potential effect of age on BMN 111 PK was evaluated in normal rats 
aged between 7 days and 12-13 weeks. 
Infants and young children with ACH have a high incidence of medical complications and currently 
there is no approved pharmacological therapy for ACH in the US or EU. The most severe 
complication, cervicomedullary compression (CMC), occurs in a subset of subjects with ACH due to 
abnormal endochondral bone growth and narrowing of the foramen magnum (White, 2016). CMC has 
been linked to serious respiratory and neurological complications including hypotonia, apnea, ataxia, 
developmental delay, and respiratory arrest associated with sudden death (Mukherjee, 2014). Foramen 
magnum decompression surgery is currently the only treatment for this condition.   
Sleep apnea has also been extensively described in ACH, and sleep-disordered breathing may affect up 
to 85% of all children with ACH (Ireland, 2012). This is thought to be due to midface hypoplasia, 
relative adenotonsillar hypertrophy, and potential posterior cranial fossa compression secondary to 
abnormal endochondral bone growth. Sleep apnea in ACH not only results in the need for surgical 
intervention, but has also been linked to sudden death in rare cases (Pauli, 1984).   
Similarly, the dysregulation of endochondral bone growth in ACH leads to other medical 


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
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complications which are prevalent in this subject population, such as the following: 
 
Spinal stenosis, kyphosis, and lordosis (secondary to altered growth plate ossification in the 
vertebrae and narrowing of the interpedicular distances) (Shirley, 2009) 
 
Developmental delay of gross motor and ambulatory skills (associated with proximal limb 
shortening, macrocephaly, and hypotonia) (Ireland, 2010) 
 
Delayed functional skills and increased need for caregiver assistance (eg, eating, bladder 
management, bowel management, transfer to chair, climbing stairs) (Ireland, 2011) 
Thus, BMN 111 may provide greater benefit when children begin treatment at a younger age, as earlier 
initiation of treatment allows a longer time window to improve growth and potential to improve 
medical complications of achondroplasia. This study (111-206) is being conducted to assess safety and 
the potential benefit of BMN 111 in infants and young children.   
BMN 111 was first tested in humans in Study 111-101, a Phase 1 double-blinded, placebo-controlled 
clinical trial of the safety and tolerability of BMN 111 in healthy adult male volunteers without ACH. 
Part 1 examined a series of single subcutaneous doses (5 µg/kg, 10 µg/kg and 15 µg/kg), and Part 2 
included 10 days of either fixed dosing or dose escalation (0.5 µg/kg to 8 µg/kg). BMN 111 was 
generally well tolerated at all doses. As expected, mild, transient, self-limited hypotension was 
reported (refer to current Investigators Brochure for additional information). Following SC 
administration, BMN 111 was rapidly absorbed with maximal plasma concentrations achieved in less 
than 30 minutes. BMN 111 was rapidly cleared from the plasma with a mean t1/2 ranging from 40 to 
55 minutes across dose levels. BMN 111 exposure (Cmax and AUC0-t) generally increased greater than 
proportional to the increase in dose across the 2.5-to-15-µg/kg dose range. Exposure following 
multiple dosing was found to be similar to exposure following single doses, indicating no apparent 
accumulation or time-dependence with once-daily SC administration. 
Study 111-202, the second clinical trial in humans and the first in children with ACH, is an ongoing 
Phase 2, open-label, sequential-cohort, dose-escalation study that assesses daily SC BMN 111 in 
pediatric subjects with ACH aged 5-14 years with doses ranging from 2.5 µg/kg to 30 µg/kg. The 
primary objective of Study 111-202 is to evaluate the safety and tolerability of BMN 111 administered 
for 6 months and up to 24 months; the secondary objectives are to determine change from baseline in 
annualized growth velocity (AGV), growth parameters, body proportions, and evaluate the 
pharmacokinetics (PK) of BMN 111 in children with ACH. 
Analysis of safety data from the 6-month initial phase of Study 111-202 showed that treatment with 
BMN 111 for 6 months at the doses of 2.5, 7.5, 15, and 30 µg/kg was generally well tolerated (refer to 
current Investigator’s Brochure for specific details). One subject (30 µg/kg) in 111-202 withdrew due 
to an AE. The subject developed non-serious, asymptomatic Grade 1 intermittent Wolff-Parkinson-


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
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Dossier: 
 
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White pattern, which was discovered on a routine day 10-study monitoring ECG. The most common 
AEs across all cohorts were injection site reactions, asymptomatic hypotension, headache, and 
nasopharyngitis. Based on previous experience of the ongoing Phase 2 clinical trial, including the 
24-month data cut at 15 µg/kg, injection site reactions have been identified as risks associated with 
BMN 111 injections. The majority of hypotension events were grade 1 and reported in the setting of 
routine BP measurement. All reported events of hypotension were transient and resolved without 
medical intervention. For a detailed summary of risks, please refer to the current version of the 
Investigator’s Brochure supplied by BioMarin.  
Analysis of efficacy data from the 6-month initial phase of Study 111-202 showed that subjects treated 
with BMN 111 for 6 months at doses ranging from 2.5-15 µg/kg daily had a dose-dependent 
improvement in AGV, with ~50% improvement in AGV seen at the 15 µg/kg dose. The data from 
Cohort 4 (30 µg/kg) show an apparent greater than dose-proportional increase in BMN 111 plasma 
exposure (Cmax and AUC0-t), with a marginal improvement in both absolute AGV and change from 
baseline AGV after 6 months of BMN 111 treatment when compared with Cohort 3 (15 µg/kg).    
Study 111-206 is a Phase 2 randomized, double-blind, placebo-controlled clinical trial of BMN 111 in 
infants and younger children with a diagnosis of ACH who are 0 to < 60 months old. This 52-week 
study will enable assessment of BMN 111 efficacy and safety, tolerability, pharmacodynamics 
biomarkers, and PK in this population. Additional exploratory endpoints pertaining to medical 
complications of ACH will also be evaluated.   
Efficacy/toxicity studies have been conducted in neonatal and very young animals (7-day postpartum 
mouse and rat) in both a disease (TD mouse) and non-disease (rat) model. Given that this is the first 
study in infants and young children, an age-based cohort study design is used to assess safety and PK 
in young children (Cohort 1, ≥ 24 to < 60 months) prior to dosing toddlers (Cohort 2, ≥ 6 
to < 24 months) and infants (Cohort 3, 0 to < 6 months). PK will be monitored and evaluated; Day 1 
PK data from the sentinel subjects will inform dose selection modification for the sentinel subjects and 
for the rest of the cohort to target the observed exposure of the 15-µg/kg dose group in Study 111-202. 
Safety, efficacy and PK data from Study 111-202, a Phase 2 study in children with ACH, where a dose 
of 15 µg/kg has been and continues to be studied, are expected to be the most relevant, and translatable 
to this study (111-206).    
OBJECTIVES:  
The primary objectives of the study are to: 
 
Evaluate the safety and tolerability of BMN 111 in children age 0 to < 60 months with ACH  
 
Evaluate the effect of BMN 111 on change from baseline in length/height Z-score 
 


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
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Dossier: 
 
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The secondary objectives of the study are to: 
 
Evaluate the effect of BMN 111 on AGV throughout the 52 weeks of the study  
 
Evaluate the effect of BMN 111 on bone morphology/quality by x-ray and dual x-ray 
absorptiometry (DXA) 
 
Evaluate the PK of BMN 111 in children age 0 to < 60 months with ACH  
 
Evaluate hip function 
 
Evaluate for hip, thigh, or knee pain, or change in gait from medical history 
 
Evaluate the effect of BMN 111 on developmental/functional/QOL status (Bayley-III, 
WeeFIM, Child Behavior Checklist [CBCL], ITQOL 
 
Evaluate immunogenicity of BMN 111 and assess impact on safety, PK, and efficacy measures 
 
Evaluate the effect of BMN 111 on bone metabolism and BMN 111 pharmacodynamic 
biomarkers 
The exploratory objectives of the study are to: 
 
Evaluate the effect of BMN 111 on growth parameters and body proportions, including change 
from baseline in upper:lower segment body ratio 
 
Evaluate the effect of BMN 111 on sleep apnea 
 
Document physical and phenotypic changes with clinical photography (optional) 
 
Evaluate the effect of BMN 111 on skull and brain morphology, including foramen magnum, 
ventricular and brain parenchymal dimensions 
 
Describe the incidence of surgical interventions, including cervical decompression, 
adenotonsillectomy, and tympanostomy 
STUDY DESIGN AND PLAN:  
This study, 111-206, is a Phase 2 randomized, double-blind, placebo-controlled clinical trial of 
BMN 111 in infants and younger children with a diagnosis of ACH.  
Study 111-901 is an ongoing study to collect serial growth measurements on pediatric subjects with 
ACH who are being considered for subsequent enrollment in future BioMarin studies.  Subjects 
age ≥ 3 months to < 60 months old who have documented ACH confirmed by genetic testing, at least a 
6-month period of pretreatment growth assessment in Study 111-901 immediately before study entry, 
and who meet the study eligibility criteria will participate in Study 111-206.  Eligible subjects ranging 
from 0 months to  < 3 months old may enroll directly into 111-206 and have a minimum of 3 months of 
pre-treatment observation prior to commencing treatment. 


 
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6 December 2017 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
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Approximately 70 subjects will be enrolled at approximately 10-15 clinical centers worldwide.   
The primary objectives of this study are to assess the safety and tolerability of daily SC BMN 111 
administered to infants and young children with ACH, and evaluate the effect of BMN 111 on 
length/height Z-score. Subjects will be enrolled into 3 age cohorts based on age at study screening 
starting with the eldest population.  Within Cohorts 1 and 2, subjects will be stratified by age: 
 
Cohort 1 – children aged ≥ 24 to < 60 months (n ≥ 30 total: 3 sentinel subjects who receive 
BMN 111, and at least 27 additional subjects randomized 1:1 to treatment or placebo control), 
stratified by age (≥ 24 to < 36 months and ≥ 36 months to < 60 months)  
 
Cohort 2 – children aged ≥ 6 to < 24 months (n ≥ 20 total: 3 sentinel subjects who receive 
BMN 111, and at least 17 additional subjects randomized 1:1 to treatment or placebo control), 
stratified by age (≥ 6 months to < 15 months and ≥ 15 months to < 24 months)  
 
Cohort 3 – children aged 0 to < 6 months (n ≥ 20 total: 3 sentinel subjects who will be under 
observation or receive BMN 111, and at least 17 additional subjects randomized 1:1 to 
treatment or placebo control).  Treatment begins at ≥ 3 months to  < 6 months after 3 months of 
observation. 
If subjects who enroll in Cohort 3 are not able to begin treatment by  < 6 months of age, they will 
continue in the pretreatment period for another 3 months before enrolling in Cohort 2 to fulfill the 
pretreatment requirement for Cohort 2. 
Sentinel subjects from each cohort will be enrolled, treated with BMN 111, and studied for short-term 
safety and PK data, after which subjects will be randomized to receive BMN 111 or placebo SC daily 
(1:1 ratio) for up to 52 weeks.  
At the start of the study, three sentinel subjects will be enrolled and monitored in Cohort 1. After all 
3 sentinel subjects reach Day 8, the Sponsor will review and evaluate all available safety data and 
Day 1 PK data. Based on PK data review, the weight-based dose may be adjusted for the sentinel 
subjects and the rest of the cohort, and will be the starting dose for the younger cohort sentinel 
subjects.  Upon review of the clinical and PK data, the remainder of Cohort 1 (≥ 27 additional 
subjects) will be enrolled and randomized to treatment with BMN 111 or placebo (1:1 ratio).  After the 
sentinel subjects complete 12 weeks of dosing, a DMC review will occur to evaluate all available 
safety and PK data.  Upon approval by the DMC, the next younger cohort (Cohort 2) will be opened 
and the 3 sentinel subjects will be enrolled. 
The same procedure will be followed for Cohort 2. After all 3 sentinel subjects reach Day 8, the 
Sponsor will review and evaluate all available safety data and Day 1 PK data. Based on PK data and 
criteria set in the protocol, the dose may be adjusted for the sentinel subjects and the rest of the cohort, 
and will be the starting dose for the younger cohort sentinel subjects.  Upon review of the clinical and 


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
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PK data, the remainder of Cohort 2 (≥ 17 additional subjects) will be enrolled and randomized to 
treatment with BMN 111 or placebo (1:1 ratio). After the sentinel subjects complete 12 weeks of 
dosing, a DMC review will occur to evaluate all available safety and PK data.  Upon approval by the 
DMC, the youngest cohort (Cohort 3) will be opened and the 3 sentinel subjects will be enrolled. 
The same procedure will be followed for Cohort 3. After all 3 sentinel subjects reach Day 8, the 
Sponsor will review and evaluate all available safety data and Day 1 PK data. Based on PK data and 
criteria set in the protocol, the dose may be adjusted for the sentinel subjects and the rest of the cohort, 
and will be the starting dose for the younger cohort sentinel subjects.  Upon review of the clinical and 
PK data, the remainder of Cohort 3 (≥ 17 additional subjects) will be enrolled and randomized to 
treatment with BMN 111 or placebo (1:1 ratio).  
Cohort 3 subjects must have a minimum of 3 months of observation prior to commencement of 
treatment.  These subjects will have the option to enroll in either 111-901 or 111-206, depending on 
age at enrollment: 
 
Infants ≥ 3 months and  < 6 months old (≥ 13 weeks and  < 26 weeks) will enroll in 111-901 for 
a 6-month period of pretreatment growth assessment prior to enrollment in 111-206 for 
treatment in Cohort 2. 
 
Infants between birth and < 3 months old (0 weeks and < 13 weeks) will enroll into 111-206 
with a 3-month observational period prior to treatment. 
Additional sentinels may be added to any cohort if needed for additional safety and/or PK assessment. 
Duration of the study is 52 weeks of treatment with a safety follow up at Week 56. Following 
completion of the study, subjects in all treatment groups may be eligible to receive BMN 111 in an 
open-label extension study, to assess safety and efficacy of BMN 111 over the longer term.  
For subjects enrolling into the extension study, safety follow up visit at Week 56 will be waived.  
Data Monitoring Committee (DMC) 
In addition to safety and PK monitoring by BioMarin personnel, an independent DMC will act as an 
advisory body to BioMarin and will monitor the safety and PK of subjects in the study. After the 
sentinel subjects complete 12 weeks of dosing, a DMC review will occur to evaluate all available 
safety and PK data.  Upon approval by the DMC, the next younger cohort will be opened and the 
3 sentinel subjects will be enrolled. 
The DMC will make recommendations for stopping or continuing the study on an individual subject 
level and/or on a cohort level per the pre-specified stopping criteria. Based on criteria outlined in the 
protocol, the DMC may also make endorsements for dose adjustments if needed.  
Please see DMC Charter for further details. 
 


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
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Individual Subject Stopping Criteria  
For individual subjects treated with BMN 111, DMC will be informed if any of the following 
individual subject stopping criteria should occur. Temporary dosing suspension, permanent 
discontinuation of dosing, or dose reduction for the individual subject will be considered. 
 
Any treatment-emergent adverse event (AE) assessed as at least Grade 4 by the Investigator 
and/or Sponsor Medical Monitor  
 
Any treatment-emergent AE of at least Grade 3 assessed as related to study drug by the 
Investigator and/or Sponsor Medical Monitor  
 
Any two treatment-emergent Grade 2 symptomatic hypotension events within 7 days 
(non-urgent medical intervention indicated) or any Grade 3 hypotensive event (urgent medical 
intervention or hospitalization indicated) assessed by the Investigator and/or Sponsor’s 
Medical Monitor  
 
Clinically significant finding or arrhythmia on ECG that indicates abnormal cardiac function 
or conduction or prolongation of QTc-F >500 msec 
 
Clinically significant new or worsening signs of cervicomedullary compression as determined 
by the Investigator and in consultation with Sponsor medical monitor and neurosurgical 
specialist (if needed) 
 
Adverse findings on clinical hip exam or hip imaging assessments that are determined to be 
clinically significant as determined by the Investigator and in consultation with Sponsor 
Medical Monitor and orthopedic specialist (if needed)  
If the subject meets any stopping criterion, after Investigator consultation with the BioMarin Medical 
Monitor and DMC, the subject may be re-challenged at the same dose. If the subject meets stopping 
criteria on re-challenge or if re-challenge is not clinically indicated, other options that may be 
considered include:  
 
Permanent treatment discontinuation (with an option of ongoing assessment in the study)  
Cohort Stopping Criteria  
For each cohort, a DMC review will be conducted if any of the following cohort stopping criteria 
occur in subjects treated with BMN 111.  Temporary dosing suspension, permanent discontinuation of 
dosing, or dose reduction for the cohort(s) will be considered and the impact on all other age cohorts 
will be assessed.  
 
Any treatment-emergent AE assessed as at least Grade 4 by the Investigator and/or Sponsor 
Medical Monitor  


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
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 
Any two subjects have a treatment-emergent AE of at least Grade 3 assessed as related to 
study drug by the Investigator and/or Sponsor Medical Monitor  
 
Any two subjects have two treatment-emergent Grade 2 symptomatic hypotension events 
within 7 days (non-urgent medical intervention indicated) or any two subjects cohort have a 
Grade 3 hypotensive event (urgent medical intervention or hospitalization indicated) assessed 
by the Investigator and/or Sponsor’s Medical Monitor  
 
Any two subjects have a clinically significant finding or arrhythmia on ECG that indicates 
abnormal cardiac function or conduction or prolongation of QTc-F >500 msec 
 
Any two subjects have adverse findings on clinical hip exam or hip imaging assessments that 
are determined to be clinically significant as decided by principal investigator and in 
consultation with Sponsor medical monitor and orthopedic specialist (if needed)  
Dose Adjustments 
Analysis of available PK data from studies 111-101 and 111-202 indicated that differences in subject 
body weight did not directly translate to differences in total body clearance of BMN 111.  The same 
weight-based dose in the pediatric population of Study 111-202 (5-12 years old) yielded lower 
exposure (Cmax and AUC) than that characterized in the adult population of Study 111-101.  Therefore, 
the same weight-based dose in the young pediatric population in this study may yield exposure less 
than the target exposure range characterized to be safe and effective in Study 111-202 at the 15-µg/kg 
dose. Since this is the first experience with BMN 111 in this young pediatric population, it is also 
possible the exposure at 15 μg/kg could be greater than the target exposure range, and dose adjustment 
may be warranted. Thus, an option for adjustment of the weight-based dose is provided to ensure that 
the appropriate target exposure for safety and efficacy is reached for the young subjects in this study.   
The need for dose adjustment will be evaluated as follows: three sentinel subjects in Cohort 1 will 
receive an initial dose of 15 µg/kg. After all three sentinel subjects reach Day 8, a review will occur to 
evaluate all available safety and PK data (at minimum). If the criteria for dose adjustment are met, the 
three sentinel subjects will be started on the new adjusted dose at their next scheduled visit, and vital 
signs will be obtained for at least 4 hours post-dose. 
The remainder of the subjects in the age cohort will also be enrolled starting at the new adjusted dose. 
After the third sentinel subject reaches day 30 post dose adjustment, a DMC review will occur to 
evaluate all safety and PK data and, upon endorsement, the three sentinel subjects from the next 
younger cohort will be enrolled starting at the new adjusted dose.  The three sentinel subjects for the 
second and third cohorts will be evaluated similarly to the sentinel subjects in the first cohort for 
potential dose adjustment. 
 


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
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Safety and Efficacy Monitoring 
Each treated subject will have expanded outpatient safety monitoring for a minimum of 3 days of 
dosing, during which they will be closely observed and non-invasive hemodynamic monitoring will be 
conducted for at least 4-8 hours post-dosing. Because younger children may not be able to verbalize 
complaints of dizziness or lightheadedness that are potentially associated with hypotension, study 
personnel and caregivers will be trained to recognize the signs of hypotension in this population, which 
may include tachycardia, pallor, diaphoresis, lethargy, delayed capillary refill, and poor feeding. 
Appropriate rigorous training will be required for parents and caregivers prior to daily injections at 
home. Training includes the storage, reconstitution, and administration of BMN 111, as well as 
documentation/reporting of AEs and vigilance for signs of hypotension. 
It is generally expected that after subjects are tolerating the drug well and specified criteria have been 
met, caregivers will begin administering study drug. Home health care is not required at any point but 
may be provided if the caregiver is unable or unavailable to administer the study drug. A Home 
Healthcare nurse will train the caregiver(s) if training has not been completed by the Day 3 visit. A 
phone call by the study staff member to the caregiver will be required weekly for 6 months and then 
every 2 weeks for the remainder of the study. During these contacts, study staff will ask the caregiver 
about dose administration and seek information on AEs and SAEs by specific questioning. If the 
caregiver cannot be contacted by phone after two attempts, contact can be made via email.   
Safety will be evaluated by the incidence of AEs, serious AEs (SAEs), laboratory test results 
(urinalysis, chemistry, and hematology), vital signs, physical examination, ECG and echocardiogram, 
hip clinical assessment, and anti-BMN 111 immunogenicity assessments.  Clinical laboratory tests, 
PK, immunogenicity and blood biomarker assessments will be limited to the minimum necessary for 
evaluation of safety and efficacy in order to minimize blood volume in the pediatric population. 
Efficacy will be assessed by change from baseline in AGV and length/height Z-score. Exploratory 
assessments will include change from baseline in growth parameters and body proportions by 
anthropometry. X-rays will be performed of the lower extremities and spine to evaluate for changes in 
bone morphology, quality, and growth. An MRI will be performed to assess the effect of BMN 111 on 
skull and brain morphology, including foramen magnum, ventricular and brain parenchymal 
dimensions.  A board-certified, fellowship-trained (or equivalent) pediatric anesthesiologist will 
administer anesthesia during MRI measurements in the event that the subject is unable to remain still 
for the duration of the scan. Sleep studies will be conducted to evaluate sleep apnea. Additional 
assessments will be conducted to evaluate changes from baseline in bone metabolism and BMN111 
pharmacodynamic biomarkers, and developmental/functional status.   
NUMBER OF SUBJECTS PLANNED: Approximately 70 subjects, including at least 30 subjects in 
Cohort 1, at least 20 subjects in Cohort 2, and at least 20 subjects in Cohort 3. 


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:  
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Diagnosis of ACH, confirmed by genetic testing.  If subjects had previous genetic testing, 
subjects must have a lab report from a certified laboratory with the study specific mutation 
documented. 
2. Age   0 to  < 60 months, at study entry (Day 1) 
3. Cohort 1 and 2 subjects must have at least a 6-month period of pretreatment growth 
assessment in Study 111-901 immediately before study entry, and have one documented 
measurement of height/body length a minimum of 6 months (+/- 10 days) prior to the 
screening visit for 111-206.  Cohort 3 subjects must have a minimum of 3 months of 
observation prior to treatment.  This observational period can be obtained either (1) via prior 
enrollment in Study 111-901 or (2) via enrollment in this Study 111-206 for a minimum of 
3 months of non-treatment observation prior to commencement of treatment. 
4. Parent(s) or guardian(s) (and the subjects themselves, if required by local regulations or ethics 
committee) are willing and able to provide written, signed informed consent after the nature of 
the study has been explained and prior to performance of any research-related procedure 
5. Willing and able to perform all study procedures as physically possible 
6. Parent(s) or caregiver(s) are willing to administer daily injections to the subjects and complete 
the required training 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
1. Have hypochondroplasia or short-stature condition other than achondroplasia (e.g., trisomy 21, 
pseudoachondroplasia, etc.) 
2. Subject weighs < 5.0 kg (Cohorts 1 and 2) or <  4.0 kg (Cohort 3) 
3. Have any of the following: 
 
Hypothyroidism or hyperthyroidism 
 
Insulin-requiring diabetes mellitus 
 
Autoimmune inflammatory disease (including celiac disease, systemic lupus 
erythematosus, juvenile dermatomyositis, scleroderma, etc.) 
 
Inflammatory bowel disease 
 
Autonomic neuropathy 
4. Have a history of any of the following: 
 
Renal insufficiency defined as serum creatinine > 2 mg/dL 
 
Chronic anemia or Hgb  < 10.0 g/dL (based on screening clinical laboratory testing) 
 
Baseline systolic blood pressure (BP) below age and gender specified normal range or 


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
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AUTHORITY USE 
ONLY: 
recurrent symptomatic hypotension (defined as episodes of low BP generally accompanied 
by symptoms e.g., dizziness, fainting) or recurrent symptomatic orthostatic hypotension 
 
Cardiac or vascular disease, including the following 
o Cardiac dysfunction (abnormal echocardiogram determined to be clinically 
significant by PI and medical monitor) at Screening Visit  
o Hypertrophic cardiomyopathy 
o Pulmonary hypertension 
o Congenital heart disease with ongoing cardiac dysfunction  
o Cerebrovascular disease 
o Aortic insufficiency or other clinically significant valvular dysfunction 
o Clinically significant atrial or ventricular arrhythmias 
5. Have a clinically significant finding or arrhythmia that indicates abnormal cardiac function or 
conduction or QTc-F  > 450 msec on screening ECG 
6. Have evidence of cervicomedullary compression (CMC) likely to require surgical intervention 
within 60 days of Screening as determined by the Investigator based on the following 
assessments:  
 
Physical exam (eg, neurologic findings of clonus, opisthotonus, exaggerated reflexes, 
dilated facial veins) 
 
Polysomnography (eg, severe central sleep apnea) 
 
MRI indicating presence of severe CMC or spinal cord damage  
7. Have an unstable medical condition likely to require surgical intervention in the next 
6 months, or planned spine or long-bone surgery (i.e., surgery involving significant disruption 
of bone cortex) during the study period 
8. Have documented uncorrected Vitamin D deficiency: 25(OH)D   ≤ 15 ng/mL (37.5 nmol/L) 
9. Require any other investigational product prior to completion of the study period 
10. Have received another investigational product or investigational medical device within 30 days 
prior to the Screening visit 
11. Have used any other investigational product or investigational medical device for the treatment 
of achondroplasia or short stature at any time  
12. Require current chronic therapy with antihypertensive medication or any medication that, in 
the investigator’s judgment, may compromise the safety or ability of the subject to participate 
in this clinical study  
13. Have been treated with growth hormone, insulin-like growth factor 1 (IGF-1), or anabolic 
steroids in the 6 months prior to screening, or long-term treatment (> 3 months) at any time 
14. Have had regular long-term treatment (> 1 month) with oral corticosteroids (low-dose ongoing 
inhaled steroid for asthma, or intranasal steroids, are acceptable) in the 12 months prior to 


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
screening 
15. Have ever had spine or long-bone surgery (ie, surgery involving disruption of bone cortex) or 
have ever had bone-related surgery with chronic complications 
16. Have ever had limb-lengthening surgery or plan to have limb-lengthening surgery during the 
study period 
17. Have had a fracture of the long bones or spine within 6 months prior to screening 
18. Have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or total bilirubin 
greater than upper limit of normal at screening (except for subjects with a known history of 
Gilberts or newborns entering screening in Cohort 3) 
19. Have evidence of severe untreated sleep apnea; or have newly initiated sleep apnea treatment 
(eg, CPAP or sleep apnea-mitigating surgery) in the 2 months prior to screening  
20. Have current malignancy, history of malignancy, or currently under work-up for suspected 
malignancy 
21. Have known hypersensitivity to BMN 111 or its excipients 
22. Have a history of hip surgery or severe hip dysplasia 
23. Have a history of clinically significant hip injury in the 30 days prior to screening  
24. Have a history of slipped capital femoral epiphysis or avascular necrosis of the femoral head  
25. Have abnormal findings on baseline clinical hip exam or imaging assessments that are 
determined to be clinically significant as determined by the Investigator 
26. Have a condition or circumstance that, in the view of the Investigator, places the subject at 
high risk for poor treatment compliance or for not completing the study 
27. Have any concurrent disease or condition that, in the view of the Investigator, would interfere 
with study participation or safety evaluations, for any reason 
INVESTIGATIONAL PRODUCT, DOSE, ROUTE, and REGIMEN: The clinical drug product 
will be supplied in sterile, single-dose, Type I glass vials with coated stopper and flip-off aluminum 
cap. BMN 111 drug product is supplied as a 0.8-mg or 2-mg lyophilized, preservative-free, white-to-
yellow powder for reconstitution with either a sterile diluent or sterile water for injection. The 
reconstituted solution is colorless to yellow and contains 0.8 mg/mL to 2 mg/mL of BMN 111, as well 
as citric acid, sodium citrate, trehalose, mannitol, methionine, polysorbate 80, and sterile water for 
injection. The target pH of the reconstituted solution is 5.5. Sterile water for injection will be 
commercially sourced and sterile diluent solution containing all of the above excipients will be 
supplied for reconstitution. All reconstitution and dose preparation steps will be performed as indicated 
in the BMN 111 Injection Guide and Injection video.  
BMN 111 will be administered as a single SC injection given daily at approximately the same time 
each day whenever possible. Following administration of each dose at clinic visits, subjects should be 
observed for 8 hours after the injection on Days 1 and 2; 4 hours on Days 3 and 8; and 1 hour on 


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
subsequent dosing visits. Subjects should be observed for 30 minutes after every injection that is not 
administered at the clinic. 
REFERENCE THERAPY, DOSE, ROUTE, and REGIMEN: BMN 111-placebo lyophilized 
product will be supplied in sterile, single-dose, Type I glass vials with coated stopper and flip-off 
aluminum cap. The placebo is designed to be comparable in appearance to the drug product and 
contains all of the components of the drug product except the drug substance.  
All reconstitution and dose preparation steps should be performed as indicated in the Study Drug 
Injection Guide and Injection instruction media. 
Placebo will be administered as a single SC injection given daily at approximately the same time each 
day whenever possible. Following administration of each dose at clinic visits, subjects should be 
observed for 8 hours after the injection on Days 1 and 2; 4 hours on Days 3 and 8; and 1 hour on 
subsequent dosing visits. Subjects should be observed for 30 minutes after every injection that is not 
administered at the clinic. 
DURATION OF TREATMENT: Up to 52 weeks 
CRITERIA FOR EVALUATION: 
Safety: The following safety outcome measurements will be assessed: 
 
Incidence of AEs and SAEs 
 
Vital signs (heart rate, blood pressure, respiratory rate, and temperature) 
 
Physical examination (including neurological assessment) 
 
Hip clinical assessment 
 
Laboratory test results (urinalysis, chemistry, hematology) 
 
Electrocardiogram (ECG) 
 
Echocardiogram  
 
Anti-BMN 111 immunogenicity assessments 
 
Cortisol levels 
 
Prolactin levels 
Efficacy: The following efficacy outcome measurements will be assessed: 
 
Change from baseline in AGV  
 
Change from baseline in length/height Z-score 
Pharmacokinetics: Whenever possible, the following PK parameters will be estimated by 
non-compartmental analysis: 
 
Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞)  


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
 
Area under the plasma concentration-time curve from 0 to the time of last measurable 
concentration (AUC0-t) 
 
Maximum plasma concentration (Cmax)  
 
Time to reach Cmax (Tmax)  
 
Elimination half-life (t1/2)  
 
Apparent clearance of drug (CL/F)  
 
Apparent volume of distribution based upon the terminal phase (Vz/F)  
Drug accumulation after repeat-dose administration will also be evaluated. PK parameters at Week 13, 
26, 39 and 52 will be compared to Day 1. The impact of immunogenicity (if present) on PK will also 
be evaluated. 
Bone metabolism and BMN 111 pharmacodynamic biomarkers:  
 
Changes in bone and collagen metabolism and BMN 111 activity will be assessed.  
Clinical outcome assessments: 
 
Bayley-III  
 
WeeFIM  
 
CBCL 
 
ITQOL  
Exploratory: The following exploratory measurements will be assessed: 
 
Upper:lower body segment ratio 
 
Imaging assessments (X-rays of the spine and lower extremities) 
 
MRI to define skull and brain morphology (including dimensions of foramen magnum, 
ventricular and brain parenchymal dimensions) 
 
Sleep study 
 
Clinical photography (optional)
STATISTICAL METHODS:  
Sample Size Determination: Approximately 70 subjects age 0 to < 60 months at study entry will 
participate in this study. No formal sample size calculations were performed. The number of subjects is 
considered appropriate to evaluate the safety and efficacy of BMN 111 in the target population.    
Safety Analysis: All subjects who receive at least one dose of study treatment or who are randomized 
to the placebo-control group in this study will be included in the safety analysis. The safety analysis 
will be descriptive. 
All AEs will be coded using the most current version of Medical Dictionary for Regulatory Activities 


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
(MedDRA) to assign system organ class and preferred term classification to event and disease, based 
on the original terms entered on the eCRF. The incidence of AEs will be summarized by system organ 
class, preferred term, relationship to study treatment as assessed by the investigator, seriousness, and 
severity. All AEs, including SAEs and AEs that lead to permanent discontinuation from the study and 
from the study treatment, will be listed. 
All other safety measures including laboratory tests, vital signs, ECG, echocardiogram, hip clinical 
assessment, and concomitant medication data will also be summarized descriptively. Data summaries 
will be presented by treatment group (when applicable) for each cohort and overall. All safety results 
will be listed.  
Efficacy Analysis: 
All randomized subjects who receive at least one dose of study treatment or placebo in the study will 
be included in the efficacy analysis.  
Efficacy variables, including AGV (based on length/height) and length/height Z-score according to 
normal reference standards (not ACH), along with their change from baseline will be summarized by 
treatment group and cohort. Comparisons between treatment groups by cohort on these variables will 
be carried out where appropriate. Statistical comparisons will be considered descriptive. 95% CIs will 
be provided along with p values for treatment group comparisons.  
Sentinel subjects will be summarized apart for both efficacy and safety. 


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3 TABLE OF CONTENTS 
1    TITLE PAGE……………………………………………………………………………...1 
2 SYNOPSIS ...........................................................................................................................2 
3 TABLE OF CONTENTS ...................................................................................................17 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................23 
5 ETHICS..............................................................................................................................26 
5.1 Institutional Review Board or Independent Ethics Committee ................................26 
5.2 Ethical Conduct of Study ..........................................................................................27 
5.3 Subject Information and Informed Consent ..............................................................27 
6 INVESTIGATORS AND STUDY ADMINSTIRATIVE STRUCTURE ........................29 
7 INTRODUCTION .............................................................................................................30 
7.1 Nonclinical Studies ...................................................................................................31 
7.2 Previous Clinical Studies ..........................................................................................32 
7.2.1 
Study 111-101 .............................................................................................32 
7.3 Ongoing Clinical Studies ..........................................................................................33 
7.3.1 
Study 111-901 .............................................................................................33 
7.3.2 
Study 111-202 .............................................................................................33 
7.3.3 
Study 111-205 .............................................................................................34 
7.3.4 
Study 111-301 .............................................................................................34 
7.4 Study Rationale .........................................................................................................34 
7.5 Summary of Overall Risks and Benefits ...................................................................37 
7.5.1 
Summary of Risks from Nonclinical Studies ..............................................37 
7.5.2 
Summary of Risks from Clinical Studies ....................................................37 
7.5.2.1 
Study 111-101 ..............................................................................37 
7.5.2.2 
Ongoing Studies ...........................................................................37 
7.5.3 
Summary of Potential Benefits from Clinical Studies ................................38 
8 STUDY OBJECTIVES ......................................................................................................39 
9 INVESTIGATIONAL PLAN ............................................................................................40 
9.1 Overall Study Design and Plan .................................................................................40 


 
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9.1.1 
Dose Adjustments ........................................................................................51 
9.1.2 
Stopping Criteria .........................................................................................52 
9.2 Discussion of Study Design, Including Choice of Control Group ............................53 
9.3 Selection of Study Population ...................................................................................54 
9.3.1 
Inclusion Criteria .........................................................................................54 
9.3.2 
Exclusion Criteria ........................................................................................55 
9.3.3 
Removal of Subjects from Treatment or Assessment .................................57 
9.3.4 
Subject Identification ..................................................................................58 
9.3.5 
Duration of Subject Participation ................................................................58 
9.4 Treatments .................................................................................................................59 
9.4.1 
Treatments Administered ............................................................................59 
9.4.1.1 
Study Drug Administration ..........................................................59 
9.4.2 
Identity of BMN 111 ...................................................................................60 
9.4.2.1 
Product Characteristics and Labeling ..........................................60 
9.4.3 
Storage .........................................................................................................61 
9.4.4 
Directions for Administration .....................................................................61 
9.4.5 
Method of Assigning Subjects to Treatment Groups ..................................62 
9.4.6 
Selection of Dose and Dosing Schedule Used in the Study ........................62 
9.4.6.1 
Selection of Timing of Dose for Each Subject ............................63 
9.4.7 
Blinding .......................................................................................................63 
9.4.8 
Prior and Concomitant Medications ............................................................63 
9.4.9 
Treatment Compliance ................................................................................64 
9.5 Investigational Product Accountability (BMN 111 or Placebo) ...............................64 
9.5.1 
Return and Disposition of Clinical Supplies ...............................................64 
9.6 Dietary or Other Protocol Restrictions ......................................................................65 
9.7 Demographic Data and Medical History ..................................................................65 
9.8 Biological Parental Standing Height .........................................................................65 
9.9 Physical Examination Findings .................................................................................65 
9.10 Echocardiogram ........................................................................................................66 
9.11 Efficacy and Safety Variables ...................................................................................66 


 
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9.11.1 Efficacy and Safety Measurements Assessed .............................................66 
9.11.2 Primary Efficacy Variables .........................................................................66 
9.11.3 Secondary Efficacy Variables .....................................................................66 
9.11.4 Exploratory Efficacy Variables ...................................................................67 
9.11.4.1 
Body Proportion Ratios of the Extremities ..................................67 
9.11.4.2 
Imaging Assessment Procedures (per Schedule of Events) .........67 
9.11.4.3 
Exploratory Biomarker Research Sample Analyses ....................68 
9.11.4.4 
Genomic Biomarker Analysis ......................................................68 
9.11.4.5 
Sleep Study ..................................................................................68 
9.11.4.6 
Clinical Photography ...................................................................68 
9.11.4.7 
Clinical Outcome Assessments ....................................................69 
9.11.5 Pharmacokinetics Variables ........................................................................71 
9.11.6 Safety Variables ..........................................................................................71 
9.11.6.1 
Adverse Events ............................................................................71 
9.11.6.2 
Procedures due to Achondroplasia...............................................73 
9.11.6.3 
Clinical Laboratory Assessments .................................................73 
9.11.6.4 
Other Laboratory Assessments ....................................................74 
9.11.6.5 
Vital Signs, Physical Examinations and Other 
Observations Related to Safety ....................................................75 
9.11.6.6 
Mitigating the Risk of Potential Hypotension .............................76 
9.11.6.7 
Electrocardiography .....................................................................77 
9.11.6.8 
Hip Clinical Assessment ..............................................................77 
9.11.6.9 
Pediatric Blood Volume ...............................................................77 
9.11.6.10 Anti- BMN 111 Immunogenicity Assessments and IgE 
Testing..........................................................................................78 
9.11.6.11 HPA Axis Assessments................................................................78 
9.11.6.12 Ad Hoc Safety Assessments ........................................................78 
9.11.6.13 Unscheduled Safety Visits ...........................................................79 
10 REPORTING ADVERSE EVENTS .................................................................................80 
10.1 Safety Parameters and Definitions ............................................................................80 
10.1.1 Adverse Events ............................................................................................80 


 
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10.1.2 Serious Adverse Events ...............................................................................80 
10.1.3 Events of Special Interest (EOSI) ...............................................................81 
10.2 Methods and Timing for Capturing and Assessing Safety Parameters .....................81 
10.2.1 Adverse Event Reporting Period .................................................................81 
10.2.2 Eliciting Adverse Events .............................................................................81 
10.2.3 Assessment of Seriousness, Severity, and Causality ...................................82 
10.2.3.1 
Seriousness ...................................................................................82 
10.2.3.2 
Severity ........................................................................................82 
10.2.3.3 
Causality ......................................................................................83 
10.3 Procedures for Recording Adverse Events ...............................................................85 
10.3.1 Recording Adverse Events on a eCRF ........................................................85 
10.3.1.1 
Diagnosis versus Signs and Symptoms........................................85 
10.3.1.2 
Adverse Events Occurring Secondary to Other Events ...............85 
10.3.1.3 
Persistent or Recurrent Adverse Events .......................................85 
10.3.1.4 
Hypotension .................................................................................85 
10.3.1.5 
Injection Site Reactions ...............................................................86 
10.3.1.6 
Abnormal Laboratory Values ......................................................86 
10.3.1.7 
Pre-existing Conditions ................................................................87 
10.3.1.8 
General Physical Examination Findings ......................................87 
10.3.1.9 
Hospitalization, Prolonged Hospitalization, or Surgery ..............87 
10.3.1.10 Deaths ..........................................................................................88 
10.4 Reporting Requirements ...........................................................................................88 
10.4.1 Expedited Reporting Requirements .............................................................88 
10.4.2 IRB Reporting Requirements ......................................................................89 
10.5 Follow-up of Subjects after Adverse Events .............................................................89 
10.6 Post-Study Adverse Events .......................................................................................89 
10.7 Urgent Safety Measures ............................................................................................89 
10.8 BioMarin Pharmacovigilance Contact Information ..................................................91 
11 APPROPRIATENESS OF MEASUREMENTS ...............................................................92 
12 STUDY PROCEDURES ...................................................................................................93 


 
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12.1 Treatment Visit(s) .....................................................................................................93 
12.1.1 Screening/Baseline Day -30 to Day -1 ........................................................93 
12.1.2 Day 1 and Week 13 (±7d) ...........................................................................94 
12.1.3 Days 2 and 3 ................................................................................................94 
12.1.4 Day 8 (±1d) and Week 20 (±7d) ..................................................................95 
12.1.5 Week 3 (±7d) ...............................................................................................95 
12.1.6 Week 6 (±7d) ...............................................................................................96 
12.1.7 Week 26 (±7d) .............................................................................................96 
12.1.8 Week 39 (±7d) .............................................................................................97 
12.1.9 Week 52 (±7d) .............................................................................................98 
12.1.10 Week 56 Safety Follow-up (±7d) ................................................................99 
12.1.11 Early Termination Visit ...............................................................................99 
12.2 Observational Period for Cohort 3 (Infants between birth and  < 3 months 
old [0 days to   < 13 weeks]) ...................................................................................100 
12.2.1 Screening Visit ..........................................................................................100 
12.2.2 Day 1 (Month 0) ........................................................................................100 
12.2.3 3 Months (± 10 days) .................................................................................101 
13 DATA QUALITY ASSURANCE ...................................................................................102 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ................103 
14.1 Statistical and Analytical Plans ...............................................................................103 
14.1.1 Interim Analyses ........................................................................................103 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data ........103 
14.2 Safety Analysis .......................................................................................................103 
14.3 Efficacy Analysis ....................................................................................................104 
14.4 Pharmacokinetic Analyses ......................................................................................105 
14.5 Immunogenicity Analysis .......................................................................................105 
14.6 Determination of Sample Size ................................................................................105 
14.7 Analysis Populations ...............................................................................................105 
14.7.1 Efficacy Population ...................................................................................105 
14.7.2 Safety Population ......................................................................................105 


 
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15 DATA MONITORING COMMITTEE ...........................................................................106 
16 COSTS, COMPENSATION, AND SUBJECT INJURY ................................................107 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS ............................................108 
18 STUDY MONITORING AND AUDITING ...................................................................110 
19 RETENTION OF RECORDS..........................................................................................111 
20 USE OF INFORMATION AND PUBLICATION ..........................................................112 
21 REFERENCES ................................................................................................................113 
22 INVESTIGATOR RESPONSIBILITIES ........................................................................115 
22.1 Conduct of Study and Protection of Human Subjects .............................................115 
23 SIGNATURE PAGE .......................................................................................................116 
 
LIST OF TABLES 
Table 9.1.1:  Schedule of Events .............................................................................................44 
Table 9.1.2:  Schedule of Events Observational Period for Cohort 3 ......................................49 
Table 9.11.6.3.1:  Clinical Laboratory Tests ...........................................................................73 
Table 9.11.6.4.1:  Biomarkers and Anti-BMN 111 Antibodies ...............................................74 
Table 9.11.6.5.1:  Vital Sign Assessment Frequency ..............................................................76 
Table 10.2.3.2.1:  Adverse Event Grading (Severity) Scale ....................................................83 
Table 10.2.3.3.1:  Causality Attribution Guidance ..................................................................84 
 
LIST OF FIGURES 
Figure 9.1.1:  Study Design .....................................................................................................43 
Figure 9.11.4.7.1:  Clinical Outcomes Assessment Tools .......................................................69 
 


 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
°C 
degree Celsius 
ACE 
angiotensin-converting enzyme 
Ach 
Fgfr3G380R achondroplasia mouse model 
ACH  
achondroplasia 
ADL 
Activity of Daily Living 
ADR 
adverse drug reaction 
AE 
adverse event 
AGV 
annualized growth velocity 
ALT 
alanine aminotransaminase 
ANP 
atrial natriuretic peptide 
AP 
anterior-posterior 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve  
BMC 
bone mineral content 
BMD  
bone mineral density 
BNP 
B-type Natriuretic Peptide 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
cGMP 
cyclic guanosine monophosphate 
Cmax 
maximum observed plasma concentration 
CBCL 
Child Behavior Checklist 
CNP  
C-type natriuretic peptide 
CNP53 
C-type natriuretic peptide (53 amino acids in length) 
CRA 
clinical research associate 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
cardiovascular 
DCF 
data clarification form 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
FGF 
fibroblast growth factor 
G380R 
substitution in the transmembrane domain of the FGFR3 receptor at position 380 
GCP 
Good Clinical Practice 


 
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HIPAA 
Health Insurance Portability and Accountability Act 
HR 
heart rate 
HRQOL 
health-related quality of life 
IB 
investigator brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICH E6 [R2] 
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
IEC 
Independent ethics committee 
IgE 
immunoglobulin E 
IND 
Investigational New Drug (application) 
IP 
investigational product 
IRB 
institutional review board 
ITQOL 
Infant Toddler Quality of Life questionnaire 
LV 
left ventricular 
MAPK 
mitogen-activated protein kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mL 
milliliter 
msec 
millisecond 
NAb 
neutralizing antibodies 
NEP 
neutral endopeptidase 
NP 
natriuretic peptide 
NPR-B 
natriuretic peptide receptor type B 
PA 
posterior-anterior 
PD 
pharmacodynamics 
PI 
Principal Investigator 
PK 
pharmacokinetics 
QT 
a measure of the time between the start of the Q wave and the end of the T wave  
QTc-F 
Fridericia’s corrected QT interval 
REB 
research ethics board 
rhCNP  
recombinant C-type natriuretic peptide 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SOI 
Statement of Investigator Form 
t1/2 
elimination half-life 
TAb 
total antibody 


 
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Tmax 
time to reach Cmax 
ULN 
upper limit of normal 
US 
United States 
WeeFIM 
Functional independence measure for children 
WFI 
water for injection 
µg/kg 
microgram/kilogram 
 
Definition of Terms:  
Investigational Product (IP): 
“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use” 
(from International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline: 
Guideline for Good Clinical Practice E6 [ICH E6] (R2)]).  
The terms “IP” and “study drug” may be used interchangeably in the protocol. 
 


 
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5 
ETHICS 
BioMarin Pharmaceutical Inc. (hereafter referred to as BioMarin or the Sponsor) conducts its 
studies according to the highest ethical and scientific standards. The following sections 
articulate standards to which Investigators will be held accountable, as well as matters of 
compliance to document adherence to such standards. 
5.1 
Institutional Review Board or Independent Ethics Committee 
Investigators are expected to interact with independent Ethics Committees (IECs) promptly, 
as required, during the course of the study. This includes, but is not limited to, providing 
appropriate documentation to support study initiation and maintaining appropriate flow of 
safety and other information during the course of the study and for study close-out activities. 
BioMarin (or designee) will assist Investigators with access to timely and accurate 
information and with assurance of prompt resolution of any queries. 
Prior to initiating the study, the Investigator will obtain written confirmation that the 
institutional review board (IRB) or independent ethics committee (IEC), or Research Ethics 
Board (REB) is properly constituted and compliant with International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) and Good Clinical Practice (GCP) requirements, applicable laws, and local 
regulations. A copy of the confirmation from the IRB/IEC/REB will be provided to BioMarin 
Pharmaceutical Inc. (BioMarin) or its designee.  
The Investigator will provide the IRB/IEC/REB with all appropriate material, including the 
protocol, Investigator’s Brochure (IB), the Informed Consent Form (ICF) including 
compensation procedures, and any other written information provided to the subjects, 
including all ICFs translated for subjects who do not speak the local language at the clinical 
site. The study will not be initiated and Investigational Product (IP) supplies will not be 
shipped to the site until appropriate documents from the IRB/IEC/REB confirming 
unconditional approval of the protocol, the ICF and all subject recruitment materials are 
obtained in writing by the Investigator and copies are received at BioMarin or its designee. 
The approval document should refer to the study by protocol title and BioMarin protocol 
number (if possible), identify the documents reviewed, and include the date of the review and 
approval. BioMarin will ensure that the appropriate reports on the progress of the study are 
made to the IRB/IEC/REB and BioMarin by the Investigator in accordance with applicable 
guidance documents and governmental regulations. 


 
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5.2 
Ethical Conduct of Study 
It is expected that Investigators understand and comply with the protocol. This includes, but 
is not limited to: establishing and meeting enrollment commitments, including providing 
eligible subjects for study enrollment; adhering to adverse event reporting, diagnostic, or 
other procedures as specified in the protocol; and assuring appropriate compliance with study 
treatment administration and accountability. 
This study will be conducted in accordance with the following: 
 European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC, for studies conducted within any European country 
 US Code of Federal Regulations (CFR) sections that address clinical research studies, 
and/or other national and local regulations, as applicable 
 ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
(ICH E6) or E6(R2) (ICH E6R2) if adopted 
 The ethical principles established by the Declaration of Helsinki 
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB/IEC/REB and will be conducted by scientifically and medically qualified persons. 
The benefits of the study are in proportion to the risks. The rights and welfare of the subjects 
will be respected and the investigators conducting the study do not find the hazards to 
outweigh the potential benefits. Each subject, or his/her legally authorized representative will 
provide written, informed consent before any study-related tests or evaluations are 
performed. 
5.3 
Subject Information and Informed Consent 
A properly written and executed informed consent form (ICF), in compliance with the 
Declaration of Helsinki, ICH E6 (Section 4.8), United States Code of Federal Regulations 
(CFR) 21 CFR §50, European Clinical Trial Directive 2001/20/EC and Good Clinical 
Practice Directive 2005/28/EC, and other applicable local regulations, will be obtained for 
each subject prior to entering the subject into the study. The Investigator will prepare the ICF 
and provide the documents to BioMarin for approval prior to submission to the IRB/EC/REB 
approval. BioMarin and the IRB/IEC/REB must approve the documents before they are 
implemented. A copy of the approved ICF (minor assent form and parental ICF for studies 
involving minors), and if applicable, a copy of the approved subject information sheet and all 
ICFs translated to a language other than the native language of the clinical site must also be 
received by BioMarin or designee prior to any study-specific procedures being performed. 


 
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Subjects under the age of 18 years will provide written assent (if required), and his/her 
legally authorized representative (parent or legal guardian) will provide written informed 
consent for such subjects. The Investigator will provide copies of the signed ICF to each 
subject (or the legally authorized representative of the subject) and will maintain the original 
in the record file of the subject. 
 


 
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6 
INVESTIGATORS AND STUDY ADMINSTIRATIVE STRUCTURE  
During administration of informed consent, expectations regarding participation in the study 
should be made clear to subjects. Subjects who are not willing and/or are not able to comply 
with all aspects of the study should not be encouraged to participate. 
Prior to beginning the study, the Investigator at each site must provide to BioMarin or 
designee a fully executed and signed Statement of Investigator (SOI) form.  A US Food and 
Drug Administration (FDA) Form FDA 1572 serves as an acceptable SOI form.  If Form 
FDA 1572 may not be used in a particular region, the Investigator must provide a fully 
executed SOI on the form provided by the Sponsor.  All Investigators and Sub-Investigators 
must be listed on Form FDA 1672 or its equivalent SOI.  Financial Disclosure Forms must 
also be completed for all Investigators and Sub-Investigators listed on the Form FDA 1572 or 
SOI who will be directly involved in the treatment or evaluation of subjects in this study. 
The study will be administered by and monitored by employees or representatives of 
BioMarin. Clinical research associates (CRAs) or trained designees will monitor each site on 
a periodic basis and perform verification of source documentation for each subject as well as 
other required review processes. BioMarin’s Pharmacovigilance Department (or designee) 
will be responsible for the timely reporting of serious adverse events (SAEs) to appropriate 
regulatory authorities as required. 
In multicenter studies, a Coordinating Investigator will be identified who will be responsible 
for study overview. The Coordinating Investigator will read the clinical study report (CSR) 
and confirm that it accurately describes the conduct and results of the study, to the best of his 
or her knowledge. The Coordinating Investigator will be chosen on the basis of active 
participation in the study, ability to interpret data, and willingness to review and sign the 
report in a specified timeframe. The identity of the Coordinating Investigator and a list of all 
Investigators participating in the study will be provided in the CSR. 


 
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7 
INTRODUCTION 
BMN 111 is a proposed pharmacologic therapeutic option for ACH, the most common form 
of dwarfism. 
ACH is a rare disease with a prevalence of 1/25000 in the US (Wynn, 2007) The average 
adult heights for men and women with ACH are 131 cm and 124 cm, respectively (NIH, 
Genetics Home Reference, 2012).  Characteristic features include long and narrow trunk, a 
large head with frontal bossing, hypoplasia of the mid-face, bowed legs and stenosis of the 
foramen and spinal canals that can be life-threatening. Foramen magnum stenosis can lead to 
cervicomedullary compression in infants with complications including hydrocephalus, 
hypotonia, respiratory insufficiency, apnea, cyanotic episodes, feeding problems, 
quadriparesis, and sudden death.  
There is no approved pharmacological therapy for achondroplasia in the US or EU. Current 
treatments for achondroplasia are focused on neurosurgical interventions for foramen 
magnum stenosis or lumbar stenosis, thoracolumbar braces to help ameliorate the kyphosis, 
or limb lengthening requiring multiple operations over 2 to 3 years (Shirley, 2009), 
(Horton, 2007).  
ACH is caused by a gain-of-function mutation in FGFR3, a negative regulator of 
chondrocyte proliferation and differentiation.  The most common mutation (98%) in ACH 
patients is a G380R substitution in the transmembrane domain of FGFR3.  The majority of 
new cases (80%) originate from parents with normal stature.   
The extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) 
pathway mediates part of FGFR3 inhibition of chondrocyte proliferation and differentiation 
(Foldynova-Trantirkova, 2012).  The ERK MAPK pathway is modulated by CNP, a positive 
regulator of chondrocyte proliferation and differentiation.  Binding of CNP to the Natriuretic 
Peptide-Receptor B (NPR-B) antagonizes FGFR3 downstream signaling by inhibiting the 
MAPK (ERK1/2) pathway at the level of RAF-1 (Krejci, 2005.); (Yasoda, 2004.); 
(Yasoda, 2009); (Pejchalova, 2007).  This crosstalk was demonstrated in a mouse model of 
FGFR3-related chondrodysplasia (Yasoda, 2004); (Yasoda, 2009).  The dwarfism phenotype 
of mice harboring the FGFR3G380R mutation was rescued by expression of CNP in cartilage 
or by the continuous administration of CNP (infusion). 
CNP is a member of the natriuretic peptide (NP) family that includes Atrial Natriuretic 
Peptide (ANP) and B-type Natriuretic Peptide (BNP). These peptides are structurally related 
but are distinct paracrine/autocrine (CNP) or endocrine (ANP and BNP) factors that regulate 


 
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the cardiovascular (CV), skeletal, nervous, reproductive and other systems. Synthetic analogs 
of ANP (anaritide and carperitide) and BNP (nesiritide) have been investigated as potential 
therapies for the treatment of decompensated heart failure and cardiovascular-related 
diseases. 
BMN 111 is a 39-amino acid CNP analogue harboring the 37 amino acids of the human 
CNP53 C-terminal sequence and modified by the addition of two amino acids (Pro-Gly) on 
the N-terminus.  It is a recombinant human peptide fused to human transcription factor 
(TAF) and expressed as an inclusion body in E. coli.  BMN 111 is liberated and solubilized 
from the TAF-fusion protein by formic acid cleavage, and purified by column 
chromatography (Long, 2012).  BMN 111 was designed to 1) mimic CNP activities in terms 
of receptor binding and pharmacological activity and 2) be resistant to neutral endopeptidase 
(NEP) digestion in order to have an extended half-life in comparison to CNP that is 
presumed to increase exposure to the target growth plate (Wendt, 2015).  
A comprehensive review of BMN 111 is contained in the current version of the Investigator’s 
Brochure supplied by BioMarin.  Investigators are required to review the Investigator’s 
Brochure prior to initiating this study. 
7.1 
Nonclinical Studies 
The pharmacological activity of BMN 111 was explored in two mouse models of ACH, a 
severe, Fgfr3Y367C/+ model (Lorget, 2012), and a mild [Ach] /+ model.  Partial or complete 
reversion of the ACH phenotype was observed in these mouse models after BMN 111 
administration.  Additionally, in wild-type mice, and normal rats and monkeys, BMN 111 
administration resulted in growth plate expansion and dose-dependent skeletal growth at 
hemodynamically tolerated dose levels (Wendt, 2015).  
BMN 111-related adverse findings in nonclinical species (mice, rats, cynomolgus monkeys) 
were limited to the known mechanism of action of CNP on the growth plate and vasculature.  
Reversible subcutaneous injection site reactions were reported, including injection site 
discoloration and microscopic findings of perivascular mononuclear cell infiltrates that were 
seen with slightly higher incidence and severity in BMN 111-treated rats and monkeys 
compared to the vehicle control.  Adverse skeletal changes associated with exaggerated 
growth were seen in normal nonclinical species with open growth plates, and were dose-, 
exposure- and time-dependent. Decreases in blood pressure and compensatory increases in 
heart rate were detected in monkeys across multiple studies, with overt CV-related clinical 
signs observed in some animals at doses ≥ 236 µg/kg. These overt clinical signs consisted of 
transient, short and repeated bouts of sternal or lateral recumbency and/or reduced motor 


 
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activity, typically within 1-hour post-dose administration.  Additional detailed information 
about nonclinical studies of BMN 111 is provided in the current version of the Investigator’s 
Brochure supplied by BioMarin.   
7.2 
Previous Clinical Studies 
7.2.1 Study 111-101 
Study 111-101, “A Phase 1, Two Part, Double Blind, Placebo-Controlled Study to Evaluate 
the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Doses of BMN 111 
Administered to Healthy Adult Volunteers,” was a first-in-human study conducted in 2 parts 
to allow for assessment of the safety, tolerability, and PK of BMN 111 administered as a 
single dose and as a multiple dose to healthy adult male volunteers. 
Doses ranging from 5.0 µg/kg to 15.0 µg/kg were administered as a single daily SC dose; 
doses ranging from 0.5 µg/kg to 8.0 µg/kg were administered in the multiple ascending dose 
segment of the study. As expected, mild, transient, self-limited hypotension occurred. 
The majority of these cases were asymptomatic and observed upon assumption of an upright 
posture following recumbence. Hypotension events were reported in the BMN 111 treatment 
groups with higher frequency compared with placebo. All events were judged to be mild in 
severity and resolved spontaneously without an intervention. These events occurred across 
dose ranges.  Due to the limited number of events at each dose, it is unclear if symptomatic 
hypotension is dose related.  No dose limiting toxicities were identified outside of these 
cardiovascular events. The only AEs occurring in more than one subject receiving BMN 111 
were orthostatic hypotension, contact dermatitis, and back pain, and injection site reactions. 
Most AEs in the study were of mild severity, and no SAEs were reported. There were no AEs 
that led to premature discontinuation of study drug.   
The PK parameters for BMN 111 were obtained from Part 1 of the study and from the first 
dose on Day 1 of the multiple dose study in Part 2. The results demonstrate that BMN 111 
was rapidly absorbed in human, reaching a mean time to peak concentration (Tmax) between 
15-26 minutes. After reaching maximal plasma concentrations, BMN 111 levels rapidly 
declined, with a t1/2 of 40-55 minutes. Mean plasma concentration-time profiles indicate that 
exposure increased with dose from 2.5 to 15 µg/kg. The corresponding increases in plasma 
Cmax and area under the curve (AUC) exposure parameters were greater than dose 
proportional. The increase in Cmax with dose was linear over the dose range evaluated.  
In Part 2, with multiple dosing at 5 µg/kg for 10 days, the plasma concentration-time curves 
obtained on each of the three sampling days were nearly superimposable. Comparison of PK 
exposure parameters for AUC and Cmax indicate that Cmax is unchanged and AUC is 


 
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increased slightly by +33% over Day 1.  Overall the results indicate that changes in 
BMN 111 exposure are minimal with repeat dosing out to 10 days. 
7.3 
Ongoing Clinical Studies 
7.3.1 Study 111-901 
Study 111-901 is a multicenter, multinational study to collect serial growth measurements on 
pediatric subjects with ACH who are being considered for subsequent enrollment in future 
studies sponsored by BioMarin. To obtain accurate baseline measurements, at least 6 months 
of growth data are collected.  
Data gathered from this study are used to characterize baseline growth data in children or 
infants (defined as children < 2 years of age) who may subsequently be enrolled in future 
studies sponsored by BioMarin, and may also be used to establish historical control cohort 
for use in other BioMarin-sponsored studies, when appropriate. For that reason, data related 
to ACH symptoms, tests, and interventions are collected. 
7.3.2 Study 111-202 
Study 111-202 is an ongoing Phase 2, open-label, sequential cohort, dose escalation study 
that assesses daily SC administration of BMN 111 in pediatric subjects with ACH. 
The primary objective of Study 111-202 is to evaluate the safety and tolerability of BMN 111 
administered for 6 months and up to 24 months; the secondary objectives are to determine 
change from baseline in annualized growth velocity (AGV), growth parameters, body 
proportions, and evaluate the dose-exposure and PK profiles of BMN 111 in children with 
ACH.  
Analysis of safety data from the 6-month initial phase of Study 111-202 showed that 
treatment with BMN 111 for 6 months at dose cohorts of 2.5, 7.5, 15, and 30 µg/kg 
(Cohorts 1 to 4, respectively) was generally well tolerated. The most common AEs were mild 
injection site reactions, asymptomatic hypotension, headache, and nasopharyngitis. For a 
detailed summary of risks, please refer to the current version of the Investigator’s Brochure 
supplied by BioMarin.  
Analysis of efficacy data from the 6-month initial phase of Study 111-202 demonstrated that 
the mean (standard deviation) change from baseline AGV when BMN 111 is administered at 
2.5, 7.5, 15, and 30 µg/kg subcutaneously daily for 6 months is -0.37 (1.592), 1.28 (1.439), 
2.01 (1.999), and 2.08 (2.137) cm/year, respectively.  Thus, a positive dose-dependent 
response was observed in change from baseline AGV at doses ranging from 2.5-15 µg/kg 
daily.   


 
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For longer term follow up data from the 202 study, please refer to the current Investigator 
Brochure supplied by BioMarin. 
7.3.3 Study 111-205 
Study 111-205 is an ongoing open-label, Phase 2 extension study to assess long-term safety, 
tolerability, and efficacy of BMN 111 in children with ACH. Subjects continue receiving the 
same stable dose of BMN 111 received upon completion of the 111-202 study (up to 
30 µg/kg daily). This 5-year study allows for long-term assessment of the effect of daily 
BMN 111 administration on safety, tolerability, growth velocity, height, and body 
proportions in subject completing 2 years of BMN 111 treatment in Study 111-202 (7 years 
total BMN 111 treatment duration). Additional exploratory endpoints are being examined to 
determine long-term effects of BMN 111 on bone physiology and the medical complications 
of ACH. 
7.3.4 Study 111-301 
Study 111-301 is an ongoing Phase 3, double-blind, placebo-controlled multicenter study to 
further characterize and confirm efficacy and safety of BMN 111 at 15 µg/kg in a 58-week 
study (up to 4 weeks of screening, 52 weeks of treatment, plus an additional 2 weeks of 
safety follow up). The study assesses the effect of daily BMN 111 administration on change 
from baseline in AGV, height, and body proportions in subjects treated with BMN 111 
compared with control subjects in the placebo group; and further characterizes safety and 
tolerability of BMN 111 in children with ACH. Additional exploratory endpoints are being 
examined to determine the effect of BMN 111 on bone physiology and to assess quality of 
life and daily function of study subjects. 
7.4 
Study Rationale 
BMN 111 is a recombinant CNP analogue that has been engineered to resist degradation by 
NEP, allowing for a longer half-life. 
The pharmacological activity of BMN 111 was explored in two mouse models of ACH, a 
severe, Fgfr3Y367C/+ (TD) model (Lorget, 2012), and a milder [Ach] /+ (Ach) model. These 
included studies in 7-day old TD mice given BMN 111 daily by SC administration for up to 
20 days and a study in 3 week old Ach mice given BMN 111 daily by SC administration for 
5 weeks. Partial or complete reversion of the ACH phenotype was observed in these mouse 
models after BMN 111 administration. In wild-type mice, and normal rats and monkeys, 
BMN 111 administration resulted in growth plate expansion and dose-dependent skeletal 
growth at hemodynamically tolerated dose levels (Wendt, 2015). Additionally, the potential 


 
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effect of age on BMN 111 PK was evaluated in normal rats aged between 7 days and 
12-13 weeks. 
Infants and young children with ACH have a high incidence of medical complications and 
currently there is no approved pharmacological therapy for ACH in the US or EU. The most 
severe complication, cervicomedullary compression (CMC), occurs in a subset of subjects 
with ACH due to abnormal endochondral bone growth and narrowing of the foramen 
magnum (White, 2016). CMC has been linked to serious respiratory and neurological 
complications including hypotonia, apnea, ataxia, developmental delay, and respiratory arrest 
associated with sudden death (Mukherjee, 2014). Foramen magnum decompression surgery 
is currently the only treatment for this condition.   
Sleep apnea has also been extensively described in ACH, and sleep-disordered breathing may 
affect up to 85% of all children with ACH (Ireland, 2012). This is thought to be due to 
midface hypoplasia, relative adenotonsillar hypertrophy, and potential posterior cranial fossa 
compression secondary to abnormal endochondral bone growth. Sleep apnea in ACH not 
only results in the need for surgical intervention, but has also been linked to sudden death in 
rare cases (Pauli, 1984).   
Similarly, the dysregulation of endochondral bone growth in ACH leads to other medical 
complications which are prevalent in this subject population, such as the following: 
 Spinal stenosis, kyphosis, and lordosis (secondary to altered growth plate ossification 
in the vertebrae and narrowing of the interpedicular distances) (Shirley, 2009) 
 Developmental delay of gross motor and ambulatory skills (associated with proximal 
limb shortening, macrocephaly, and hypotonia) (Ireland, 2010) 
 Delayed functional skills and increased need for caregiver assistance (eg, eating, 
bladder management, bowel management, transfer to chair, climbing stairs) 
(Ireland, 2011) 
Thus, BMN 111 may provide greater benefit when children begin treatment at a younger age, 
as earlier initiation of treatment allows a longer time window to improve growth and 
potential to improve medical complications of achondroplasia. This study (111-206) is being 
conducted to assess safety and the potential benefit of BMN 111 in infants and young 
children.   
BioMarin has engineered a CNP analog (BMN 111) that has a longer half-life than 
endogenous CNP, thereby allowing daily SC administration. Similar to CNP, BMN 111 
activates NPR-B signaling with subsequent inhibition of FGFR3 downstream signaling, 
leading to the promotion of chondrocyte proliferation and differentiation and subsequent 


 
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increased endochondral bone formation. BMN 111 administration has been shown to 
promote endochondral bone formation at hemodynamically tolerated dose levels in both 
normal animals and mouse models of ACH reported (refer to current Investigator’s Brochure 
for additional information). 
Human studies to date have also demonstrated that BMN 111 is generally well tolerated at 
doses that result in improvements in growth velocity approaching that of children of average 
stature. 
Study 111-202 is an ongoing Phase 2, open-label, sequential cohort, dose escalation study 
that assesses daily SC administration of BMN 111 in pediatric subjects with ACH, in which 
the primary objective is to evaluate the safety and tolerability of BMN 111 administered for 
6 months and up to 24 months and includes secondary objectives consisting of determination 
of change from baseline in AGV, growth parameters, body proportions, and evaluation of the 
dose-exposure and PK profiles of BMN 111 in children with ACH.  
Analysis of safety data from the 6-month initial phase of Study 111-202 showed that 
treatment with BMN 111 was generally well tolerated at all dose levels (refer to current 
Investigators Brochure for specific details).  
Analysis of efficacy data from Study 111-202 demonstrated that that subjects given 
BMN 111 at the dose of 15 µg/kg daily had an improvement in AGV, with approximately 
~50% increase over baseline seen with treatment for 6 months which was sustained after 
continued treatment for 12 months.  
Subjects treated with 30 µg/kg daily also showed similar improvement in mean AGV after 
6 months and their mean changes from baseline in AGV were similar to subjects treated with 
15 µg/kg daily. Safety data for the 30-µg/kg daily dose was also similar to the 15-µg/kg daily 
dose.  Given that no clinically significant difference could be identified between the 
15-µg/kg and 30-µg/kg daily dose in the Phase 2, 6-month safety and efficacy data, the lower 
of the two doses has been chosen for this Phase 2 study.  
Study 111-206 is a Phase 2 randomized, double-blind, placebo-controlled clinical trial of 
BMN 111 in infants and younger children with a diagnosis of ACH who are age 0 to 
< 60 months. This 52-week study will enable assessment of BMN 111 safety, tolerability, 
pharmacodynamics biomarkers, and PK in this population, and also allow for examination of 
potential impact on efficacy endpoints. Additional exploratory endpoints pertaining to 
medical complications of ACH will also be evaluated.  


 
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7.5 
Summary of Overall Risks and Benefits 
7.5.1 Summary of Risks from Nonclinical Studies 
Individuals in this study will be exposed to a recombinant analogue of human C-type 
natriuretic peptide (CNP). Based on the results of experimentation in animals, the most 
relevant potential toxicities relate to the expected pharmacological effects of exogenous CNP 
administration, including hemodynamic changes, skeletal overgrowth, and injection site 
reactions. Transient and sporadic decreases in blood pressure and compensating increases in 
heart rate occurred within the first hour post-dose in cynomolgus monkeys; the effects were 
mainly asymptomatic with a subset of animals given doses ≥ 236 µg/kg observed with 
symptomatic effects consisting of transient, short and repeated bouts of sternal or lateral 
recumbency and/or reduced motor activity. These hemodynamic effects can be monitored, 
but have the potential to be an acute dose-limiting factor in patients.  Exaggerated 
appendicular bone responses to the drug included abnormally shaped femoral head, 
acetabular growth center/plate dysplasia and concomitant articular cartilage degeneration 
with clinical manifestations of restricted use of hips. Adverse skeletal changes associated 
with exaggerated growth were dose-, exposure- and time-dependent. Additional detailed 
information about risks identified in nonclinical studies of BMN 111 is provided in the 
current version of the Investigator’s Brochure supplied by BioMarin.   
7.5.2 Summary of Risks from Clinical Studies 
7.5.2.1 
Study 111-101 
Based on review of the first-in-human Phase 1 study of BMN 111 in healthy adult volunteers, 
Study 111-101, BMN 111 administered SC daily was well tolerated with doses ranging from 
0.5 µg/kg to 15 µg/kg. All AEs were of mild severity, and no SAEs were reported. The most 
common AE was mild, transient, self-limited orthostatic hypotension, of which the majority 
of cases were asymptomatic and observed only upon assumption of an upright posture 
following recumbence. No dose-limiting toxicities were identified outside of these CV 
events. 
7.5.2.2 
Ongoing Studies 
Based on analysis of safety data from ongoing phase 2 and 3 studies, treatment with 
BMN 111 was generally well tolerated. Injection site reactions were the most common 
adverse events reported and are considered to be an identified risk. All injection site reactions 
events have been reported as non-serious, Grade 1 in severity, and transient. Hypotension and 
hypersensitivity reactions including development of BMN 111 antibodies are potential risks 


 
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associated with BMN 111 injections. For a detailed summary of risks, please refer to the 
current version of the Investigator’s Brochure supplied by BioMarin. 
7.5.3 Summary of Potential Benefits from Clinical Studies 
For children with ACH who will receive BMN 111 as part of Study 111-206, potential 
benefits may include improvement of AGV rates such that their increase in growth velocity 
may approach that of children of average stature.  Additional potential benefits may include 
improvement of the disproportionate growth as well as improvement in quality of life, 
activities of daily living, and medical complications of ACH.  For example, improvement in 
height could have an impact on daily activity performance. 
 


 
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8 
STUDY OBJECTIVES 
The primary objectives of the study are to: 
 Evaluate the safety and tolerability of BMN 111 in children age 0 to < 60 months 
with ACH  
 Evaluate the effect of BMN 111 on change from baseline in length/height Z-score  
The secondary objectives of the study are to: 
 Evaluate the effect of BMN 111 on AGV throughout the 52 weeks of the study 
 Evaluate the effect of BMN 111 on bone morphology/quality by x-ray and dual x-ray 
absorptiometry (DXA) 
 Evaluate the PK of BMN 111 in children age 0 to < 60 months with ACH  
 Evaluate hip function 
 Evaluate for hip, thigh, or knee pain, or change in gait from medical history 
 Evaluate the effect of BMN 111 on developmental/functional/QOL status (Bayley-III, 
WeeFIM, Child Behavior Checklist [CBCL], ITQOL  
 Evaluate immunogenicity of BMN 111 and assess impact on safety, PK, and efficacy 
measures  
 Evaluate the effect of BMN 111 on bone metabolism and BMN 111 
pharmacodynamic biomarkers 
The exploratory objectives of the study are to: 
 Evaluate the effect of BMN 111 on growth parameters and body proportions, 
including change from baseline in upper:lower body segment ratio 
 Evaluate the effect of BMN 111 on sleep apnea 
 Document physical and phenotypic changes with clinical photography (optional)  
 Evaluate the effect of BMN 111 on skull and brain morphology, including foramen 
magnum, ventricular and brain parenchymal dimensions 
 Describe the incidence of surgical interventions, including cervical decompression, 
adenotonsillectomy, and tympanostomy 


 
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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a Phase 2 randomized, double-blind, placebo-controlled clinical trial of BMN 111 in 
infants and younger children with a diagnosis of ACH.  
Subjects age ≥ 3 months to < 60 months old who have documented ACH confirmed by 
genetic testing, at least a 6-month period of pretreatment growth assessment in Study 
111-901 immediately before study entry and who meet the study eligibility criteria will 
participate. Eligible subjects ranging from 0 months to < 3 months old may enroll directly 
into 111-206 and have a minimum of 3 months of pre-treatment observation prior to 
commencing treatment. 
Approximately 70 subjects will be enrolled at approximately 10-15 clinical centers 
worldwide.   
The primary objectives of this study are to assess the safety and tolerability of daily SC 
BMN 111 administered to infants and young children with ACH, and evaluate the effect of 
BMN 111 on Z-scores. Subjects will be enrolled into 3 age cohorts based on age at study 
screening starting with the eldest population. Within Cohorts 1 and 2, subjects will be 
stratified by age: 
 Cohort 1 – children aged ≥ 24 to < 60 months (n ≥ 30 total: 3 sentinel subjects who 
receive BMN 111, and at least 27 additional subjects randomized 1:1 to treatment or 
placebo control), stratified by age (≥ 24 to < 36 months and ≥ 36 months to 
< 60 months)  
 Cohort 2 – children aged  ≥  6 to   < 24 months (n ≥ 20 total: 3 sentinel subjects who 
receive BMN 111, and at least 17 additional subjects randomized 1:1 to treatment or 
placebo control), stratified by age (≥ 6 months to < 15 months and ≥ 15 months to 
< 24 months)  
 Cohort 3 – children aged 0 to < 6 months (n ≥ 20 total: 3 sentinel subjects who 
receive BMN 111, and at least 20 additional subjects randomized 1:1 to treatment or 
placebo control).  Treatment begins at ≥ 3 months to < 6 months after 3 months of 
observation. 
If subjects who enroll in Cohort 3 are not able to begin treatment by < 6 months of age, they 
will continue in the pretreatment period for another 3 months before enrolling in Cohort 2 to 
fulfill the pretreatment requirement for Cohort 2.  
 


 
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Sentinel subjects from each cohort will be enrolled and studied for short-term safety and PK 
data, after which subjects in all 3 cohorts will be randomized to receive BMN 111 or placebo 
SC daily (1:1 ratio) for up to 52 weeks. At the start of the study, 3 sentinel subjects will be 
enrolled and monitored in Cohort 1. After all 3 sentinel subjects reach Day 8, the Sponsor 
will review and evaluate all available safety data and Day 1 PK data. Based on PK data and 
criteria set in the protocol, the dose may be adjusted for the sentinel subjects and the rest of 
the cohort, and will be the starting dose for the younger cohort sentinel subjects.  Upon 
review of the clinical and PK data, the remainder of Cohort 1 (≥ 27 additional subjects) will 
be enrolled and randomized to treatment with BMN 111 or placebo (1:1 ratio).  After the 
sentinel subjects complete 12 weeks of dosing, a DMC review will occur to evaluate all 
available safety and PK data.  Upon approval by the DMC, the next younger cohort 
(Cohort 2) will be opened and the 3 sentinel subjects will be enrolled. 
The same procedure will be followed for Cohort 2. After all 3 sentinel subjects reach Day 8, 
the Sponsor will review and evaluate all available safety data and Day 1 PK data. Based on 
PK data and criteria set in the protocol, the dose may be adjusted for the sentinel subjects and 
the rest of the cohort, and will be the starting dose for the younger cohort sentinel subjects.  
Upon review of the clinical and PK data, the remainder of Cohort 2 (≥ 17 additional subjects) 
will be enrolled and randomized to treatment with BMN 111 or placebo (1:1 ratio). After the 
sentinel subjects complete 12 weeks of dosing, a DMC review will occur to evaluate all 
available safety and PK data.  Upon approval by the DMC, the youngest cohort (Cohort 3) 
will be opened and the 3 sentinel subjects will be enrolled.  
The same procedure will be followed for Cohort 3. After all 3 sentinel subjects reach Day 8, 
the Sponsor will review and evaluate all available safety data and Day 1 PK data. Based on 
PK data and criteria set in the protocol, the dose may be adjusted for the sentinel subjects and 
the rest of the cohort, and will be the starting dose for the younger cohort sentinel subjects.  
Upon review of the clinical and PK data, the remainder of Cohort 3 (≥ 17 additional subjects) 
will be enrolled and randomized to treatment with BMN 111 or placebo (1:1 ratio).  
Cohort 3 subjects must have a minimum of 3 months of observation prior to commencement 
of treatment.  These subjects will have the option to enroll in either 111-901 or 111-206, 
depending on age at enrollment: 
 Infants ≥ 3 months and  < 6 months old (≥ 13 weeks and < 26 weeks) will enroll in 
111 901 for a 6-month period of pretreatment growth assessment prior to enrollment 
in 111 206 for treatment in Cohort 2. 
 Infants between birth and < 3 months old (0 weeks and < 13 weeks) will enroll into 
111 206 with a 3-month observational period prior to treatment. 


 
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Additional sentinels may be added to any cohort if needed for additional safety and/or PK 
assessment. 
Each treated subject will have expanded outpatient safety monitoring for a minimum of 
3 days of dosing, during which they will be closely observed and non-invasive hemodynamic 
monitoring will be conducted for at least 4-8 hours post-dosing. Because younger children 
may not be able to verbalize complaints of dizziness or lightheadedness that are potentially 
associated with hypotension, study personnel and caregivers will be trained to recognize the 
signs of hypotension in this population, which may include tachycardia, pallor, diaphoresis, 
lethargy, delayed capillary refill, and poor feeding. Appropriate rigorous training will be 
required for parents and caregivers prior to daily injections at home. Training includes the 
storage, reconstitution, and administration of BMN 111, as well as documentation/reporting 
of AEs and vigilance for signs of hypotension. 
It is generally expected that after subjects are tolerating the drug well and specified criteria 
have been met, caregivers will begin administering study drug. Home health care is not 
required at any point but may be provided if the caregiver is unable or unavailable to 
administer the study drug. A Home Healthcare nurse will train the caregiver(s) if training has 
not been completed by the Day 3 visit. A phone call by the study staff member to the 
caregiver will be required weekly for 6 months and then every 2 weeks for the remainder of 
the study. During these contacts, study staff will ask the caregiver about dose administration 
and seek information on AEs and SAEs by specific questioning. If the caregiver cannot be 
contacted by phone after two attempts, contact can be made via email.   
Duration of the study is 52 weeks of treatment with a safety follow up at Week 56. Following 
completion of the study, subjects in all treatments groups may be eligible to receive 
BMN 111 in an open-label extension study, to assess safety and efficacy of BMN 111 over 
the longer term.  For subjects enrolling into the extension study, safety follow up visit at 
Week 56 will be waived. 
A summary of events and assessments are provided by visit in Table 9.1.1 and Table 9.1.2. 
For a discussion of efficacy assessments, see Section 9.11.2 and Section 9.11.3; exploratory 
efficacy assessments, Section 9.11.4; safety assessments, Section 9.11.6; and PK variables, 
Section 9.11.5. The 111-206 study design is presented in Figure 9.1.1.   
 


 
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Figure 9.1.1:  Study Design 
 
 
 


 
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Table 9.1.1:  Schedule of Events 
Procedurea 
Screening/
Baseline 
Day -30 to 
Day -1b 
Day
1u 
Day
2 
Day
3 
Day 
8 
(±1d) 
Week
3 
(±7d) 
Week
6 
(±7d) 
Week 
13 
(±7d) 
Week
20 
(±7d) 
Week
26 
(±7d) 
Week
39 
(±7d) 
Week
52 
(±7d) 
Week 56 
Safety 
Follow-Up 
(±7d)y 
Early
Term 
Visit 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parental heightd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnostic genetic testing 
to confirm achondroplasia 
(if needed)e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogramh 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anthropometric 
measurementsi 
X 
X 
 
 
 
 
X 
X 
 
X 
X 
X 
 
X 
Clinical laboratory 
assessments (hematology, 
chemistry, urinalysis)j 
X 
 
 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
Thyroid function tests 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Vitamin D, 25-hydroxy test 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Salivary cortisol 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Serum prolactin 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Pharmacokinetics 
assessmentsk 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
Anti-BMN 111 
immunogenicityl 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
Genomic biomarkers 
(optional) 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 


 
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Procedurea 
Screening/
Baseline 
Day -30 to 
Day -1b 
Day
1u 
Day
2 
Day
3 
Day 
8 
(±1d) 
Week
3 
(±7d) 
Week
6 
(±7d) 
Week 
13 
(±7d) 
Week
20 
(±7d) 
Week
26 
(±7d) 
Week
39 
(±7d) 
Week
52 
(±7d) 
Week 56 
Safety 
Follow-Up 
(±7d)y 
Early
Term 
Visit 
Bone metabolism blood 
biomarkersm 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Bone metabolism urine 
biomarkersn 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
BMN 111 
pharmacodynamic urine 
biomarkersn 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Urine chemistryn 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Screening baseline hip 
assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hip monitoringo 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
MRI brain/skullp 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Sleep studyq 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Clinical outcome 
assessment: Bayley-III 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Clinical outcome 
assessment: WeeFIMr 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Clinical outcome 
assessment: ITQOL 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Clinical outcome 
assessment: CBCLr 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
DXA (BMD and BMC of 
whole body [less head], 
including spine, one third 
forearm and tibia, ultra 
distal radius 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
AP and lateral X-rays of 
spines 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 


 
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Procedurea 
Screening/
Baseline 
Day -30 to 
Day -1b 
Day
1u 
Day
2 
Day
3 
Day 
8 
(±1d) 
Week
3 
(±7d) 
Week
6 
(±7d) 
Week 
13 
(±7d) 
Week
20 
(±7d) 
Week
26 
(±7d) 
Week
39 
(±7d) 
Week
52 
(±7d) 
Week 56 
Safety 
Follow-Up 
(±7d)y 
Early
Term 
Visit 
AP X-rays of lower 
extremitiess  
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Clinical photographs 
(optional)t   
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Capture achondroplasia-
related procedures 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BMN 111 or placebo 
administrationu 
 
All visits 
 
 
BMN 111 or placebo 
accountability  
 
All visits 
 
X 
Adverse eventsv 
 
All visits 
X 
X 
Concomitant medicationsw 
X 
All visits 
X 
X 
Phone call or home health 
visitx 
 
Weekly calls for 6 months and then every 2 weeks for the remainder of the study 
 
 
a Clinic visits (except Days 1, 2, 3, and 8) have a ± 7-day window.   Anthropometric measurement and imaging assessments can be conducted either pre-dose or 
post-dose.  
b All blood tests at Screening visit should be obtained between Day -30 and Day -14. 
c Medical history, including growth history and ACH-related history, should elicit all major illnesses, diagnoses, and surgeries that the subject has ever had; any 
prior or existing medical conditions that might interfere with study participation or safety. 
d Standing height of the participant’s biological parents will be assessed.  Prior to the measurement being taken, each parent is required to complete an ICF 
specific to parent height assessment.  The ICF will be signed prior to the assessment, which can be done at any point in the study.  If biological parent is not 
available during the course of the study to take their standing height, the parent can provide their stated height instead if consent has been given. 
e If subjects had previous genetic testing, subjects must have a lab certification documenting the specific mutation required for the 111-206 study, including the 
identification of FGFR3 mutation (G346E, G375C, G380R, or “other”).  
f Complete physical exam includes major body systems, including assessment of general appearance; CV; dermatologic; head, eyes, ears, nose, and throat; 
lymphatic; respiratory; gastrointestinal (GI); musculoskeletal; and neurological/psychological and genitourinary. 
g All treatment visits have pre-dose vital sign assessments.  Vital signs at pre-dose include: body temperature in degrees Celsius (°C), heart rate, BP, and 
respiratory rate.  Post-dose measurements include heart rate, BP, and respiratory rate. 


 
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Vital Sign Assessment Frequency  
Screening 
After at least 5 min of rest, subject’s vital signs are taken, preferably in sitting position.  Vital sign measurements should be 
repeated and documented 3 times with at least 5 min intervals between assessments.   
 
Assessment Frequency 
Dosing Visits 
0-1 hr post-dose 
0-2 hr post-dose 
2-4 hr post dose 
4-8 hr post-dose 
Days 1, 2 
 
q 15 min (± 5 min) 
q 30 min (± 5 min) 
q 60 min (± 10 min) 
Days 3, 8 
 
q 15 min (± 5 min) 
q 30 min (± 5 min) 
 
Subsequent dosing visits 
q 15 min (± 5 min); 
final assessment prior to end of 
visit (if longer than 1 hr) 
 
 
 
1. 
Vital sign measurements are taken once per time point, preferably in a sitting position, after at least 5 minutes of rest.   
2. 
Heart rate, blood pressure, and respiratory rate should be taken and recorded at each indicated time point.   
3. 
When blood samples and vital sign assessments are scheduled at the same time or within the same time window, vital signs should be measured before blood samples are 
drawn.   
4. 
If a vital sign measurement must be taken after a blood draw, ensure adequate analgesia for the blood draw and wait several minutes before measuring vital signs.   
5. 
Vital signs may be monitored more frequently or for longer duration post-dose as clinically indicated. 
6. 
If a subject has a hypotensive event, or signs potentially consistent with hypotension, or a decrease of 20 mm Hg systolic BP or more from baseline (defined by pre-dose 
vitals collected that day), vital signs should be measured and recorded approximately every 15 minutes (± 5 minutes) for the first hour and every 30 minutes (± 5 minutes) 
thereafter until the BP returns to baseline (or within the normal range for this subject as defined by PI) and signs (if present) resolve.  
7. 
If the decision is made to adjust the dose, vital signs will be obtained for at least 4 hr following the first dose at the adjusted dose level, similar to the Day 3, 8 schedule. 
h A standard 12-lead ECG will include heart rate, rhythm, intervals, axis, conduction defects, and anatomic abnormalities. The time of collection will be 
recorded. ECGs should be performed in triplicate with the subject supine at the visits indicated in the Schedule of Events.  For study day visits in which study 
drug is given, ECGs will be performed post-dose. For Day 1, in addition to post-dose, ECGs will be performed pre-dose.  
i Growth measures may be collected in triplicate approximately the same time each day (± 2 hr around the time when the first measurement assessment was 
taken at Screening). Measurements may include but are not limited to length, standing height (if able to stand unsupported), crown-to-rump length, head 
circumference, upper and lower arm and leg, and arm span. Measurements not taken in the midsagittal plane should be taken on the right side of the body if 
possible and should always be taken on the same side of the body throughout the study.  
j Clinical labs (hematology, chemistry, and urinalysis) are all pre-dose draws samples and can be drawn anytime during the visit if there is no drug 
administration. 
k PK plasma samples will be collected pre-dose and at 5 (± 2 min), 15 (± 2 min), 30 (± 5 min), 45 (± 5 min), 60 (± 5 min), 90 (± 5 min), and 120 (± 5 min) 
minutes post-dose. On Day 1, additional PK samples will be collected at 180 (± 5 min) and 240 (± 5 min) minutes. 
l Antibodies:  Total anti-BMN 111 (TAb) and neutralizing antibody (NAb) samples (serum) will be drawn pre-dose at each time point listed on the SOE. NAb 
testing will be performed only on TAb positive samples from subjects weighing ≥ 7.0 kg and waived for subjects < 7.0 kg. Drug-specific IgE will be drawn 


 
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pre-dose on Day 1 for subjects weighing ≥ 7.0 kg and waived for subjects < 7.0 kg to stay within the limits of permitted blood volume collections in infants. 
Total immunoglobulin E (IgE) and drug-specific IgE will be drawn in the event of Grade 3 hypersensitivity adverse event) or at Investigator or Sponsor 
discretion. If such an event occurs, the drug-specific IgE sample should be drawn at least 8 hours after the event start time or before the next dose. A sample for 
total IgE and serum tryptase should be drawn within an hour of the start of the event when possible or during an unscheduled safety visit.  
m Bone metabolism blood biomarkers will be waived at screening for subjects weighing < 7.0 kg to limit the blood volume on the smallest subjects at this visit. 
Serum samples for bone metabolism biomarkers will be collected pre-dose on the indicated visits. 
n Urine biomarkers and urine chemistry (urine creatinine test) should be obtained pre- and post-dose (approximately 2-4 hours after study drug administration) 
for subjects when possible at the indicated visits. The time of collection will be recorded.  
o Hip monitoring: this assessment will include medical history of the hip and physical exam to determine changes in hip function or pain with hip range of 
motion. Adverse changes from baseline will trigger further evaluation. 
p Obtained at the early termination visit only if the previous assessment was done more than 3 months prior to early termination (unless additional study is 
recommended by Investigator, BioMarin, or DMC). 
q If sleep study is uninterpretable, subject may need to repeat assessment.  Obtained at the early termination visit only if the previous assessment was done more 
than 3 months prior to early termination (unless additional study is recommended by Investigator, BioMarin, or DMC). 
r WeeFim is waived for children < 6 months old; CBCL is waived for children < 18 months old.  
s AP lumbar, lateral lumbar, and AP lower extremities are obtained at the early termination visit only if the previous assessment was done more than 6 months 
prior to early termination (unless additional study is recommended by Investigator, BioMarin, or DMC). AP lower extremities X-ray at the Week 52 visit is 
waived for subjects who cannot stand upright unsupported. 
t To document the physical and phenotypic findings of achondroplasia with and without treatment with study drug, clinical photography of the full body, face, 
spine, and extremities will be conducted. This assessment is optional. If the parents/caregivers decline clinical photography, the assessment will be waived for 
the duration of the study. 
u All subjects should be injected in the left upper thigh on Day 1 unless clinically contraindicated.  Thereafter, injection site should be rotated as described in the 
BMN-111 Injection Guide. 
v After written informed consent but before study treatment initiation, only SAEs associated with protocol-imposed interventions will be recorded. After study 
drug initiation, all AEs and SAEs will be recorded until 4 weeks after either the last administration of study drug or the Early Termination visit. If a subject is 
discontinued from the study prematurely, AEs and SAEs will be recorded at the Early Termination visit.   
w All medications (prescription, over-the-counter, herbal, topical) and nutritional supplements taken 30 days prior to screening and throughout the study should 
be documented. 
x During the call study staff will ask the caregiver about correct administration procedures, record adverse events (AEs), record concomitant medications, and 
answer questions.  
y The 4-week safety follow up visit will be waived for subjects who enter another BMN 111 study or registry within the 4-week period following last dose of 
study drug. 
 


 
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Table 9.1.2:  Schedule of Events Observational Period for Cohort 3 
Assessments  
Screeningb 
Day 1b 
(Month 0) 
3 Months (± 10 days) 
Informed consenta 
X 
 
 
Medical history, including growth history and ACH related 
history 
X 
 
 
Concomitant medications 
X 
X 
X 
Physical examinationc 
X 
 
 
Vital signsd 
X 
X 
X 
Anthropometric measurementse 
 
X 
X 
Vitamin D, 25-hydroxyf 
X 
 
X 
Alkaline phosphatasef 
X 
 
X 
Bone metabolism blood biomarkers 
X 
 
X 
Bone metabolism urine biomarkers 
X 
 
X 
Genomic biomarkers (optional)g 
 
X 
 
Weight 
 
X 
X 
Body mass index (calculated) 
 
X 
X 
Clinical outcome assessment: Bayley-IIIh 
 
X 
 
Clinical outcome assessment: ITQOLh 
 
X 
 
Adverse eventsi 
X 
X 
X 
a Written informed consent and assent (as appropriate) will be obtained within 10 days before Study Day 1 (Month 0). 
b Screening and Day 1 (Month 0) assessments may be performed on the same calendar day at the discretion of the investigator. If Screening and Day 1 
(Month 0) are done on the same day, vital signs are taken only once. Please refer to eCRF Completion Instructions. 
c A complete physical examination will be performed at Screening at the 3-month visit. Complete physical exam includes major body systems, including 
assessment of general appearance; CV; dermatologic; head, eyes, ears, nose, and throat; lymphatic; respiratory; gastrointestinal (GI); musculoskeletal; and 
neurological/psychological and genitourinary. 
d Vital signs will be measured with appropriate blood pressure cuffs for achondroplasia children following detailed instructions in Study Reference Manual. 
At screening, blood pressure should be taken with subject in a sitting position, after the subject has been resting for at least 5 minutes, then the subject will 


 
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stand and BP will be taken again at approximately 1 and 3 minutes after standing. At all other visits, blood pressure should be taken one time after at least 
5 minutes of rest, with subject in a sitting position. Heart rate should be taken at each time point that blood pressure is measured. Left brachial arm should 
be the first method of assessment considered, and the same site should be used for blood pressure measurement in each subject throughout the study. The 
method and site of blood pressure measurement will be recorded and should be utilized consistently throughout the remainder of the study. 
e Growth parameters (anthropometric measurements) may include but are not limited to height, standing height, sitting height, weight, upper and lower arm 
and leg length, and arm span. Body proportion measurements may include but are not limited to upper:lower body segment ratio, upper arm:forearm length 
ratio, upper leg:lower leg length ratio, and arm span:standing height ratio. Refer to the Anthropometric Measurement Guidelines for specific instructions 
regarding the collection of growth measurements. All age-appropriate physical measurements will be collected at approximately the same time each visit 
(±2 hours) by a trained study staff member; every effort will be made to have the measurements collected by the same study staff member, if possible, 
throughout the study. Each measurement will be taken in triplicate (excluding weight, taken once).  
f Vitamin D (25-hydroxy) and alkaline phosphatase will be measured during Screening and at the 3-month visit. 
g If sample is not collected at Day 1, it may be drawn at any time during the study. The sample will be used for exploratory genomics including, but not 
limited to, NPR-B, BRAF, and other genes associated with CNP signaling.  
h Bayley-III is waived for subjects < 1 month old; ITQOL is waived for subjects < 2 months old.  
i AEs will be collected at screening after the ICF is signed. 
 
 


 
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9.1.1 Dose Adjustments 
Analysis of available PK data from studies 111-101 and 111-202 indicated that differences in 
subject body weight did not directly translate to differences in total body clearance of 
BMN 111.  The same weight-based dose in the pediatric population of Study 111-202 
(5-12 years old) yielded lower exposure (Cmax and AUC) than that characterized in the adult 
population of Study 111-101.  Therefore, the same weight-based dose in the young pediatric 
population in this study may yield exposure less than the target exposure range characterized 
to be safe and effective in Study 111-202 at the 15-µg/kg dose. Since this is the first 
experience with BMN 111 in this young pediatric population, it is also possible the exposure 
at 15 μg/kg could be greater than the target exposure range, and dose adjustment may be 
warranted. Thus, an option for adjustment of the weight-based dose is provided to ensure that 
the appropriate target exposure for safety and efficacy is reached for the young subjects in 
this study.   
The need for dose adjustment will be evaluated as follows: three sentinel subjects in Cohort 1 
will receive an initial dose of 15 µg/kg. After all three sentinel subjects reach Day 8, the 
Sponsor will review and evaluate all available safety and PK data (at minimum). If the 
criteria for dose adjustment are met, the three sentinel subjects will be started on the new 
adjusted dose at their next scheduled visit, and vital signs will be obtained for at least 4 hours 
post-dose. 
The remainder of the subjects in the age cohort will also be enrolled starting at the new 
adjusted dose. After the third sentinel subject reaches day 30 post dose adjustment, a DMC 
review will occur to evaluate all safety and PK data and, upon endorsement, the three 
sentinel subjects from the next younger cohort will be enrolled starting at the new adjusted 
dose.  The three sentinel subjects for the second and third cohorts will be evaluated similarly 
to the sentinel subjects in the first cohort for potential dose adjustment. 
Criteria for Dose Adjustment 
The criteria for dose adjustment are based on obtaining equivalent exposure characterized to 
be safe and effective with the 15-μg/kg dose in Study 111-202 in each of the age cohorts 
evaluated in this study. BMN 111 dose may be adjusted if the mean observed AUC0-120 from 
sentinel subjects is less than the 25th percentile for AUC0-120 in Cohort 3 (15 μg/kg) of Study 
111-202 or greater than the 75th percentile in Cohort 3 of Study 111-202. If these criteria are 
met, an allometric scaling coefficient, α, for BMN 111 clearance by subject body weight will 
be determined using a population PK modelling approach and available data from this study 


 
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and Studies 111-202 and 111-101. The recommended adjusted dose will be determined using 
the following expression: 
 
 
where WTref and Doseref are the typical (i.e., median) subject body weight and total dose, 
respectively, at the 15 μg/kg dose level in Cohort 3 of Study 111-202, and WTch is the 
anticipated median weight in the age cohort being studied. As such, the recommended 
adjusted dose will target the median AUC0-120 observed at the 15 μg/kg dose level of Study 
111-202. The recommended adjusted dose, Dosech, will be normalized by WTch, to provide 
the recommended adjusted weight-based dose. The following rules will be used for dose 
adjustment: 
 A maximum of a 2-fold increase in dose/kg will be permitted between dose 
adjustments regardless of exposure. 
 The total dose will not exceed the highest total dose administered in Study 111-202. 
9.1.2 Stopping Criteria 
Individual Subject Stopping Criteria  
For individual subjects treated with BMN 111, DMC will be informed if any of the following 
individual subject stopping criteria should occur. Temporary dosing suspension, permanent 
discontinuation of dosing, or dose reduction for the individual subject will be considered. 
 Any treatment-emergent adverse event (AE) assessed as at least Grade 4 by the 
Investigator and/or Sponsor Medical Monitor  
 Any treatment-emergent AE of at least Grade 3 assessed as related to study drug by 
the Investigator and/or Sponsor Medical Monitor  
 Any two treatment-emergent Grade 2 symptomatic hypotension events within 7 days 
(non-urgent medical intervention indicated) or any Grade 3 hypotensive event (urgent 
medical intervention or hospitalization indicated) assessed by the Investigator and/or 
Sponsor’s Medical Monitor  
 Clinically significant finding or arrhythmia on ECG that indicates abnormal cardiac 
function or conduction or prolongation of QTc-F >500 msec 
 Clinically significant new or worsening signs of cervicomedullary compression as 
determined by the Investigator and in consultation with Sponsor medical monitor and 
neurosurgical specialist (if needed) 


 
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 Adverse findings on clinical hip exam or hip imaging assessments that are determined 
to be clinically significant as determined by the Investigator and in consultation with 
Sponsor Medical Monitor and orthopedic specialist (if needed)  
If the subject meets any stopping criterion, after Investigator consultation with the BioMarin 
Medical Monitor and DMC, the subject may be re-challenged at the same dose. If the subject 
meets stopping criteria on re-challenge or if re-challenge at same dose is not clinically 
indicated, other options that may be considered include:  
 Re-challenge at lower dose with consideration given to upward titration to tolerated 
dose  
 Permanent treatment discontinuation (with an option of ongoing assessment in the 
study)  
Cohort Stopping Criteria  
For each cohort, a DMC review will be conducted if any of the following cohort stopping 
criteria occur in subjects treated with BMN 111.  Temporary dosing suspension, permanent 
discontinuation of dosing, or dose reduction for the cohort(s) will be considered and the 
impact on all other age cohorts will be assessed.  
 Any treatment-emergent AE assessed as at least Grade 4 by the Investigator and/or 
Sponsor Medical Monitor  
 Any two subjects have a treatment-emergent AE of at least Grade 3 assessed as 
related to study drug by the Investigator and/or Sponsor Medical Monitor  
 Any two subjects have two treatment-emergent Grade 2 symptomatic hypotension 
events within 7 days (non-urgent medical intervention indicated) or any two subjects 
cohort have a Grade 3 hypotensive event (urgent medical intervention or 
hospitalization indicated) assessed by the Investigator and/or Sponsor’s Medical 
Monitor  
 Any two subjects have a clinically significant finding or arrhythmia on ECG that 
indicates abnormal cardiac function or conduction or prolongation of 
QTc-F >500 msec 
 Any two subjects have adverse findings on clinical hip exam or hip imaging 
assessments that are determined to be clinically significant as decided by principal 
investigator and in consultation with Sponsor medical monitor and orthopedic 
specialist (if needed)  
9.2 
Discussion of Study Design, Including Choice of Control Group 
Study 111-206 is a Phase 2 randomized, double-blind, placebo-controlled clinical trial of 
BMN 111 in infants and younger children with a diagnosis of ACH who are age 0 to 


 
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< 60 months. Identification of efficacy at this age range is congruent with mechanism of 
action of BMN 111, because BMN 111 is expected to act at open epiphyseal growth plates. 
Therefore, to have a potential therapeutic benefit for subjects with ACH, treatment is 
expected to be required prior to epiphyseal growth plate closure. 
In terms of the study design, a randomized double-blind placebo control will be used to 
mitigate the risk of selection bias and any potential bias in data collection and study conduct.  
Additionally, this design provides a framework for interpretation of any endpoints with a 
subjective component, e.g. HRQOL and ADL questionnaires and any subjective assessment 
of safety. 
9.3 
Selection of Study Population 
Subjects age 0 months to  < 60 months old, with documented ACH confirmed by genetic 
testing, and who meet the study eligibility criteria will participate. 
Additional criteria for participation in the study are provided in Sections 9.3.1 and 9.3.2. 
9.3.1 Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Diagnosis of ACH, confirmed by genetic testing.  If subjects had previous genetic 
testing, subjects must have a lab report from a certified laboratory with the study 
specific mutation documented. 
2. Age 0 to  < 60 months, at study entry (Day 1) 
3. Cohort 1 and 2 subjects must have at least a 6-month period of pretreatment growth 
assessment in Study 111 901 immediately before study entry, and have one 
documented measurement of height/body length a minimum of 6 months 
(+/- 10 days) prior to the screening visit for 111-206.  Cohort 3 subjects must have a 
minimum of 3 months of observation prior to treatment.  This observational period 
can be obtained either (1) via prior enrollment in Study 111-901 or (2) via enrollment 
in this Study 111 206 for a minimum of 3 months of non-treatment observation prior 
to commencement of treatment.  
4. Parent(s) or guardian(s) (and the subjects themselves, if required by local regulations 
or ethics committee) are willing and able to provide written, signed informed consent 
after the nature of the study has been explained and prior to performance of any 
research-related procedure 
5. Willing and able to perform all study procedures as physically possible 
6. Parent(s) or caregiver(s) are willing to administer daily injections to the subjects and 
complete the required training 


 
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9.3.2 Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1. Have hypochondroplasia or short-stature condition other than achondroplasia 
(e.g., trisomy 21, pseudoachondroplasia, etc.) 
2. Subject weighs < 5.0 kg (Cohort 1 and 2) or < 4.0 kg (Cohort 3) 
3. Have any of the following: 
 Hypothyroidism or hyperthyroidism 
 Insulin-requiring diabetes mellitus 
 Autoimmune inflammatory disease (including celiac disease, systemic lupus 
erythematosus, juvenile dermatomyositis, scleroderma, etc.) 
 Inflammatory bowel disease 
 Autonomic neuropathy 
4. Have a history of any of the following: 
 Renal insufficiency defined as serum creatinine > 2 mg/dL 
 Chronic anemia or Hgb  < 10.0 g/dL (based on screening clinical laboratory 
testing) 
 Baseline systolic blood pressure (BP) below age and gender specified normal 
range or recurrent symptomatic hypotension (defined as episodes of low BP 
generally accompanied by symptoms e.g., dizziness, fainting) or recurrent 
symptomatic orthostatic hypotension 
 Cardiac or vascular disease, including the following 
o Cardiac dysfunction (abnormal echocardiogram determined to be 
clinically significant by PI and medical monitor) at Screening Visit  
o Hypertrophic cardiomyopathy 
o Pulmonary hypertension 
o Congenital heart disease with ongoing cardiac dysfunction  
o Cerebrovascular disease 
o Aortic insufficiency or other clinically significant valvular dysfunction 
o Clinically significant atrial or ventricular arrhythmias 
5. Have a clinically significant finding or arrhythmia that indicates abnormal cardiac 
function or conduction or QTc-F  > 450 msec on screening ECG 
6. Have evidence of cervicomedullary compression (CMC) likely to require surgical 
intervention within 60 days of Screening as determined by the Investigator based on 
the following assessments:  
 Physical exam (e.g., neurologic findings of clonus, opisthotonus, exaggerated 
reflexes, dilated facial veins) 
 Polysomnography (e.g., severe central sleep apnea) 
 MRI indicating presence of severe CMC or spinal cord damage  


 
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7. Have an unstable medical condition likely to require surgical intervention in the next 
6 months, or planned spine or long-bone surgery (i.e., surgery involving significant 
disruption of bone cortex) during the study period 
8. Have documented uncorrected Vitamin D deficiency: 25(OH)D   ≤ 15 ng/mL 
(37.5 nmol/L) 
9. Require any other investigational product prior to completion of the study period 
10. Have received another investigational product or investigational medical device 
within 30 days prior to the Screening visit 
11. Have used any other investigational product or investigational medical device for the 
treatment of achondroplasia or short stature at any time  
12. Require current chronic therapy with antihypertensive medication or any medication 
that, in the investigator’s judgment, may compromise the safety or ability of the 
subject to participate in this clinical study  
13. Have been treated with growth hormone, insulin-like growth factor 1 (IGF-1), or 
anabolic steroids in the 6 months prior to screening, or long-term treatment 
(> 3 months) at any time 
14. Have had regular long-term treatment (> 1 month) with oral corticosteroids (low-dose 
ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable) in the 
12 months prior to screening 
15. Have ever had spine or long-bone surgery (i.e., surgery involving disruption of bone 
cortex) or have ever had bone-related surgery with chronic complications 
16. Have ever had limb-lengthening surgery or plan to have limb-lengthening surgery 
during the study period 
17. Have had a fracture of the long bones or spine within 6 months prior to screening 
18. Have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or total 
bilirubin greater than upper limit of normal (ULN) at screening (except for subjects 
with a known history of Gilberts or newborns entering screening in Cohort 3) 
19. Have evidence of severe untreated sleep apnea; or have newly initiated sleep apnea 
treatment (eg, CPAP or sleep apnea-mitigating surgery) in the 2 months prior to 
screening 
20. Have current malignancy, history of malignancy, or currently under work-up for 
suspected malignancy 
21. Have known hypersensitivity to BMN 111 or its excipients 
22. Have a history of hip surgery or severe hip dysplasia 
23. Have a history of clinically significant hip injury in the 30 days prior to screening  
24. Have a history of slipped capital femoral epiphysis or avascular necrosis of the 
femoral head  
25. Have abnormal findings on baseline clinical hip exam or imaging assessments that are 
determined to be clinically significant as determined by the Investigator 
26. Have a condition or circumstance that, in the view of the Investigator, places the 
subject at high risk for poor treatment compliance or for not completing the study 
27. Have any concurrent disease or condition that, in the view of the Investigator, would 
interfere with study participation or safety evaluations, for any reason 


 
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9.3.3 Removal of Subjects from Treatment or Assessment 
Subjects (or their legally authorized representative) may withdraw their consent to participate 
in the study at any time without prejudice. The Investigator must withdraw from the study 
any subject who requests to be withdrawn. A subject’s participation in the study may be 
discontinued at any time at the discretion of the Investigator and in accordance with his/her 
clinical judgment. When possible, the tests and evaluations listed for the termination visit 
should be carried out.  BioMarin must be notified of all subject withdrawals as soon as 
possible.  
Investigators may discontinue administration of BMN 111 or placebo at any time. Reasons 
for which the investigator or BioMarin will withdraw a subject from study treatment include, 
but are not limited to, the following:  
1. Subject experiences a serious or intolerable AE due to BMN 111 as determined by the 
subject, investigator, or sponsor 
2. Subject requires medication or medical procedure prohibited by the protocol 
3. Subject does not adhere to study requirements specified in the protocol 
4. Subject is lost to follow-up 
If a subject fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the subject cannot be reached by telephone, a certified letter should 
be sent to the subject (or the subject’s legally authorized representative, if appropriate) 
requesting contact with the Investigator. This information should be recorded in the study 
records.  
The Investigator or designee must explain to each subject, before enrollment into the study, 
that for evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with the study sponsor, regulatory agencies, and IRB/IEC/REB. It is 
the Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as HIPAA in the US, from each 
subject, or if appropriate, the subject’s legally authorized representative. If permission to use 
protected health information is withdrawn, it is the Investigator’s responsibility to obtain a 
written request, to ensure that no further data will be collected from the subject and the 
subject will be removed from the study. 
It is a priority of the study to maximize study subject retention and adherence to 
study-specific procedures. The completeness of the study data may affect the integrity and 
accuracy of the study results.  Therefore, subjects who discontinue study treatment should be 


 
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encouraged to continue to undergo as many of the protocol-specified procedures and 
assessments as possible for the remainder of the study, as long as such continued 
participation does not detrimentally affect the health, safety, or welfare of the subject.   
For subjects who discontinue BMN 111 or placebo but remain in the study, PK and 
BMN 111 activity assessments will be waived completely; vital signs and clinical 
labs/biomarkers will be obtained only once at each visit subsequent to BMN 111 or placebo 
discontinuation.  Pre-and post-dose designations will not apply as the subject has 
discontinued dosing and vital sign and clinical lab/biomarkers assessments previously 
designated as “post-dose” will be waived.  All other assessments at each visit should be 
completed if possible and the subject is willing.  Data from the study procedures and 
assessments may be used to further characterize the natural progression of ACH.  
BioMarin reserves the right to discontinue the study at any time.  Premature termination of 
the study may occur because of regulatory authority decision, a change in the opinion of the 
IRB/IEC/REB, clinical or safety reasons, or at the discretion of the Sponsor.  The Sponsor 
reserves the right to discontinue the development of BMN 111 at any time, or to discontinue 
participation by an individual Investigator or site for poor enrollment or 
noncompliance.  Any decision to terminate the study will be promptly communicated to 
Investigators, regulatory authorities, and IRB/IEC/REB.  The Investigator is responsible for 
communicating any decision to terminate a study to hospital staff involved in the conduct of 
the study and the participating subjects (and their families). 
9.3.4 Subject Identification  
Each subject will be assigned a unique subject identifier. This unique identifier will be on all 
eCRF pages. In legal jurisdictions where use of initials is not permitted, a substitute identifier 
will be used. 
9.3.5 Duration of Subject Participation 
Duration of the study is 52 weeks of treatment with a safety follow up at Week 56. Following 
completion of the study, subjects in both treatments groups may be eligible to receive 
BMN 111 in an open-label extension study, to assess safety and efficacy of BMN 111 over 
the longer term.  For subjects enrolling into the extension study, safety follow up visit at 
Week 56 will be waived.  
Subjects who are not eligible to receive BMN 111 in a separate study will return at Week 56 
for the Safety Follow-Up visit to assess for any AEs that may have occurred following 
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Follow-up assessments and procedures should be performed as outlined in the Study 
111-206 Schedule of Events (Table 9.1.1 and Table 9.1.2).  
Subjects who discontinue from study treatment will be asked to complete study assessments 
and procedures for the remainder of the study.  If subjects discontinue from study treatment 
and decline to participate for the remainder of the study, they will be asked to return for a 
final follow-up visit 2 weeks after their last study visit, and the agreement should be 
documented. 
Subjects will participate in the study until completion or until one of the following occurs: 
the subject withdraws consent and discontinues from the study, the subject is discontinued 
from the study at the discretion of the investigator or BioMarin (upon consultation and in 
agreement with the investigator) or the study is terminated. 
9.4 
Treatments 
9.4.1 Treatments Administered 
BioMarin and/or its designee will provide the study site with a supply of IP sufficient for the 
completion of the study. 
Subjects will be randomized to BMN 111 at a daily dose of 15 µg/kg or placebo for the 
duration of the study. The normal dosing schedule is a single daily subcutaneous injection 
given 7 days a week.  
If a recent acute illness associated with volume depletion (e.g., nausea, vomiting, diarrhea) 
has not completely resolved prior to the first dose of BMN 111 or placebo, the dosing will be 
delayed until hydration status has improved (up to the maximum period allowed for the visit 
window). 
9.4.1.1 
Study Drug Administration 
During the study, BMN 111 or placebo will be administered as a single 15 µg/kg SC 
injection given daily at approximately the same time each day whenever possible.  The same 
injection site should not be used 2 days in a row, and should be rotated between the 
4 injection sites (upper thigh, upper back of arm, abdomen or buttocks). Doses may be 
administered in any of the common SC areas (upper arm, thigh, abdomen, buttocks). 
Following administration of each dose, subjects will be observed for at least 2 hours after the 
injection for Days 1 to 3, and 30 minutes for all other days of dose administration (longer if 
clinically indicated) either in the clinic by study personnel, by a home health nurse, or by a 
parent/caregiver. Instructions for home administration of BMN 111 or placebo for subjects 


 
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who qualify for parent/caregiver administration are provided in the Study Drug Injection 
Guide and Injection media. 
9.4.2 Identity of BMN 111 
BMN 111 is cloned into the pJexpress401 vector, expressed in E. coli and then purified. 
The drug substance is a modified CNP peptide that retains wild-type activity and specificity. 
The modified CNP sequence is: 
PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC 
The amino acid sequence is an analogue of the naturally occurring tissue-expressed form of 
C-type natriuretic peptide (CNP-53). BMN 111 is a recombinant 39 amino acid peptide that 
includes the 37 C-terminal amino acids of the human CNP-53 sequence, and is engineered to 
include two additional amino acids (Pro-Gly) on the N-terminus, which renders the peptide 
more resistant to degradation. It is a cyclic peptide formed by an intramolecular disulfide 
bond. The molecular weight of the purified product is 4.1 kDa. 
9.4.2.1 
Product Characteristics and Labeling 
The clinical drug product will be supplied in sterile, single-dose, Type I glass vials with 
coated stopper and flip-off aluminum cap. BMN 111 drug product is supplied as a 0.8-mg or 
2-mg lyophilized, preservative-free, white-to-yellow powder for reconstitution with either a 
sterile diluent or sterile water for injection. The reconstituted solution is colorless to yellow 
and contains 0.8 mg/mL to 2 mg/mL of BMN 111, as well as citric acid, sodium citrate, 
trehalose, mannitol, methionine, polysorbate 80, and sterile water for injection. The target pH 
of the reconstituted solution is 5.5. Sterile water for injection will be commercially sourced 
and sterile diluent solution containing all of the above excipients will be supplied for 
reconstitution. All reconstitution and dose preparation steps will be performed as indicated in 
the BMN 111 Injection Guide and Injection video. 
BMN 111-placebo lyophilized product will be supplied in sterile, single-dose, Type I glass 
vials with coated stopper and flip-off aluminum cap. The placebo is designed to be 
comparable in appearance to the drug product and contains all of the components of the drug 
product including commercially sourced sterile WFI except the drug substance. 
The BMN 111 or placebo kit label includes the following information: the contents, 
directions, lot number, quantity, subject ID, vial ID, investigator, the required storage 
conditions, a precautionary statement, the expiry date, the study number, and BioMarin 
Pharmaceutical name and location. This may vary based on country requirements. 


 
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9.4.3 Storage 
At the study site, all IP must be stored under the conditions specified in the Investigator’s 
Brochure in a secure area accessible only to the designated pharmacists and clinical site 
personnel. All IP must be stored and inventoried and the inventories must be carefully and 
accurately documented according to applicable state, federal and local regulations, ICH GCP, 
and study procedures. 
Specific information for storage and return of BMN 111 or placebo is provided in the 
Pharmacy Binder, Study Drug Injection Guide, and Injection media. 
9.4.4 Directions for Administration 
Refer to the Study Drug Injection Guide for complete BMN 111 or placebo preparation 
instructions.  
The injection will be administered as a daily dose of BMN 111 15 µg/kg or placebo given as 
a single subcutaneous injection. The dose should be given at approximately the same time 
every day whenever possible.  Following administration of each dose at clinic visits, subjects 
should be observed for 8 hours after the injection on Days 1 and 2; 4 hours on Days 3 and 8; 
and 1 hour on subsequent dosing visits. Subjects should be observed for 30 minutes after 
every injection that is not administered at the clinic. Subjects should have adequate food 
intake prior to dosing. In the hour prior to injection, all subjects should have been fed prior to 
administration of BMN 111 or placebo. 
Caregivers will administer BMN 111 or placebo at home once approved by the investigator 
and adequate training is demonstrated. Instructions on how to complete and document the 
training can be found in the Study Reference Manual.   
A caregiver will be eligible to administer BMN 111 or placebo if he or she meets all of the 
following criteria: 
 The subject has been on a stable dosing regimen for a minimum of 3 days  
 PI has approved administration of BMN 111 or placebo by the caregiver 
 The caregiver has completed the Administration Training conducted by qualified 
study site personnel and has been observed by the study site personnel to be able to 
adequately prepare the proper dose and perform the injections safely 
For dosing between planned clinic visits prior to caregiver approval, a home health nurse 
may administer BMN 111 or placebo, or subjects may be administered BMN 111 or placebo 
in the clinic by study staff or trained caregiver.   


 
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The caregiver will be provided with a study diary and will be asked to record daily dosing 
information, changes in health status, medications and injection sites used, date and time of 
the injection, and injection site reactions, if any. 
A subject’s suitability for continued at-home drug administration will be evaluated by the 
investigator and the Sponsor’s Medical Monitor if a subject experiences a CTCAE Grade 3 
or higher AE that is considered possibly or probably drug-related, and/or a hypersensitivity 
reaction during the study.   
9.4.5 Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized in a 1:1 ratio, i.e., injection with placebo:15 µg/kg of BMN 111, 
using IXRS.  An independent third party vendor will develop the randomization schedule so 
that BioMarin and site personnel are blinded to treatment assignments. 
9.4.6 Selection of Dose and Dosing Schedule Used in the Study 
Study 111-202, the second clinical trial in humans and the first in children with ACH, is an 
ongoing Phase 2, open-label, sequential-cohort, dose-escalation study that assesses daily SC 
BMN 111 in pediatric subjects with ACH aged 5-14 years with doses ranging from 2.5 µg/kg 
to 30 µg/kg.  
Analysis of safety data from the 6-month initial phase of Study 111-202 showed that 
treatment with BMN 111 for 6 months at the doses of 2.5, 7.5, 15, and 30 µg/kg was 
generally well tolerated. The most common AEs across all cohorts were injection site 
reactions, asymptomatic hypotension, headache, and nasopharyngitis. Based on previous 
experience of the ongoing Phase 2 clinical trial, including the 24-month data cut at 15 µg/kg, 
injection site reactions have been identified as risks associated with BMN 111 injections. For 
a detailed summary of risks, please refer to the current version of the Investigator’s Brochure 
supplied by BioMarin.  
Analysis of efficacy data from the 6-month initial phase of Study 111-202 showed that 
subjects treated with BMN 111 for 6 months at doses ranging from 2.5 to 15 µg/kg daily had 
a dose-dependent improvement in AGV, with ~50% improvement in AGV seen at the 
15 µg/kg dose. The data from Cohort 4 (30 µg/kg) show an apparent greater than dose-
proportional increase in BMN 111 plasma exposure (Cmax and AUC0-t), with a marginal 
improvement in both absolute AGV and change from baseline AGV after 6 months of 
BMN 111 treatment when compared with Cohort 3 (15 µg/kg).    
Efficacy/toxicity studies have been conducted in neonatal and very young animals (7-day 
postpartum mouse and rat) in both a disease (TD mouse) and non-disease (rat) model. 


 
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Given that this is the first study in infants and young children, an age-based cohort study 
design is used to assess safety and PK in young children (Cohort 1, ≥ 24 to < 60 months) 
prior to dosing toddlers (Cohort 2, ≥ 6 to < 24 months) and infants (Cohort 3, 
0 to  <  6 months). PK will be monitored and evaluated; Day 1 PK data from the sentinel 
subjects will inform dose selection modification for the sentinel subjects and for the rest of 
the cohort to target the observed exposure of the 15-µg/kg dose group in Study 111-202. 
Safety, efficacy and PK data from Study 111-202, a Phase 2 study in children with ACH, 
where a dose of 15 µg/kg has been and continues to be studied, are expected to be the most 
relevant, and translatable to this study (111-206).   
9.4.6.1 
Selection of Timing of Dose for Each Subject 
9.4.7 Blinding 
An independent third-party vendor will develop the randomization schedule so that BioMarin 
and site personnel will not know treatment assignments. BMN 111 or placebo will be labeled 
with the study number and a unique identification number. Subjects and the participating site 
members will be blinded to the two study treatments (15 µg/kg BMN 111 or placebo).  
The investigator and other members of staff involved with the study will remain blinded to 
the treatment randomization code during the assembly procedure. In the event of an 
emergency medical situation where subject management would be determined or 
significantly altered by knowing the treatment assignment, the investigator may be unblinded 
without prior written approval from the Medical Monitor.  Following such an emergency 
unblinding, the investigator will contact the medical monitor and provide written rationale 
according to the unscheduled unblinding procedure set forth in the Study Manual.  
The Medical Monitor will review the rationale, evaluate whether there are any additional 
safety considerations that need to be implemented for the subject and/or the study, and 
determine whether the investigator requires further guidance on unblinding.  The Medical 
Monitor may also communicate with the investigator advice on the care of the subject and 
define the plan for the subject’s future participation in the study. 
9.4.8 Prior and Concomitant Medications 
All medications (prescription, over-the-counter [OTC] and herbal), and nutritional 
supplements 30 days prior to screening and throughout the study will be recorded on the 
designated eCRF.  The Investigator may prescribe additional medications during the study, as 
long as the prescribed medication is not prohibited by the protocol. In the event of an 
emergency, any needed medications may be prescribed without prior approval, but the 
medical monitor must be notified of the use of any contraindicated medications immediately 


 
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thereafter. Any concomitant medications added or discontinued during the study should be 
recorded on the eCRF. 
9.4.9 Treatment Compliance 
Subjects will be instructed to return all used and unused BMN 111 or placebo kits at each 
study visit. Subject compliance with the dosing regimen will be assessed by reconciliation of 
the used and unused vials. The quantity dispensed, returned, used, lost, etc. must be recorded 
on the dispensing log provided for the study. 
The date, time, and volume of each dose of BMN 111 or placebo administered to each 
subject must be recorded. These data will be used to assess treatment compliance.  
9.5 
Investigational Product Accountability (BMN 111 or Placebo) 
The Investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of IP(s) received, subjects to whom IP is dispensed (subject-by-subject dose 
specific accounting), and IP lost or accidentally or deliberately destroyed. The Investigator or 
designee must retain all unused or expired study supplies until the study monitor (on-site 
CRA) has confirmed the accountability data. 
9.5.1 Return and Disposition of Clinical Supplies 
Unused BMN 111 or placebo must be kept in a secure location for accountability and 
reconciliation by the study monitor. The Investigator or designee must provide an 
explanation for any destroyed or missing BMN 111 or placebo kits/vials. 
Unused BMN 111 or placebo may be destroyed on site, per the site’s standard operating 
procedures, but only after BioMarin has granted approval for destruction. The study monitor 
must account for all BMN 111 or placebo kits/vials in a formal reconciliation process prior to 
destruction. The site must document all BMN 111 or placebo destroyed on site, and 
documentation must be provided to BioMarin and retained in the investigator study files. If a 
site is unable to destroy BMN 111 or placebo appropriately, the site can, upon request, return 
unused BMN 111 or placebo to the BioMarin contracted facility. The return of all BMN 111 
or placebo kits/vials must also be documented and accounted for per instructions provided by 
BioMarin. 
All BMN 111 or placebo and related materials should be stored, inventoried, reconciled, and 
destroyed or returned according to applicable state and federal regulations and study 
procedures. 


 
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9.6 
Dietary or Other Protocol Restrictions 
BMN 111 will be administered as a single daily dose of 15 µg/kg SC injection given daily at 
approximately the same time each day whenever possible. Placebo will be administered as a 
single SC injection given daily at approximately the same time each day whenever possible. 
Following administration of each dose, subjects will be observed for at least 2 hours after the 
injection for observation for Days 1 to 3, and 30 minutes for all other days of dose 
administration.  
Subjects should have an adequate food intake.  In the hour prior to injection, all subjects 
should be fed prior to administration of BMN 111 or placebo. 
9.7 
Demographic Data and Medical History  
Demographic data and a detailed medical history will be obtained at Screening. This medical 
history, including growth history and ACH-related history, should elicit all major illnesses, 
diagnoses, and surgeries that the subject has ever had; any prior or existing medical 
conditions that might interfere with study participation or safety; and evaluation for knee, 
thigh, hip or groin pain, or change in gait/activity.   
9.8 
Biological Parental Standing Height 
Standing height of the subject’s biological parents may be assessed (optional) via height 
measurement or stated height. Height measurement can be done at any point in the study.  
Prior to the measurement being taken, each parent is required to complete an ICF specific to 
parent height assessment.  The ICF will be signed prior to the assessment, which can be done 
at any point in the study. If the biological parent is not available during the course of the 
study to take his/her standing height, if consented, the biological parent can provide his/her 
stated height.  
9.9 
Physical Examination Findings 
Physical examination will include assessment of general appearance; CV; dermatologic; 
head, eyes, ears, nose, and throat; lymphatic; respiratory; GI; musculoskeletal; and 
neurological/psychological and genitourinary. Other body systems may be examined. 
Screening results will be the baseline values and clinically significant changes from baseline 
will be recorded as an AE or SAE and study drug related or unrelated when appropriate 
based on the investigator’s clinical judgment. 


 
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9.10 
Echocardiogram 
Cardiac anatomy and function will be evaluated by a standard 2-dimensional Doppler 
echocardiogram by a cardiologist. Echocardiograms will be performed at screening, and 
provide information regarding cardiac anatomy and function prior to enrollment in the study. 
9.11 
Efficacy and Safety Variables 
9.11.1 Efficacy and Safety Measurements Assessed 
The Schedule of Events (Table 9.1.1 and Table 9.1.2) describes the timing of required 
evaluations. 
9.11.2 Primary Efficacy Variables 
The primary efficacy endpoint is change from baseline in length/height Z-score. 
Growth measures may be collected approximately the same time each visit (± 2 hr from the 
time when the first measurement assessment was taken at Screening) by a study staff 
member, preferably the same person throughout the study, who has been trained by a 
BioMarin representative. Standardized measuring equipment and detailed measurement 
techniques are detailed in the Anthropometric Measurement Guidelines.  
9.11.3 Secondary Efficacy Variables 
The secondary efficacy endpoints include change from baseline in AGV (annualized to 
cm/yr), biomarker samples to evaluate the effect of BMN 111 on bone metabolism, and 
BMN 111 pharmacodynamic biomarkers. 
Weight will be measured at Screening and at study visits as indicated on the Schedule of 
Events (Table 9.1.1 and Table 9.1.2). 
Biomarkers may include but are not limited to assessment of changes in bone and collagen 
metabolism and BMN 111 bioactivity. BioMarin or designee will perform analysis, and 
samples may also be used for assay development.   
Samples for blood and/or urine biomarkers will be collected at the time points presented in 
the Schedule of Events (Table 9.1.1 and Table 9.1.2). Refer to the Study Laboratory Manual 
for instructions regarding obtaining and shipping samples. The sample type will also be 
included in the Study Laboratory Manual. 


 
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9.11.4 Exploratory Efficacy Variables 
9.11.4.1 
Body Proportion Ratios of the Extremities 
Change from baseline in body proportion ratios of the extremities will be evaluated using 
anthropometric measurements and measurement ratios.  Refer to the Anthropometric 
Measurement Guidelines for specific instructions regarding the collection of growth 
measurements. All age-appropriate physical measurements will be collected at approximately 
the same time each visit (±2 hours around the time when the first measurement assessment 
was taken at Screening) by a trained study staff member; every effort will be made to have 
the measurements collected by the same study staff member, if possible, throughout the 
study. Each measurement will be taken in triplicate (excluding weight, taken once). 
Anthropometric measurement can be conducted either pre-dose or post-dose. Measurements 
may include but are not limited to length, standing height (if able to stand unsupported), 
crown-to-rump length, head circumference, upper and lower arm and leg, and arm span. 
Measurements not taken in the midsagittal plane should be taken on the right side of the body 
if possible and should always be taken on the same side of the body throughout the study 
Body proportion measurements may include but are not limited to upper arm:forearm length 
ratio, upper leg:lower leg length ratio, and armspan:standing height ratio. 
9.11.4.2 
Imaging Assessment Procedures (per Schedule of Events) 
Imaging assessment procedures for all visits must be performed using the same instruments.  
Imaging assessments can be conducted either pre-dose or post-dose. 
 Bilateral lower extremity x-rays including both anterior-posterior (AP) and lateral 
views to assess growth plates.  
 Hip imaging via pelvis x-ray to identify hip pathology (if changes from baseline 
trigger further evaluation) 
 Lumbar spine x-rays to measure changes from baseline in bone morphology and 
pathology.   
 MRI to evaluate the effect of BMN 111 on skull and brain morphology, including 
foramen magnum, ventricular and brain parenchymal dimensions. 
 DXA scan (whole body [less head], including spine, one third forearm and tibia, ultra 
distal radius) to assess bone mineral density (BMD) and bone mineral content 
(BMC). 
Additional imaging may be conducted should there be any issues or concerns with the 
subject’s imaging assessments. Imaging assessments will be collected and interpreted by a 


 
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central reader. If clinically significant abnormalities are noted, the investigator or designee is 
required to assess whether it is appropriate to report an AE and if the subject should continue 
in the study. Refer to the vendor Imaging Guidelines for detailed imaging assessment 
requirements and procedures. 
9.11.4.3 
Exploratory Biomarker Research Sample Analyses 
All samples collected in this study may be used for on-study, exploratory biomarker research 
once the primary use has been completed.  
For each portion of the blood and urine samples reserved for protocol-specified analyses, 
there may be multiple sample aliquots. Once samples have been successfully analyzed during 
the study, unused sample portions may be used during the study for assay development or 
other purposes stated in this section. No exploratory genomic research will be conducted 
without consent from the subject and his/her legally authorized representative (parent or legal 
guardian). 
9.11.4.4 
Genomic Biomarker Analysis 
While the inherited FGFR3 mutations associated with achondroplasia are well characterized, 
disease phenotype in monogeneic diseases is often modified by variants in other genes. 
To identify and study genetic variants that may modify achondroplasia, a whole blood 
sample will be collected.  Exploratory genomics will include, but are not limited to NPR-B, 
BRAF, and other genes associated with CNP signaling.  Exploratory genomic analysis of 
plasma DNA may inform understanding of the BMN 111 mechanism of action in 
achondroplasia.  Exploratory genomics will not be conducted without express consent from 
the subject and his/her legally authorized representative (parent or legal guardian).  
9.11.4.5 
Sleep Study 
Given that sleep apnea is a finding in children with ACH (Waters, 1993) and has implications 
on functional and health outcomes, a sleep study will be performed in a limited number of 
qualified sleep centers.  A sleep-testing device will be used to assess the presence and 
severity of sleep-disordered breathing by measurement of blood oxygen saturation, pulse 
rate, and airflow during overnight monitoring. Assessment of episodes of sleep apnea will 
include, but may not be limited to, the number of episodes of apnea and hypopnea per hour 
(Apnea/Hypopnea Index).   
9.11.4.6 
Clinical Photography 
To document the physical and phenotypic findings of achondroplasia with and without 
treatment with study drug, clinical photography of the full body, face, spine, and extremities 


 
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will be conducted. This assessment is optional. If the parents/caregivers decline clinical 
photography, the assessment will be waived for the duration of the study. 
9.11.4.7 
Clinical Outcome Assessments 
Clinical outcome assessments will be administered to assess the health-related quality of life 
of study subjects. ADL questionnaires will be performed in study subjects to assess 
functional performance. Clinical outcome assessments will be performed at the time points 
indicated in the Schedules of Events (Table 9.1.1 and Table 9.1.2). The age ranges for 
clinical outcome assessment tools are shown in Figure 9.11.4.7.1. 
Figure 9.11.4.7.1:  Clinical Outcomes Assessment Tools 
 
9.11.4.7.1 Bayley-III 
The Bayley-III is a performance based outcome assessment for use in children from 1 to 
42 months. It is individually administered by the trained clinician to the subject/child. 
The time required varies from 15-60 minutes depending on the child’s developmental level 
and cooperation.  
Scales include Cognitive subscale, Receptive and Expressive subscales, and Gross and Fine 
Motor subscales. The two language scales make up a composite Language Scale score and 
the Gross and Fine Motor subscales yield a composite Motor Scale score. In addition, there is 
a Social-Emotional Scale and Adaptive Behavior Scale, which is a questionnaire read and 
completed by parent or caregiver.  


 
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The scales have clinical and research utility as a diagnostic assessment for young children 
with varied disorders and disabilities, and reflect current professional standards for early 
childhood assessment (Bayley, 2006).  
In addition to its use for subjects ranging from 1 to 42 months old, the Bayley-III assessment 
will be administered to those between 42 and 60 months old (Figure 9.11.4.7.1), as this 
assessment can capture ongoing developmental issues associated with Achondroplasia.  
Bayley-III is waived for subjects < 1 month old. 
9.11.4.7.2 Activity of Daily Living and Functional Independence Measure (Wee-FIM) 
The Wee-FIM instrument is an ADL assessment tool that measures functional performance 
across three domains (self-care, mobility and cognition) (Ireland, 2011; Ireland, 2012). 
The Wee-FIM instrument has been used in previous research in children with ACH, and has 
identified ongoing limitations in functional performance across these domains extending 
beyond the age of 7 years (Ireland, 2011). Because the WeeFIM considers the child’s 
performance from a caregiver’s perspective (Ireland, 2012), this tool in turn gives an 
indication of “burden of care” for families and caregivers of children with ACH.  WeeFim is 
waived for children < 6 months old. 
9.11.4.7.3 ITQOL 
The ITQOL is an observer-reported outcome tool developed for use in children from 
2 months to 5 years old that attempts to capture physical, mental and social well-being. 
The ITQOL adopts the World Health Organization’s definition of health as a state of 
complete physical, mental and social well-being, and not merely the absence of disease. 
The ITQOL also assesses the quality of the parent/guardians life.  The 97-item full-length 
version (ITQOL) will be used for this study. Completion time varies.  ITQOL is waived for 
subjects < 2 months old. 
9.11.4.7.4 Child Behavior Checklist  
The Child Behavior Checklist (CBCL) is for use in children from 1.5-5 years old.  
The CBCL comprises 99 questions addressing symptoms related to mood, behavior issues, 
and sleep disturbance.  It is completed by the parent or primary caregiver.  
The form requires approximately 15 minutes to complete. The checklist yields scores in the 
following areas: reactivity, anxiety, depression, somatic complaints, withdrawal, sleep 
problems, attention problems, and aggressive behavior. CBCL is waived for 
children < 18 months old. 


 
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9.11.5 Pharmacokinetics Variables 
PK plasma samples will be collected pre-dose and at 5 (± 2 min), 15 (± 2 min), 30 (± 5 min), 
45 (± 5 min), 60 (± 5 min), 90 (± 5 min), and 120 (± 5 min) minutes post-dose. On Day 1, 
additional PK samples will be collected at 180 (± 5 min) and 240 (± 5 min) minutes. 
Whenever possible, the following PK parameters will be estimated by non-compartmental 
analysis: 
 Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) 
 Area under the plasma concentration-time curve from 0 to the time of last measurable 
concentration (AUC0-t) 
 Cmax 
 tmax 
 Elimination half-life (t1/2) 
 Apparent clearance of drug (CL/F) 
 Apparent volume of distribution based upon the terminal phase (Vz/F) 
Refer to the Study Laboratory Manual for additional instructions regarding obtaining and 
shipping samples. BioMarin will perform sample analysis, and samples may also be used for 
assay development.  
9.11.6 Safety Variables 
Safety will be evaluated by the incidence of AEs, SAEs, and clinically significant changes in 
vital signs, physical examination, ECG, imaging, and laboratory test results (urinalysis, 
chemistry, hematology). Additionally, imaging, hip monitoring, biomarker, immunogenicity, 
cortisol and prolactin levels, and physical measurement data will be utilized for safety-related 
reviews and analysis.  
9.11.6.1 
Adverse Events 
The occurrence of AEs will be assessed continuously from the time the subject receives study 
drug. The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10.2.1. Assessments of AEs will occur at the time points shown in the Schedule of 
Events (Table 9.1.1 and Table 9.1.2). Additionally, contact by a study staff member to the 
caregiver will be required every week for 6 months, and then every 2 weeks for the 
remainder of the study. During these contacts, study staff will ask the caregiver about dose 
administration and seek information on AEs and SAEs by specific questioning. Information 


 
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on all AEs and SAEs should be recorded in the subject’s medical record and on the AE 
eCRF.  


 
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9.11.6.2 
Procedures due to Achondroplasia 
All procedures/intervention/surgery due to underlying ACH will be recorded after informed 
consent is obtained and after the first administration of study drug, until 2 weeks after either 
the last administration of study drug or the Early Termination visit. If a subject is 
discontinued from the study prematurely, all procedures/intervention/surgery due to 
underlying ACH will be recorded at the Early Termination visit. 
9.11.6.3 
Clinical Laboratory Assessments 
Specific visits for obtaining clinical laboratory assessment samples are provided in 
Table 9.1.1 and Table 9.1.2. The scheduled clinical laboratory tests are listed in 
Table 9.11.6.3.1. Refer to the Study Reference Manual for instructions on obtaining and 
shipping samples. 
Any abnormal test results determined to be clinically significant by the Investigator should 
be repeated (at the Investigator’s discretion) until the cause of the abnormality is determined, 
the value returns to baseline or to within normal limits, or the Investigator determines that the 
abnormal value is no longer clinically significant. 
The investigator should assess all abnormal clinical results and include a comment on 
whether or not the result is clinically significant. Each clinically significant laboratory result 
should be recorded as an adverse event. 
The diagnosis, if known, associated with abnormalities in clinical laboratory tests that are 
considered clinically significant by the Investigator will be recorded on the AE eCRF. 
Table 9.11.6.3.1:  Clinical Laboratory Tests 
Blood Chemistry 
Hematology 
Urinalysis 
Albumin 
Hemoglobin 
Appearance 
Alkaline phosphatase, total 
Hematocrit 
Color 
ALT (SGPT) 
WBC count 
pH 
AST (SGOT) 
RBC count 
Specific gravity 
Direct bilirubin 
Platelet count 
Ketones 
Total bilirubin 
Differential cell count 
Protein 
BUN 
 
Glucose 
Calcium 
 
Bilirubin 
Chloride 
 
Nitrite 
Potassium 
 
Urobilinogen 
Sodium 
 
Hemoglobin 
Glucose 
 
 


 
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Blood Chemistry 
Hematology 
Urinalysis 
Bicarbonate 
 
 
Urine Chemistry  
Urine creatinine 
Urine sodium 
Urine potassium 
LDH 
Phosphorus 
 
 
Total protein 
25-hydroxy Vitamin D  
 
 
Creatinine 
Thyroid function (TSH, FT4; if either 
TSH and FT4 are abnormal then T3 
may be measured in addition) 
 
 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; FT4, free thyroxine; LDH, 
lactate dehydrogenase; RBC, red blood cell; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-
pyruvic transaminase; T3, triiodothyronine; TSH, thyroid stimulating hormone; WBC, white blood cell. 
 
9.11.6.4 
Other Laboratory Assessments  
Subjects will be asked to provide blood and urine at the times indicated in the Schedule of 
Events (Table 9.1.1 and Table 9.1.2).  Blood volume for testing has been reduced to the 
minimum necessary for adequate evaluation of efficacy and safety of BMN 111. 
For subjects who have not previously had genetic testing confirming diagnosis of ACH, 
molecular genetic diagnosis to identify the FGFR3 mutation (G346E, G375C, G380R, or 
“other”) will be performed.  If subjects had previous genetic testing, subjects must have a lab 
report from a certified laboratory with the study specific mutation documented. 
Salivary cortisol and serum prolactin will be collected at the times indicated in the Schedule 
of Events (Table 9.1.1). 
Scheduled biomarker and anti-BMN 111 antibody tests are listed in Table 9.11.6.4.1. 
Table 9.11.6.4.1:  Biomarkers and Anti-BMN 111 Antibodies 
Blood Special Chemistry 
Urine Biomarkers 
Exploratory bone metabolism biomarkers 
Exploratory bone metabolism urine biomarkers 
Genomic biomarkers 
BMN 111 pharmacodynamics biomarkers (cGMP) 
Anti-BMN 111 antibodies 
 
cGMP, cyclic guanosine monophosphate 
 


 
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9.11.6.5 
Vital Signs, Physical Examinations and Other Observations Related to Safety 
Vital signs assessed pre-dose will include seated systolic blood pressure (SBP) and diastolic 
blood pressure (DBP) measured in mm Hg, heart rate in beats per minute, respiration rate in 
breaths per minute, and temperature in degrees Celsius (°C). All treatment visits have 
pre-dose vital sign assessments. Post-dose measurements include heart rate and BP. For all 
dosing visits, assessment frequency is detailed in Table 9.11.6.5.1 (Schedule of Events, 
Table 9.1.1 and Table 9.1.2). 
At Screening, after at least 5 minutes of rest, subject’s BP is taken in sitting position. 
Then the subject will stand and BP will be taken again at approximately 1 and 3 minutes after 
standing. Left brachial arm should be the first method of assessment considered, and the 
same site should be used for blood pressure measurement in each subject throughout the 
study. The method and site of blood pressure measurement will be recorded and should be 
utilized consistently throughout the remainder of the study. 
At other visits, vital sign measurements are taken once per time point in a sitting position 
after at least 5 minutes of rest. Heart rate should be taken at each time point that BP is 
measured. When blood samples and BP assessments are scheduled at the same time or within 
the same time window, BP should be measured before blood samples are drawn. If a BP 
measurement must be taken after a blood draw, ensure adequate analgesia for the blood draw 
and wait several minutes before measuring BP. Pre-dose vital signs should always be taken 
and recorded prior to pre-dose blood draw. Vital signs may be monitored more frequently or 
for longer duration post-dose as clinically indicated.   
If a subject has signs potentially consistent with hypotension or a decrease in systolic BP of 
20 mm Hg or more from pre-dose systolic BP, blood pressure and heart rate (BP/HR) should 
be measured and recorded approximately every 15 minutes for the first hour and every 
30 minutes thereafter until the systolic BP returns to pre-dose systolic BP (or within the 
normal range for this subject as defined by PI) and signs (if present) resolve.  If the 
hypotension resolves within the first hour and returns to the normal range, additional BP 
monitoring as described above is not required. Detailed guidance for blood pressure 
measurements is provided in the Blood Pressure Instrument and Technique Guidelines.  


 
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Table 9.11.6.5.1:  Vital Sign Assessment Frequency  
Vital Sign Assessment Frequency Pre-Dose 
Screening 
After at least 5 min of rest, subject’s BP is taken in sitting position. Then the 
subject will stand and BP will be taken again at approximately 1 and 3 minutes 
after standing. 
All other visits 
After at least 5 min of rest, subject’s BP is taken 1 time in sitting position 
Assessment Frequency Post-Dose 
Dosing Visits 
0-1 hr post-dose 
1-2 hr. post-dose 
Days 1 
 
Day 2 -3 
Q15 min ((± 5 min) 
 
Q30 min ((± 5 min) 
Q 30 min (± 5 min) 
 
Q30 min ((± 5 min) 
All other dosing visits: vital 
sign measurements are taken 
once per time point in a 
sitting position after at least 5 
minutes of rest. 
Q 30 min (± 5 min); 
 for 1 hour 
 
 
9.11.6.6 
Mitigating the Risk of Potential Hypotension  
Study personnel and caregivers should be made aware of the potential risk of hypotension 
with BMN 111 administration.  Subjects must be well hydrated and at a minimum be fed 
prior to administration of BMN 111 or placebo.  If a recent acute illness associated with 
volume depletion (e.g., nausea, vomiting, diarrhea) has not completely resolved prior to the 
first dose of BMN 111 or placebo, BMN 111 or placebo dosing may be delayed until 
hydration status has improved (up to the maximum period allowed for the screening 
window). 
Caregivers should be trained to observe and recognize the signs of dehydration (e.g. from 
fever, vomiting, diarrhea, etc.) and contact the investigator prior to BMN 111 or placebo 
administration if dehydration is suspected. Site personnel and caregivers should be trained to 
identify the signs of hypotension and, if they occur, should implement first-aid strategies at 
the discretion of the investigator such as having the subject lie down supine, elevating the 
lower extremities, and administering fluids. For guidelines on how to report adverse events 
associated with hypotension, refer to Section 10.3.1.4. 


 
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9.11.6.7 
Electrocardiography 
A standard 12-lead ECG will include heart rate, rhythm, intervals, axis, conduction defects, 
and anatomic abnormalities. The time of collection will be recorded. ECGs should be 
performed in triplicate with the subject supine at the visits indicated in the Schedule of 
Events (Table 9.1.1 and Table 9.1.2). For study day visits in which study drug is given, ECGs 
will be performed post-dose. For Day 1, in addition to post-dose, ECGs will be performed 
pre-dose.  If clinically significant abnormalities are noted, the investigator or designee is 
required to assess whether it is appropriate for the subject to continue in the study. 
9.11.6.8 
Hip Clinical Assessment 
The hip clinical assessment should be completed by an appropriately qualified physical 
therapist or a physician (MD) i.e., the investigator or the sub-investigator at the time points 
indicated in the Schedule of Events (Table 9.1.1 and Table 9.1.2). Medical history will be 
obtained to evaluate for hip, thigh, or knee pain, or change in gait. The physical exam 
(including observation of gait when possible) identifies and evaluates any changes in hip 
function or pain with assessment of active and passive range of motion. Changes from 
baseline may trigger further evaluation based on the investigator’s clinical assessment, which 
may include hip imaging and/or orthopedic consultation. If findings on clinical hip exam are 
determined to be clinically significant by the investigator and in consultation with Sponsor’s 
Medical Monitor and orthopedic specialist (if needed), the DMC will be notified of AEs 
resulting from clinically significant abnormal hip monitoring assessments. DMC may 
provide recommendations as to if/when BMN 111 or placebo treatment should be 
temporarily or permanently discontinued.  
9.11.6.9 
Pediatric Blood Volume 
Clinical labs and immunogenicity samples are necessary to perform to adequate safety 
assessment in this study.  The objectives of testing pharmacodynamics biomarkers are to 
demonstrate biologic activity of BMN 111 and to understand the impact of immune 
responses on drug activity; and for blood biomarkers, to investigate the effects of treatment 
on changes in bone metabolism and endogenous CNP production. 
To minimize blood collection volumes, assay technologies were chosen that are capable of 
sensitively detecting analytes using the lowest possible volume of blood for analysis.  
Additionally, assays capable of detecting analytes in urine rather than blood have been 
selected where possible. 


 
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9.11.6.10 Anti- BMN 111 Immunogenicity Assessments and IgE Testing 
Subjects randomized to receive BMN 111 or placebo will undergo immunogenicity testing. 
Blood (serum) samples for immunogenicity assessments will be collected at the time points 
indicated in the Schedule of Events (Table 9.1.1), and testing performed using validated 
assays. Neutralizing antibody (NAb) testing will be performed on Baseline and TAb positive 
samples drawn from subjects weighing ≥ 7.0 kg and waived for subjects < 7.0 kg.  
Scheduled samples will be tested in one or more of the following assessments: 
 Anti- BMN 111 total antibody (TAb) 
 Anti-BMN 111 antibody cross-reactive with endogenous CNP, ANP, and BNP (TAb) 
 Anti- BMN 111 NAb 
Testing for the presence of cross-reactive antibodies that bind to endogenous CNP, ANP, or 
BNP and for the presence of BMN 111 NAbs will be performed on baseline samples and 
anti- BMN 111 TAb-positive samples. Baseline NAb sample and cross-reactive TAb sample 
testing will be done at any time prior to the end of study. 
9.11.6.11 HPA Axis Assessments 
To address potential effects of BMN 111 on activation of the hypothalamic pituitary adrenal 
(HPA) axis, assessment of salivary cortisol and serum Prolactin levels will be analyzed at the 
time points indicated in the Schedule of Events (Table 9.1.1). Both tests will be done at 
Baseline, Week 26, and Week 52.  
9.11.6.12 Ad Hoc Safety Assessments 
Samples for total IgE and drug-specific IgE testing will be drawn on Day 1 and in the event 
of a significant hypersensitivity AE, or at the discretion of the investigator and/or BioMarin. 
A significant hypersensitivity AE is defined as an event that is grade 3 or higher, requires 
temporary or permanent cessation of BMN 111, or is determined to be significant at the 
discretion of investigator and/or BioMarin (excluding reactions that are solely a localized 
injection site reaction). If a hypersensitivity AE occurs, an unscheduled safety visit should 
occur no later than 48 hours of the start of the reaction, including inspection of the injection 
site and clinical laboratory tests.  
Blood (serum) samples should be collected and tested in one or more of the following 
assessments: 
  Drug-specific IgE 
 Total IgE 


 
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 Serum tryptase 
If feasible, a sample for drug-specific IgE should be drawn no sooner than 8 hours after the 
event start time or before the next dose. A sample for total IgE and serum tryptase should 
also be drawn within 1 hour of the start of the event when possible or during the unscheduled 
safety visit.  
A localized injection site reaction is defined as skin signs or signs restricted to one affected 
primary location, i.e., hives, wheals, or swelling or an area of erythema, redness, induration, 
pain, or itching at or near the site of injection. Management of such localized reactions 
should be determined by the investigator’s clinical judgment in consultation with the 
Sponsor’s Medical Monitor (if warranted). 
9.11.6.13 Unscheduled Safety Visits 
Unforeseen circumstances may arise in which an unscheduled visit may be needed. In such a 
case, the procedures performed at the unscheduled visit will be completed on a case-by-case 
basis. 


 
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10 
REPORTING ADVERSE EVENTS 
10.1 
Safety Parameters and Definitions 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified hematology, clinical chemistry, and urinalysis variables; 
measurement of protocol-specified vital signs; and other protocol-defined events of special 
interest that are deemed critical to the safety evaluation of the study drug. 
10.1.1 Adverse Events 
For this protocol, a reportable adverse event (AE) is any untoward medical occurrence 
(e.g., sign, symptom, illness, disease or injury) in a subject administered the study drug or 
other protocol-imposed intervention, regardless of attribution. This includes the following: 
 AEs not previously observed in the subject that emerge during the course of the 
study. 
 Pre-existing medical conditions judged by the Investigator to have worsened in 
severity or frequency or changed in character during the study. 
 Complications that occur as a result of non-drug protocol-imposed interventions 
(eg, AEs related to screening procedures, medication washout, or no-treatment 
run-in). 
An adverse drug reaction is any AE for which there is a reasonable possibility that the 
study-drug caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the study-drug and the AE. 
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series 
of terms relating to a diagnosis. 
10.1.2 Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose meets 
1 or more of the following criteria: 
 Is fatal 
 Is life threatening  
Note: Life-threatening refers to an event that places the subject at immediate risk of 
death. This definition does not include a reaction that, had it occurred in a more 
severe form, might have caused death. 
 Requires or prolongs inpatient hospitalization.  Hospitalization for less than 24 hours 
will not be considered to be an SAE.  


 
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 Results in persistent or significant disability or incapacity 
 Is a congenital anomaly or birth defect in the child or fetus of a subject exposed to IP 
prior to conception or during pregnancy 
 
Is an important medical event or reaction – that, based on medical judgment, may 
jeopardize the subject or require intervention to prevent one of the above 
consequences (e.g. anaphylaxis) 
All adverse events that do not meet any of the criteria for SAEs should be regarded as 
non-serious AEs. 
10.1.3 Events of Special Interest (EOSI)  
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, 
irrespective of seriousness, severity or causality:  
 
Fracture 
 
Slipped Capital Femoral Epiphysis (SCFE) 
 
Avascular necrosis or Osteonecrosis 
10.2 
Methods and Timing for Capturing and Assessing Safety Parameters 
10.2.1 Adverse Event Reporting Period 
For subjects enrolled in Cohort 1 ( ≥  24 to < 60 months old) and Cohort 2 ( ≥ 6 to   < 24 months 
old), the study AE reporting period is as follows: after informed consent but prior to initiation 
of study treatment, only SAEs associated with any protocol-imposed interventions will be 
reported.  After informed consent is obtained and the first administration of study drug, all 
non-serious AEs and SAEs reporting period begins and continues until 4 weeks following 
either the last administration of study drug or the early termination visit, whichever is longer 
(refer to Section 12.1.11). The criteria for determining, and the reporting of, SAEs is 
provided in Section 10.1.2.  For subjects enrolled in Cohort 3 (0 to  < 6 months old), AE 
collection period begins after screening. 
10.2.2 Eliciting Adverse Events 
Investigators will seek information on AEs and SAEs and EOSI, if applicable at each subject 
contact by specific questioning and, as appropriate, by examination.  Information on all AEs 
and SAEs and EOSI, if applicable should be recorded in the subject’s medical record and on 
the AE Electronic Case Report Form (eCRF). 


 
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10.2.3 Assessment of Seriousness, Severity, and Causality 
The Investigator or qualified designee responsible for the care of the subject will assess AEs 
for severity, relationship to study drug, and seriousness (refer to Section 10.1.2 for SAE 
definitions).  These assessments should be made by a study clinician with the training and 
authority to make a diagnosis (e.g., MD/DO, physician’s assistant, nurse practitioner, or 
DDS). 
10.2.3.1 
Seriousness 
The investigator will assess if an AE should be classified as “serious” based on the 
seriousness criteria enumerated in Section 10.1.2.  Seriousness serves as a guide for defining 
regulatory reporting obligations. 
10.2.3.2 
Severity 
Severity (as in mild, moderate, or severe headache) is not equivalent to seriousness, which is 
based on subject/event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning.  The severity of each will be assessed using the 
defined categories in Table 10.2.3.2.1. 
The Investigator or qualified designee will determine the severity of each AE and SAE, and 
EOSI using the NCI CTCAE v4. Adverse events that do not have a corresponding CTCAE 
term will be assessed according to the general guidelines for grading used in the CTCAE v4 
as stated below. 


 
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Table 10.2.3.2.1:  Adverse Event Grading (Severity) Scale 
Grade 
Description 
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
2 
Moderate: minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)a 
3 
Severe or medically significant but not immediately life-threatening: hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADLb 
4 
Life threatening or debilitating: consequences; urgent 
intervention indicated 
Grade 4 and 5 AEs 
should always be 
reported as SAEs 
5 
Death related to AE 
a Instrumental ADL refer to the following examples: preparing meals, shopping for groceries or clothes, using the 
telephone, managing money. 
b Self-care ADL refer to the following examples: bathing, dressing and undressing, feeding oneself, using the toilet, 
taking medications, not bedridden. 
 
10.2.3.3 
Causality 
The Investigator will determine the relationship of an AE to the study drug and will record it 
on the source documents and AE eCRF.  To ensure consistency of causality assessments, 
Investigators should apply the guidance in Table 10.2.3.3.1. 


 
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Table 10.2.3.3.1:  Causality Attribution Guidance 
Relationshipa 
Description 
Not Related 
 
Exposure to the IP has not occurred 
OR 
 
The administration of the IP and the occurrence of the AE are not 
reasonably related in time  
OR 
 
The AE is considered likely to be related to an etiology other than the use 
of the IP; that is, there are no facts, evidence, or arguments to suggest a 
causal relationship to the IP. 
Related 
 
The administration of the IP and the occurrence of the AE are reasonably 
related in time 
AND 
 
The AE could possibly be explained by factors or causes other than 
exposure to the IP 
                                                  OR 
 
 
The administration of IP and the occurrence of the AE are reasonably 
related in time  
AND 
 
The AE is more likely explained by exposure to the IP than by other 
factors or causes. 
Factors suggestive of a causal relationship could include (but are not limited to): 
 Plausible temporal relationship 
 Absence of alternative explanations 
 Rarity of event in a given subject or disease state 
 Absence of event prior to study drug exposure 
 Consistency with study product pharmacology 
 Known relationship to underlying mechanism of study drug action 
 Similarity to adverse reactions seen with related drug products 
 Abatement of AE with discontinuation of study drug, and/or recurrence of AE with 
reintroduction of study drug 
The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the Investigator’s assessment of causality for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities. 


 
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10.3 
Procedures for Recording Adverse Events 
10.3.1 Recording Adverse Events on a eCRF 
Investigators should use precise medical terminology when recording AEs or SAEs on an 
eCRF.  Avoid colloquialisms and abbreviations. 
Record only one diagnosis, sign, or symptom per event field on the AE eCRF (e.g., nausea 
and vomiting should not be recorded in the same entry, but as 2 separate entries). 
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor to the 
original terms entered on the eCRF, using MedDRA (Medical Dictionary for Regulatory 
Activities) terminology. 
10.3.1.1 
Diagnosis versus Signs and Symptoms 
Using accepted medical terminology, enter the diagnosis (if known).  If not known, enter 
sign(s) and/or symptom(s).  If a diagnosis subsequently becomes available, then this 
diagnosis should be entered on the AE form, replacing the original entries where appropriate. 
10.3.1.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events) should be 
identified by their primary cause.  For example, if severe diarrhea is known to have resulted 
in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the eCRF.  
However, medically important events that may be linked and/or separated in time should be 
recorded as independent events on the eCRF.  For example, if severe hemorrhage leads to 
renal failure, both events should be recorded separately on the eCRF. 
10.3.1.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between subject 
evaluation time points.  Such an event should be recorded only once on the eCRF unless its 
severity increases or decreases (in which case it should be recorded again on the AE eCRF). 
A recurrent AE is one that occurs and resolves between subject evaluation time points, but 
then subsequently recurs.  All recurrences of the AE should be recorded on the AE eCRF. 
10.3.1.4 
Hypotension 
If an asymptomatic drop in blood pressure meets the protocol definition of AE per clinical 
judgment of the reporter, report the event as “blood pressure decreased.”  If the drop in blood 
pressure is associated with signs or symptoms, complete the symptomatic hypotension eCRF 
and use the following guidance to report the corresponding AE eCRF: If a unifying diagnosis 


 
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is available to explain the event of hypotension, report the diagnosis as an AE and capture 
signs and symptoms on the symptomatic hypotension eCRF page. If no other unifying 
diagnosis is available, report “hypotension” as the event and capture signs and symptoms on 
the symptomatic hypotension eCRF page.  
10.3.1.5 
Injection Site Reactions 
If an injection site reaction is associated with a single sign or symptom, report the event on 
AE eCRF page (e.g., redness at injection site, AE is injection site redness). If the injection 
site reaction is associated with multiple signs or symptoms, report injection site reaction as 
the adverse event on the AE page, and individual signs and symptoms will be reported on the 
ISR eCRF page (e.g., if the subject experiences redness and induration, report “Injection site 
reaction” on the AE page, and in the corresponding Injection eCRF page, report erythema 
and induration).  If the injection site reaction appears after 24 hours, add “delayed” to the 
term used to describe the event. 
10.3.1.6 
Abnormal Laboratory Values 
Laboratory test results will be recorded on the laboratory results pages of the eCRF, or 
appear on electronically produced laboratory reports submitted directly from the central 
laboratory, if applicable. 
Any laboratory result abnormality fulfilling the criteria for a SAE should be reported as such, 
in addition to being recorded as an AE in the eCRF. 
A clinical laboratory abnormality should be documented as AE if it is not otherwise refuted 
by a repeat test to confirm the abnormality and any one or more of the following conditions 
is met: 
 Accompanied by clinical symptoms 
 Leading to a change in study medication (e.g. dose modification, interruption or 
permanent discontinuation)  
 Requiring a change in concomitant therapy (e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment). 
 The abnormality suggests a disease and/or organ toxicity 
 The abnormality is of a degree that requires active management (e.g., change of dose, 
discontinuation of study drug, more frequent follow-up assessments, further 
diagnostic investigation, etc.) 


 
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This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria. 
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 
explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported.  
10.3.1.7 
Pre-existing Conditions 
A pre-existing condition is one that is present at the start of the study.  Such conditions 
should be recorded as medical history on the appropriate eCRF. 
A pre-existing condition should be recorded as an AE or SAE during the study only if the 
frequency, intensity, or character of the condition worsens during the study period.  It is 
important to convey the concept that a pre-existing condition has changed by including 
applicable language in the verbatim description of the event (e.g., more frequent headaches). 
10.3.1.8 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition (refer to Section 10.3.1.7).  During the study, any new clinically significant 
findings and/or abnormalities discovered on physical examination that meet the definition of 
an AE (or an SAE) must be recorded and document as an AE or SAE on the AE eCRF. 
10.3.1.9 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol (refer to 
Section 10.1.2). 
There are some hospitalization scenarios that do not require reporting as an SAE when there 
is no occurrence of an AE.  These scenarios include planned hospitalizations or prolonged 
hospitalizations to: 
 Perform a protocol-mandated efficacy measurement 
 Undergo a diagnostic or elective surgical procedure for a pre-existing medical 
condition that has not changed 
 Receive scheduled therapy (study drug or otherwise) for the study indication 


 
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10.3.1.10 Deaths 
All deaths that occur during the AE reporting period (refer to Section 10.2.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the Sponsor as an 
SAE. 
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF.  If the cause of death 
is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the eCRF.  If the death is attributed to progression of the 
disease or condition being studies, record “-” as the SAE term on the eCRF. 
10.4 
Reporting Requirements 
The Sponsor is responsible for identifying, preparing, and reporting all suspected unexpected 
serious adverse reactions (SUSARs) to the relevant competent authorities, ethics committees, 
and investigators in accordance with requirements identified in the Clinical Trials 
Regulations. 
10.4.1 Expedited Reporting Requirements 
All SAEs and EOSI, if applicable that occur during the course of the AE Reporting Period 
(refer to Section 10.2.1), whether or not considered related to study drug, must be reported by 
entering the information in the AE eCRF and submitting to BPV within 24 hours of the site 
becoming aware of the event.  Each SAE must also be reported on the appropriate eCRF.  
Investigators should not wait to collect information that fully documents the event before 
notifying BPV of an SAE.  BioMarin may be required to report certain SAEs to regulatory 
authorities within 7 calendar days of being notified about the event; therefore, it is important 
that Investigators submit any information requested by BioMarin as soon as it becomes 
available. 
If the electronic data capture (EDC) is unavailable, all SAEs should be reported to BPV by 
completing the SAE Report Form and faxing or emailing the completed form to BPV within 
24 hours of the site becoming aware of the event. Once the EDC is available, the information 
should be entered in the AE eCRF.  
The reporting period for SAEs begins after informed consent is obtained and continues until 
4 weeks following either the last administration of study drug or study 
discontinuation/termination, whichever is longer.  


 
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10.4.2 IRB Reporting Requirements 
Reporting of SAEs to the IRB will be done in compliance with the standard operating 
procedures and policies of the IRB and with applicable regulatory requirements. Adequate 
documentation must be obtained by BioMarin showing that the IRB was properly and 
promptly notified as required. 
10.5 
Follow-up of Subjects after Adverse Events 
The Investigator should follow all unresolved AEs/SAEs until the events are resolved or have 
stabilized, the subject is lost to follow-up, or it has been determined that the study treatment 
or participation is not the cause of the AE/SAE.  Resolution of AEs and SAEs (with dates) 
should be documented on the AE eCRF and in the subject’s medical record to facilitate 
source data verification. 
For some SAEs, the Sponsor may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details (eg, hospital discharge summary, consultant 
report, or autopsy report) deemed necessary to appropriately evaluate the SAE report. 
10.6 
Post-Study Adverse Events 
At the last scheduled visit, the Investigator should instruct each subject to report, to the 
Investigator and/or to BPV directly, any subsequent SAEs that the subject’s personal 
physician(s) believes might be related to prior study treatment. 
The Investigator should notify the study Sponsor of any death or SAE occurring at any time 
after a subject has discontinued or terminated study participation, if the Investigator believes 
that the death or SAE may have been related to prior study treatment. The Sponsor should 
also be notified if the Investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a subject who participated in 
this study.  
10.7 
Urgent Safety Measures 
The regulations governing clinical trials state that the sponsor and Investigator are required to 
take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
subjects, the sponsor and the Investigator shall take appropriate urgent safety measures to 


 
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protect the subjects against any immediate hazard. The sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
IRB/EC/REB is notified at the same time.”  
The Sponsor is responsible for identifying, preparing and reporting all SUSARs to the 
relevant competent authorities, ethics committees and investigators in accordance with the 
requirements identified in the Clinical Trials Regulations. 
The reporting period for these events which may require the implementation of urgent safety 
measures is the period from the time of signing of the ICF through the completion of the last 
study visit or at the Early Termination Visit (ETV). Investigators are required to report any 
events which may require the implementation of urgent safety measures to BioMarin within 
24 hours. 
Examples of situations that may require urgent safety measures include discovery of the 
following: 
 
Immediate need to revise the IP administration (eg, modified dose amount or frequency 
not defined in protocol) 
 
Lack of study scientific value, or detrimental study conduct or management 
 
Discovery that the quality or safety of the IP does not meet established safety 
requirements 


 
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10.8 
BioMarin Pharmacovigilance Contact Information 
Contact information for BioMarin Pharmacovigilance is as follows: 
BioMarin Pharmaceutical Inc. 
Address 
105 Digital Drive 
 
 
Novato, CA 94949 
Phone:  
 
Fax: 
 
 
E-mail: 
drugsafety@bmrn.com 
The Investigator is encouraged to discuss with the medical monitor any AEs for which the 
issue of seriousness is unclear or questioned. Contact information for the medical monitor is 
as follows: 
Name:  
 MD, PhD 
Address: 
10 Bloomsbury Way 
 
 
London WC1A 2SL 
Phone:  
 
Fax: 
 
 
E-mail: 
 
 
PI
PI
PI
PI
PI
PI


 
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11 
APPROPRIATENESS OF MEASUREMENTS 
The parameters to be evaluated in this study reflect the combined experience in the clinical 
study 111-202 and reflect the need to further define the efficacy and safety profile of 
BMN 111 in the context of achondroplasia (ACH), a complex skeletal dysplasia disorder 
with multiple clinical manifestations. 
The efficacy parameters to be evaluated in this study reflect the sponsor’s experience in the 
clinical study 111-202 and of previous studies of approved growth products (Kemp, 2009; 
Bright, 2009).  Evaluation of the parameters proposed in this study will document the effect 
of BMN 111 treatment on AGV in young children with ACH and are relevant to assessing 
the medical complications of ACH in this patient population.   
The PK assessments in this study are generally recognized as reliable, accurate, and relevant. 
Bone-related biomarkers and other biochemical markers of the pharmacological activity of 
BMN 111 in the blood or urine are secondary assessments.  Genomic biomarkers are 
exploratory assessments. 
 
 


 
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12 
STUDY PROCEDURES 
An ICF must be signed and dated by subject’s legally authorized, the investigator or 
designee, and witness (if required) before any study-related procedures are performed. 
12.1 
Treatment Visit(s) 
12.1.1 Screening/Baseline Day -30 to Day -1  
 Medical history 
 Parental height 
 Diagnostic genetic testing to confirm achondroplasia (if needed) 
 Physical examination 
 Weight 
 Vital signs 
 Electrocardiogram 
 Echocardiogram 
 Anthropometric measurements 
 Clinical laboratory assessments (hematology, chemistry, urinalysis) 
 Thyroid function tests 
 Vitamin D, 25-hydroxy test 
 Salivary cortisol 
 Serum prolactin 
 Bone metabolism blood biomarkers 
 Screening baseline hip assessment 
 MRI brain/skull 
 Sleep study 
 Clinical outcome assessment: Bayley-III  
 Clinical outcome assessment: WeeFIM  
 Clinical outcome assessment: ITQOL 
 Clinical outcome assessment: CBCL 
 DXA 


 
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 AP and lateral X-rays of spine 
 AP X-rays of lower extremities  
 Clinical photographs (optional)  
 Concomitant medications 
12.1.2 Day 1 and Week 13 (±7d) 
 Physical examination 
 Weight 
 Vital signs 
 Electrocardiogram 
 Anthropometric measurements 
 Pharmacokinetics assessments 
 Anti-BMN 111 immunogenicity 
 Bone metabolism urine biomarkers 
 BMN 111 pharmacodynamic urine biomarkers 
 Urine chemistry 
 Collection of ACH-related symptoms, tests, and interventions  
 BMN 111 or placebo administration 
 BMN 111 or placebo accountability  
 Adverse events 
 Concomitant medications 
 Phone call or home health visit 
12.1.3 Days 2 and 3 
 Physical examination 
 Weight 
 Vital signs 
 Bone metabolism urine biomarkers 
 BMN 111 pharmacodynamic urine biomarkers 
 Urine chemistry 
 Collection of ACH-related symptoms, tests, and interventions  


 
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 BMN 111 or placebo administration 
 BMN 111 or placebo accountability  
 Adverse events 
 Concomitant medications 
 Phone call or home health visit 
12.1.4 Day 8 (±1d) and Week 20 (±7d) 
 Physical examination 
 Weight 
 Vital signs 
 Electrocardiogram 
 Clinical laboratory assessments (hematology, chemistry, urinalysis) 
 Bone metabolism blood biomarkers 
 Collection of ACH-related symptoms, tests, and interventions  
 BMN 111 or placebo administration 
 BMN 111 or placebo accountability  
 Adverse events 
 Concomitant medications 
 Phone call or home health visit 
12.1.5 Week 3 (±7d) 
 Physical examination 
 Weight 
 Vital signs 
 Clinical laboratory assessments (hematology, chemistry, urinalysis) 
 Bone metabolism urine biomarkers 
 BMN 111 pharmacodynamic urine biomarkers 
 Urine chemistry 
 Collection of ACH-related symptoms, tests, and interventions  
 BMN 111 or placebo administration 
 BMN 111 or placebo accountability  


 
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 Adverse events 
 Concomitant medications 
 Phone call or home health visit 
12.1.6 Week 6 (±7d) 
 Physical examination 
 Weight 
 Vital signs 
 Electrocardiogram 
 Anthropometric measurements 
 Clinical laboratory assessments (hematology, chemistry, urinalysis) 
 Genomic biomarkers (optional) 
 Bone metabolism blood biomarkers 
 Collection of ACH-related symptoms, tests, and interventions  
 BMN 111 or placebo administration 
 BMN 111 or placebo accountability  
 Adverse events 
 Concomitant medications 
 Phone call or home health visit 
12.1.7 Week 26 (±7d) 
 Physical examination 
 Weight 
 Vital signs 
 Electrocardiogram 
 Anthropometric measurements 
 Salivary cortisol 
 Serum prolactin  
 Pharmacokinetics assessments 
 Anti-BMN 111 immunogenicity 
 Bone metabolism urine biomarkers 


 
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 BMN 111 pharmacodynamic urine biomarkers 
 Urine chemistry 
 Hip monitoring 
 Sleep study 
 Clinical outcome assessment: Bayley-III  
 Clinical outcome assessment: WeeFIM  
 Clinical outcome assessment: ITQOL 
 Clinical outcome assessment: CBCL 
 Collection of ACH-related symptoms, tests, and interventions  
 BMN 111 or placebo administration 
 BMN 111 or placebo accountability  
 Adverse events 
 Concomitant medications 
 Phone call or home health visit 
12.1.8 Week 39 (±7d) 
 Physical examination 
 Weight 
 Vital signs 
 Electrocardiogram 
 Anthropometric measurements 
 Clinical laboratory assessments (hematology, chemistry, urinalysis) 
 Pharmacokinetics assessments 
 Bone metabolism blood biomarkers 
 Collection of ACH-related symptoms, tests, and interventions  
 BMN 111 or placebo administration 
 BMN 111 or placebo accountability  
 Adverse events 
 Concomitant medications 
 Phone call or home health visit 


 
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12.1.9 Week 52 (±7d) 
 Physical examination 
 Weight 
 Vital signs 
 Electrocardiogram 
 Anthropometric measurements 
 Clinical laboratory assessments (hematology, chemistry, urinalysis) 
 Thyroid function tests 
 Vitamin D, 25-hydroxy test 
 Salivary cortisol 
 Serum prolactin  
 Pharmacokinetics assessments 
 Anti-BMN 111 immunogenicity 
 Genomic biomarkers (optional) 
 Bone metabolism urine biomarkers 
 BMN 111 pharmacodynamic urine biomarkers 
 Urine chemistry 
 Hip monitoring 
 MRI brain/skull 
 Sleep study 
 Clinical outcome assessment: Bayley-III  
 Clinical outcome assessment: WeeFIM  
 Clinical outcome assessment: ITQOL 
 Clinical outcome assessment: CBCL 
 DXA 
 AP and lateral X-rays of spine 
 AP X-rays of lower extremities  
 Clinical photographs (optional)  
 Collection of ACH-related symptoms, tests, and interventions  


 
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 BMN 111 or placebo administration 
 BMN 111 or placebo accountability  
 Adverse events 
 Concomitant medications 
 Phone call or home health visit 
12.1.10  Week 56 Safety Follow-up (±7d) 
 Physical examination 
 Vital signs 
 Electrocardiogram 
 Collection of ACH-related symptoms, tests, and interventions  
 Adverse events 
 Concomitant medications 
12.1.11  Early Termination Visit 
 Physical examination 
 Weight 
 Vital signs 
 Electrocardiogram 
 Anthropometric measurements 
 Clinical laboratory assessments (hematology, chemistry, urinalysis) 
 Salivary cortisol 
 Serum prolactin  
 Anti-BMN 111 immunogenicity 
 Bone metabolism blood biomarkers 
 Bone metabolism urine biomarkers 
 BMN 111 pharmacodynamic urine biomarkers 
 Urine chemistry 
 Hip monitoring 
 MRI brain/skull (obtained at the early termination visit only if the previous 
assessment was done more than 3 months prior to early termination) 


 
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 Sleep study (obtained at the early termination visit only if the previous assessment 
was done more than 3 months prior to early termination) 
 Clinical outcome assessment: Bayley-III  
 Clinical outcome assessment: WeeFIM  
 Clinical outcome assessment: ITQOL 
 Clinical outcome assessment: CBCL 
 DXA 
 AP and lateral X-rays of spine (obtained at the early termination visit only if the 
previous assessment was done more than 6 months prior to early termination) 
 AP X-rays of lower extremities (obtained at the early termination visit only if the 
previous assessment was done more than 6 months prior to early termination) 
 Clinical photographs (optional)  
 Collection of ACH-related symptoms, tests, and interventions  
 BMN 111 or placebo accountability  
 Adverse events 
 Concomitant medications 
12.2 
Observational Period for Cohort 3 (Infants between birth and  < 3 months old 
[0 days to   < 13 weeks]) 
12.2.1 Screening Visit 
 Medical history, including growth history and ACH-related history 
 Concomitant medications 
 Physical examination 
 Vital signs 
 Vitamin D, 25-hydroxy 
 Alkaline phosphatase 
 Bone metabolism blood biomarkers 
 Bone metabolism urine biomarkers 
 Adverse events 
12.2.2 Day 1 (Month 0) 
 Concomitant medications 


 
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 Vital signs 
 Anthropometric measurements 
 Genomic biomarkers (optional) 
 Weight 
 Body mass index (calculated) 
 Clinical outcome assessment: Bayley-III  
 Clinical outcome assessment: ITQOL  
 Adverse events 
12.2.3 3 Months (± 10 days) 
 Concomitant medications 
 Vital signs 
 Anthropometric measurements 
 Vitamin D, 25-hydroxy 
 Alkaline phosphatase 
 Bone metabolism blood biomarkers 
 Bone metabolism urine biomarkers 
 Weight 
 Body mass index (calculated) 
 Adverse events 


 
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13 
DATA QUALITY ASSURANCE 
BioMarin personnel or designees will visit the study site prior to initiation of the study to 
review with the site personnel information about the IP, protocol and other regulatory 
document requirements, any applicable randomization procedures, source document 
requirements, eCRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs.  
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on eCRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records.  
Sites will enter study data into eCRFs into the study EDC system.  Data Quality Control will 
be performed by BioMarin Clinical Data Management or designee through implementation 
of quality control checks specified in the study data management plan and edit check 
specifications.  


 
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14 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE  
14.1 
Statistical and Analytical Plans 
The statistical analysis plan (SAP) will provide additional details on the planned statistical 
analysis. Unless otherwise stated, all analyses will be performed using SAS v. 9.4. 
14.1.1 Interim Analyses 
An interim analysis will be carried out to support NDA/MAA filing. The report will be 
provided by a third party to assure that the study team, subjects, and investigators have no 
access to the individual subject treatment allocation. 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data 
Because the completeness of the data affects the integrity and accuracy of the final study 
analysis, every effort will be made to ensure complete, accurate and timely data collection 
and, therefore, avoid missing data. In addition, a subject who prematurely discontinues study 
drug should be asked if they are willing to continue to participate in the study assessments for 
remaining duration of the study, as long as in the judgment of the investigator such continued 
participation would not detrimentally affect the health, safety, or welfare of the subject. 
No missing data will be imputed for any analysis, except for unless otherwise specified for 
the efficacy analyses or for the missing dates for AEs and concomitant medications. Missing 
dates or partially missing dates will be imputed conservatively to ensure that an AE is 
considered treatment emergent and has the longest possible duration, if the partial 
information available indicates that the AE is likely treatment emergent.  
Additional details regarding the handling of missing data will be provided in the SAP. 
14.2 
Safety Analysis 
The safety analysis will be performed on safety population as defined in Section 14.7.2 and 
will be considered descriptive. 
All AEs will be coded using the most current version of MedDRA will be used by the 
Sponsor to assign system organ class and preferred term classification to events and diseases, 
based on the original terms entered on the CRF. 
All AEs will be coded using MedDRA. The incidence of AEs will be summarized by system 
organ class, preferred term, relationship to study treatment (as assessed by investigator), and 
severity. All AEs, including SAEs and AEs that lead to permanent discontinuation from the 
study and from the study treatment, will be listed. Hypersensitivity reactions and 


 
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symptomatic hypotension are of interest, and the percentage of subjects who report these AEs 
will be presented. Hypersensitivity reactions will be defined in the SAP. 
Clinical laboratory data will be summarized by the type of laboratory test. For each clinical 
laboratory test, descriptive statistics will be provided on baseline as well as all subsequent 
visits. 
All other safety measures including laboratory tests, vital signs, ECG, echocardiogram, hip 
clinical assessment, and concomitant medication data will also be summarized descriptively. 
Data summaries will be presented by treatment group (when applicable) for each cohort and 
overall. All safety results will be listed. 
14.3 
Efficacy Analysis 
Efficacy analysis will be performed on the efficacy population as defined in Section 14.7.1. 
Efficacy endpoints include length/height AGV and length/height standard score (Z-score) at 
Week 52.  
For a given interval [Date1, Date2], the AGV is defined as follows: 
AGV ൌ Length/standing height at Day 2 െ Length/standing height at Day 1
Interval Length ሺDaysሻ
 ൈ365.25 
 
where the interval length in days is calculated as Date2 – Date1. AGV will be calculated for 
the following visits/intervals: 
 Baseline: [Date of last length/height measurement in study 901 at least 6 months prior 
to screening visit in study 206, Date of Day 1] 
 Week 13: [Date of Day 1, Date of Week 13] 
 Week 26: [Date of Day 1, Date of Week 26] 
 Week 39: [Date of Day 1, Date of Week 39] 
 Week 52 (12-month): [Date of Day 1, Date of Week 52] 
The baseline of the AGV is established in the natural history study of Study111-901, based 
on the standing height measurements in the last 6 months prior to enrollment to Study 
111-206. AGV will be summarized using descriptive statistics (mean, SD, median, minimum, 
and maximum). Results will be summarized by treatment group and cohort. 


 
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The measurement of length/standing height will be converted to age-and sex-appropriate 
standard score (SDS), also referred to as Z-score, by comparison with normal reference 
standards (not ACH). The Z-score will be summarized similarly to growth velocity. 
Comparisons between treatment groups by cohort on these variables will be carried out 
where appropriate. Statistical comparisons will be considered descriptive. Additional details 
regarding efficacy analysis will be provided in the SAP. 
14.4 
Pharmacokinetic Analyses  
Subjects randomized to receive BMN 111 or placebo will undergo pharmacokinetic testing. 
For subjects randomized to BMN 111, PK parameters generated over the course of the study 
will be evaluated and summarized with descriptive statistical measures (mean, standard 
deviation, CV%, min, median and max). Correlative analyses of some of the PK parameters 
with efficacy, safety and immunogenicity measures may be conducted. 
14.5 
Immunogenicity Analysis 
Immunogenicity will be summarized as change from baseline as well as by study time point 
in subjects randomized to receive BMN 111 or placebo.  Results will be summarized as 
incidence and titer for all cohorts. Additionally, immunogenicity may be assessed for 
correlations with measures of safety, PK, and efficacy. 
14.6 
Determination of Sample Size 
Approximately 70 subjects age 0 to  < 60 months at study entry will participate in this study. 
No formal sample size calculations were performed. The number of subjects is considered 
appropriate to evaluate the safety and efficacy of BMN 111 in the target population.  
14.7 
Analysis Populations 
14.7.1 Efficacy Population 
All randomized subjects who receive at least one dose of double-blinded BMN 111 or 
placebo in this study. 
14.7.2 Safety Population   
All subjects who receive at least one dose of double-blinded BMN 111 or placebo in this 
study.  
 
 


 
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15 
DATA MONITORING COMMITTEE 
In addition to safety and PK monitoring by BioMarin personnel, an independent DMC will 
act as an advisory body to BioMarin and will monitor the safety and PK of subjects in the 
study. After the sentinel subjects complete 12 weeks of dosing, a DMC review will occur to 
evaluate all available safety and PK data.  Upon approval by the DMC, the next younger 
cohort will be opened and the 3 sentinel subjects will be enrolled. 
The DMC will make recommendations for stopping or continuing the study on an individual 
subject level and/or on a cohort level per the pre-specified stopping criteria. Based on criteria 
outlined in the protocol, the DMC may also make endorsements for dose adjustments if 
needed.  
Please see DMC Charter for further details. 
 


 
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16 
COSTS, COMPENSATION, AND SUBJECT INJURY 
There will be no charge to study subjects to be in this study. BioMarin will pay all costs of 
tests, procedures, and treatments that are part of this study. In addition, after IRB/IEC/REB 
approval, BioMarin may reimburse the reasonable cost of travel for study-related visits in 
accordance with BioMarin’s study-specific travel and reimbursement policy. BioMarin will 
not pay for any hospitalizations, tests, or treatments for medical problems of any sort related 
solely to the study subject’s disease. Costs associated with such hospitalizations, tests, and 
treatments should be billed and collected in the way that such costs are usually billed and 
collected outside the study. 
The Investigator should contact BioMarin immediately upon notification that a study subject 
has been injured by the study drug or by procedures performed as part of the study. 
Any subject who experiences a study-related injury should be instructed by the Investigator 
to seek immediate medical treatment at a pre-specified medical institution if possible, or at 
the closest medical treatment facility if necessary. The subject should be given the name of a 
person to contact to seek further information about, and assistance with, treatment for 
study-related injuries. The treating physician should bill the subject’s health insurance 
company or other third party payer for the cost of this medical treatment. If the cost of the 
medical treatment is not covered by health insurance or another third party that usually pays 
these costs, then either BioMarin or the institution may pay for reasonable and necessary 
medical services to treat the injuries caused by the study drug or study procedures. In some 
jurisdictions, BioMarin is obligated by law to pay for study-related injuries without prior 
recourse to third party payer billing and/or regardless of fault. If this is the case, BioMarin 
will comply with the law. 


 
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17 
CASE REPORT FORMS AND SOURCE DOCUMENTS 
Electronic case report forms will be provided for each subject. The Investigator must review 
and electronically sign the completed eCRF casebook to verify its accuracy. 
eCRFs must be completed using a validated web-based application. Study site personnel will 
be trained on the application and will enter the clinical data from source documentation. 
Unless explicitly allowed in the eCRF instructions, blank data fields are not acceptable.  
In the event of an entry error, or if new information becomes available, the value will be 
corrected by deselecting the erroneous response and then selecting or entering the factual 
response. In compliance with 21 CFR Part 11, the system will require the personnel making 
the correction to enter a reason for changing the value. The documented audit trail will 
include the reason for the change, the original value, the new value, the time of the correction 
and the identity of the operator. 
BioMarin’s policy is that study data on the eCRFs must be verifiable to the source data, 
which necessitates access to all original recordings, laboratory reports, and subject records. 
In addition, all source data should be attributable (signed and dated). The Investigator must 
therefore agree to allow direct access to all source data. Subjects (or their legally authorized 
representative) must also allow access to their medical records, and subjects will be informed 
of this and will confirm their agreement when giving informed consent. If direct source 
document verification of study data by the site monitor is prohibited by institutional policy or 
local law, then the Investigator must make available facilities and/or personnel to allow 
GCP-compliant source verification to occur. Examples of such methods include certified 
copies of records which have study data visible but sensitive information redacted, or other 
GCP-compliant means agreed between the Investigator and the Sponsor. 
A CRA designated by BioMarin will compare the eCRFs with the original source documents 
at the study site and evaluate them for completeness and accuracy before designating them as 
“Source Data Verified” (SDV). If an error is discovered at any time or a clarification is 
needed, the CRA, or designee, will create an electronic query on the associated field. Site 
personnel will then answer the query by either correcting the data or responding to the query. 
The CRA will then review the response and determine either to close the query or re–query 
the site if the response does not fully address the question. This process is repeated until all 
open queries have been answered and closed.  
Before a subject’s eCRF casebook can be locked, data fields must be source data verified and 
all queries closed. Refer to the Study Monitoring Plan for details on which fields must be 


 
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source data verified.  The Investigator will then electronically sign the casebook, specifying 
that the information on the eCRFs is accurate and complete. The Data Manager, or designee, 
will then set the status of the forms, visits, and the entire casebook to Locked. Upon 
completion of the CSR, an electronic copy of each site’s casebooks will be copied to a 
compact disk (CD) and sent to each site for retention with other study documents. 


 
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18 
STUDY MONITORING AND AUDITING 
Qualified individuals designated by BioMarin will monitor all aspects of the study according 
to GCP and standard operating procedures for compliance with applicable government 
regulations. The Investigator agrees to allow these monitors direct access to the clinical 
supplies, dispensing, and storage areas and to the clinical files, including original medical 
records, of the study subjects, and, if requested, agrees to assist the monitors. The 
Investigator and staff are responsible for being present or available for consultation during 
routinely scheduled site visits conducted by BioMarin or its designees. 
Members of BioMarin’s GCP Compliance Department or designees may conduct an audit of 
a clinical site at any time before, during, or after completion of the study. The Investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Representatives of the FDA or other Regulatory Agencies may also conduct an audit of the 
study. If informed of such an inspection, the Investigator should notify BioMarin 
immediately. The Investigator will ensure that the auditors have access to the clinical 
supplies, study site facilities, original source documentation, and all study files. 


 
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19 
RETENTION OF RECORDS  
The Investigator must retain all study records required by BioMarin and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a BioMarin 
representative before disposal of any study records, and must notify BioMarin of any change 
in the location, disposition or custody of the study files. The Investigator /institution must 
take measures to prevent accidental or premature destruction of essential documents, that is, 
documents that individually and collectively permit evaluation of the conduct of a study and 
the quality of the data produced, including paper copies of study records (e.g., subject charts) 
as well as any original source documents that are electronic as required by applicable 
regulatory requirements.  
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the U.S. or an ICH region or (2) at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP. The Investigator /institution 
should retain subject identifiers for at least 15 years after the completion or discontinuation 
of the study. Subject files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution or private practice, but not less than 15 years. 
These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirements or by a BioMarin agreement. BioMarin must be notified 
and will assist with retention should Investigator /institution be unable to continue 
maintenance of subject files for the full 15 years. It is the responsibility of BioMarin to 
inform the Investigator /institution as to when these documents no longer need to be retained. 


 
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20 
USE OF INFORMATION AND PUBLICATION 
BioMarin recognizes the importance of communicating medical study data and therefore 
encourages the publication of these data in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, manuscripts, 
and presentations based on the data from this study will be described in the Clinical Trial 
Agreement between BioMarin and the Investigator/Institution. Consideration for authorship 
of all publications will be based on compliance with the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals (“Uniform Requirements”) of the 
International Committee of Medical Journal Editors (ICMJE) (http://www.icmje.org/about-
icmje/faqs/icmje-recommendations/) and good publication practices (GPP).  


 
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21 
REFERENCES 
Bartels, CF, Bukulmez, H, Padayatti, P, Rhee, DK et. al. Mutations in the transmembrane natriuretic 
peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. 
Am J Hum Genet 75[1], 27-34. 2004. 
Bayley, N. Bayley Scales of Infant Development, Third Ed. Psychological Corporation, New York, 
NY. 2006. 
Bocciardi, R, Giorda, R, Buttgereit, J, Gimelli, S et. al. Overexpression of the C-type natriuretic 
peptide (CNP) is associated with overgrowth and bone anomalies in an individual with balanced 
t(2;7) translocation. Hum Mutat 28[7], 724-731. 2007. 
Bright, GM, Mendoza, JR, Rosenfeld, RG. Recombinant human insulin-like growth factor-1 
treatment: ready for primetime. Endocrinol Metab Clin North Am. 38[3]:625-38. 2009. 
Chusho, H, Tamura, N, Ogawa, Y, Yasoda, A et. al. Dwarfism and early death in mice lacking C-type 
natriuretic peptide. Proc Natl Acad Sci U S A 98[7], 4016-4021. 2001. 
Foldynova-Trantirkova, S, Wilcox, WR, Krejci, P. Sixteen years and counting: the current 
understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias. Hum 
Mutat 33[1], 29-41. 2012. 
National Institutes of Health. Genetics Home Reference Achondroplasia 2012.  Available at: 
https://ghr.nlm.nih.gov/condition/achondroplasia. 
Horton, WA, Hall, JG, Hecht, JT. Achondroplasia. Lancet 370[9582], 162-172. 2007. 
Ireland PJ, Johnson S, Donaghey S, Johnston L, McGill J, Zankl A, Ware RS, Pacey V, Ault J, 
Savarirayan R, Sillence D, Thompson E, Townshend S. Developmental milestones in infants and 
young Australasian children with achondroplasia. J Dev Behav Pediatr. Jan;31(1):41-7. 2010. 
Ireland PJ, McGill J, Zankl A, Ware RS, Pacey V, Ault J, Savarirayan R, Sillence D, Thompson EM, 
Townshend S, Johnston  LM. Functional performance in young Australian children with 
achondroplasia. Dev Med Child Neurol. Oct;53(10):944-50. 2011. 
Ireland P, Johnston LM. Measures of self-care independence for children with osteochondrodysplasia: 
a clinimetric review. Phys Occup Ther Pediatr. 32(1):80-96. 2012. 
Kemp, SF. Insulin-like growth factor-I deficiency in children with growth hormone insensitivity: 
current and future treatment options. BioDrugs 23[3]:155-63. 2009. 
Krejci, P, Masri, B, Fontaine, V, Mekikian, PB et. al. Interaction of fibroblast growth factor and C-
natriuretic peptide signaling in regulation of chondrocyte proliferation and extracellular matrix 
homeostasis. J Cell Sci 118[Pt 21], 5089-5100. 2005. 


 
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Little, R. J. A. (1993), “Pattern-Mixture Models for Multivariate Incomplete Data,” Journal of the 
American Statistical Association, 88, 125–134. 
Long, S, Wendt, D, Bell, S. A novel method for the large-scale production of PG-CNP37, a C-type 
natriuretic peptide analogue. J Biotechnol 162[2], 196-201. 2012. 
Lorget, F, Kaci, N, Peng, J, Benoist-Lasselin, C et. al. Evaluation of the therapeutic potential of a 
CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet 91[6], 1108-
1114. 2012. 
Mukherjee D, Pressman BD, Krakow D, Rimoin DL, Danielpour M. Dynamic cervicomedullary cord 
compression and alterations in cerebrospinal fluid dynamics in children with achondroplasia: review 
of an 11-year surgical case series. J Neurosurg Pediatr.  Sep;14(3):238-44. 2014. 
Molenberghs, G. and Kenward, M. G. (2007), Missing Data in Clinical Studies, New York: John 
Wiley & Sons. 
Pauli, 1984 
Pejchalova, K, Krejci, P, Wilcox, WR. C-natriuretic peptide: an important regulator of cartilage. Mol 
Genet Metab 92[3], 210-215. 2007. 
Shirley, ED, Ain, MC. Achondroplasia: manifestations and treatment. J Am Acad Orthop Surg 17[4], 
231-241. 2009. 
Waters, KA, Everett, F, Sillence, D, Fagan, E et. al. Breathing abnormalities in sleep in 
achondroplasia. Arch Dis Child 69[2], 191-196. 1993. 
Wendt, DJ, Dvorak-Ewell, M, Bullens, S, Lorget, F et. al. Neutral endopeptidase-resistant C-type 
natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth 
factor receptor 3-related dwarfism. J Pharmacol Exp Ther 353[1], 132-149. 2015. 
White KK, Parnell SE, Kifle Y, Blackledge M, Bompadre V. Is there a correlation between sleep 
disordered breathing and foramen magnum stenosis in children with achondroplasia? Am J Med 
Genet A. Jan;170A(1):32-41. 2016. 
 Wynn, J, King, TM, Gambello, MJ, Waller, DK et. al. Mortality in achondroplasia study: a 42-year 
follow-up. Am J Med Genet A 143A[21], 2502-2511. 2007. 
Yasoda, A, Kitamura, H, Fujii, T, Kondo, E et. al. Systemic administration of C-type natriuretic 
peptide as a novel therapeutic strategy for skeletal dysplasias. Endocrinology . 2009. 
Yasoda, A, Komatsu, Y, Chusho, H, Miyazawa, T et. al. Overexpression of CNP in chondrocytes 
rescues achondroplasia through a MAPK-dependent pathway. Nat Med 10[1], 80-86. 2004. 
 


 
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22 
INVESTIGATOR RESPONSIBILITIES 
22.1 
Conduct of Study and Protection of Human Subjects  
In accordance with FDA Form 1572 and/or principles of ICH E6 GCP, the Investigator will 
ensure that: 
 He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of subjects. 
 He or she will personally conduct or supervise the study. 
 He or she will inform any potential subjects, or any persons used as controls, that the 
drugs are being used for investigational purposes.  He or she will ensure that the 
requirements relating to obtaining informed consent in 21 CFR Part 50 and/or ICH E6 
Sections 2.9 and 4.8 are met, as well as IRB/IEC review and approval requirements in 
21 CFR Part 56 and/or ICH E6 GCP Section 2.6.  
 He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with 21 CFR 312.64 and/or ICH E6 GCP Section 
4.11. 
 He or she has read and understands the information in the Investigator’s Brochure, 
including potential risks and side effects of the drug. 
 His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments 
 He or she will ensure that adequate and accurate records are in accordance with 
21 CFR 312.62 and/or ICH E6 Section 4.9, and will make those records available for 
inspection in accordance with 21 CFR 312.68 and/or ICH Section 4.9.7. 
 He or she will ensure that the IRB/IEC/REB complies with the requirements of 
21 CFR Part 56, ICH Section 3.0 and other applicable regulations, and conducts 
initial and ongoing reviews and approvals of the study. He or she will also ensure that 
any change in research activity and all problems involving risks to human subjects or 
others are reported to the IRB/IEC/REB. Additionally, he or she will not make any 
changes in the research without IRB/IEC/REB approval, except where necessary to 
eliminate apparent immediate hazards to human subjects. 
 He or she agrees to comply with all other requirements regarding the obligations of 
clinical Investigators and all other pertinent requirements in 21 CFR Part 312 and/or 
ICH E6 R2. 


PI
PI
PI


 
 
Proprietary and Confidential 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical 
Trial to Evaluate the Safety and Efficacy of BMN 111 in Infants 
and Young Children with Achondroplasia, Age 0 to < 60 Months 
Protocol Number: 
111-206 
Active Investigational Product: 
BMN 111 (modified rhCNP)  
IND 
111299 
European Union Drug 
Regulating Authorities Clinical 
Trials (EudraCT) Number: 
2016-003826-18 
Indication: 
Achondroplasia 
Sponsor: 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Development Phase: 
Phase 2 
Sponsor's Responsible Medical 
Monitor: 
, MD, PhD 
  
BioMarin Pharmaceutical Inc. 
10 Bloomsbury Way 
London WC1A 2SL 
Study Design: 
Phase 2 randomized, double-blind, placebo-controlled clinical trial 
of BMN 111 in infants and younger children with a diagnosis of 
ACH 
Treatment Duration 
52 weeks 
Duration of Subject 
Participation: 
60 weeks for Cohorts 1 and 2 (screening, treatment, follow-up). 
Subjects in Cohort 3 who enter the study for a 12-week 
observational period will participate for approximately 70 weeks 
(screening, observational period, treatment, follow-up) 
Dose: 
15 µg/kg BMN 111 or placebo daily, subject to adjustment per 
protocol 
Study Population: 
Children 0 to < 60 months old with achondroplasia 
Date of Original Protocol: 
06 December 2017 
Date of Amendment 1: 
16 August 2018 
Property of BioMarin 
CONFIDENTIAL 
 
May not be divulged, published, or otherwise disclosed to others without prior written approval from BioMarin. 
 
This study will be conducted according to the principles of Good Clinical Practice as described in the U.S. Code of 
Federal Regulations and the International Conference on Harmonisation Guidelines, including the archiving of 
essential documents. 
PI
PI


 
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1 
RATIONALE AND SUMMARY OF CHANGES 
The protocol has been amended to include the following changes: 
1. The lower age range of participating subjects who have a  ≥  6-month period of 
pretreatment growth assessment in Study 111-901 immediately before study entry has 
been revised from  ≥ 3 months to  ≥ 6 months [§9.1]. 
Rationale: To harmonize the roll-over of subjects from Study 111-901 to 111-206 in each 
cohort. 
2. No two sentinel subjects will be dosed on the same day for any cohort [§9.1]. 
Rationale: To enforce a minimum period of safety observation prior to dosing the next 
subject, as in each cohort, the sentinel subjects will be the youngest children to date 
dosed with BMN 111. 
3. Echocardiogram will be performed at the Week 56 Safety Follow-up and Early 
Termination visits [Table 9.1.1; §12.1.10; §12.1.11]. 
Rationale: To enable monitoring for any unintended adverse anatomical or functional 
cardiac adverse effects at the time of study completion. 
4. Use of residual plasma samples for cGMP PD biomarker assessment in all age groups has 
been added to procedures [Table 9.1.1; Table 9.11.6.4.1; §12.1.2; §12.1.7; §12.1.8; 
§12.1.9]. 
Rationale: Use of the residual sample allows for PD assessments in infants without timed 
urine collection.  The infant group assessments can then be compared to all age groups. 
5. An anti-BMN 111 immunogenicity assessment has been added at Week 3 [Table 9.1.1; 
§12.1.5]. 
Rationale: Week 3 immunogenicity assessment has been added to characterize early 
anti-BMN 111 immune responses in this age range of the achondroplasia subject 
population. 
6. Bone metabolism urine biomarkers, BMN 111 pharmacodynamic urine biomarkers, and 
urine chemistry assessments have been added at Week 39 [Table 9.1.1; §12.1.8] 
Rationale: To obtain PD assessments at each visit that PK is collected and to obtain 
creatinine concentrations for cGMP calculations 
7. The sleep study scheduled at the Week 26 visit has been removed [Table 9.1.1; §12.1.7]. 
Rationale:  To minimize study burden on the trial participants, families and caregivers, as 
only two polysomnography studies are required to meet the study objectives. One 


 
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assessment will be performed at baseline and one at Week 52 (or the Early Termination 
Visit, if the subject leaves the study early). 
8. DXA scans will no longer include tibia scans [Table 9.1.1; §9.11.4.2]. 
Rationale:  The tibia scan was removed because DXA machines are unable to properly 
perform the scan. 
9. If the 111-901 visit at which the subject enters Study 111-206 and the 111-206 Screening 
visit are on the same day, the procedures common to both visits will be performed one 
time only [Table 9.1.1 (footnote b)].  
Rationale: To ensure that duplicate study procedures, including blood draws, are not 
repeated unnecessarily in this infant and toddler population. 
10. On days when PK samples are being drawn, ECG will be performed within a 5-minute 
window prior to the 30-minute PK assessment [Table 9.1.1 (footnote h); §9.11.6.7]. 
Rationale:  This timing allows for ECG assessment in relation to BMN 111 Cmax. 
11. Exclusion criterion #6 has been revised from “…as determined by the Investigator based 
on the following assessments…) to (…as determined by the Investigator and informed by 
the following assessments…).  The determination about whether presence of 
cervicomedullary compression is likely to require surgical intervention will be informed 
by physical exam, polysomnography, and MRI [§9.3.2]. 
Rationale:  To clarify that this is a clinical decision to be informed by signs, symptoms, 
and investigations, and not based solely on abnormal finding in an MRI. 
12. Exclusion criterion #15 has been revised to include cervicomedullary decompression 
surgery (Cohorts 2 and 3 only) [§9.3.2]. 
Rationale:  To clarify that children with prior cervicomedullary decompression surgery 
are not eligible for entry into the study in Cohort 2 or 3.  This is to enable formal 
evaluation of a potential treatment effect on the foramen magnum using MRI in children 
at ages where the foramen magnum is still growing rapidly. As the synchondroses around 
the foramen magnum are already closing after the age of two years, subjects with prior 
cervicomedullary decompression surgery may be allowed into Cohort 1 only after 
discussion and agreement with the Medical Monitor. 
13. Inclusion/exclusion criteria have been added for Cohort 3 subjects enrolling in the 
observational period [§9.3.3; §9.3.4]. 
Rationale:  These criteria are used in our observational study 111-901 and apply only to 
Cohort 3 subjects who enroll in the 111-206 observation period. 
14. A table of restricted medications, including growth hormone, has been added [§9.3.5]. 


 
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Rationale:  To ensure that growth hormone is not used concomitantly. 
15. In Section 9.11.4.4, Genomic Biomarker Analysis, the text “of plasma DNA” has been 
removed from “Exploratory genomic analysis of plasma DNA may inform understanding 
of the BMN 111 mechanism of action…” [§9.11.4.4].  
Rationale: Genomic analysis implies DNA/RNA analysis, and we are not obtaining DNA 
from plasma. 
16. For subjects enrolled in Cohort 3 (0 to < 6 months old), the collection period for all AEs 
begins after informed consent is obtained [Table 9.1.2 footnote h; §10.2.1].   
Rationale: to collect and document all AEs so as to establish robust baseline natural 
history in these subjects prior to study drug administration. 
17. Administrative updates have been made to improve consistency and clarity. 
a. Text has been changed to reflect the age of majority rather than age 18, as the age of 
majority varies between countries. Section 5.3, Subject Information and Informed 
Consent.  
b. Section 7.3, Ongoing Clinical Studies, has been updated to include a description of 
Study 111-302 (Section 7.3.5). 
c. In Section 8, Study Objectives, in the secondary objective addressing evaluation for 
hip, thigh, or knee pain, or change in gait from medical history, the phrase “…from 
medical history…” has been removed to clarify that hip assessments are performed at 
screening, and these measures serve as a baseline for future assessments. 
d. Error in Section 9.1, Overall Study Design and Plan, description of Cohort 3 has been 
corrected to state that at least 17 additional subjects will be randomized. 
e. Clarification about age-appropriate dose adjustment has been added to indicate that 
subjects will be administered the recommended dose appropriate to their current age. 
Section 9.1, Overall Study Design and Plan, and Section 9.1.1, Dose Adjustments. 
f. The time window for the Week 56 safety follow-up visit has been changed from ± to 
+ 7 days to allow a full 4 weeks between the last dose of study drug and the safety 
follow-up visit.  Table 9.1.1, Section 12.1.10, Week 56 Safety Follow-up.   
g. Clarified that the screening/baseline hip assessment includes a pelvis x-ray.  
Table 9.1.1, Section 12.1.1, Screening/Baseline Day -30 to Day -1. 
h. Because the definition of ACH-related events differed between sites, capture of 
ACH-related events has been changed to capture all procedures listed in the Schedule 
of Events to ensure all procedures are collected and analyzed.  Tables 9.1.1 and 9.1.2; 
Section 9.11.6.2; Sections 12.1.2-12.1.11; Sections 12.2.2-12.2.3. 


 
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i. Vital signs instructions now include sitting or supine positions to account for subjects 
who are too young to sit. The duration of vital signs assessments in Section 9.11.6.5 
and Table 9.11.6.5.1 has been extended to align with the assessments presented in the 
SOE.  Additionally, if a dose adjustment visit coincides with a visit at which a full PK 
is drawn, vital signs will be obtained for 8 hours, similar to the Day 1,2 schedule.  
Table 9.1.1, Vital Sign Assessment Frequency table; Section 9.11.6.5, Vital Signs; 
Table 9.11.6.5.1.   
j. In the event that a sentinel subject has an interrupted dose of study drug on Day 1, 
instructions have been included for a change in the PK collection schedule. 
Table 9.1.1 footnote L; Section 9.11.5, Pharmacokinetics Variables. 
k. Footnote m in Table 9.1.1 has been updated to correspond to the information in 
Section 9.11.6.10, Anti-BMN 111 Immunogenicity Assessments and IgE Testing. 
l. In Table 9.1.1, footnotes n and o, and Section 9.11.3, Secondary Efficacy Variables, 
text has been added to specify the biomarkers used to assess changes in bone and 
collagen metabolism. 
m. In Table 9.1.1, footnote q, instruction has been included that efforts to obtain a 
satisfactory MRI image can be discontinued after 3 unsuccessful attempts. 
n. In Table 9.1.1, footnote v now includes instructions for managing a dose interruption. 
o. Section 9.1.1, Dose Adjustments, has been corrected to state that a DMC review will 
occur after the third sentinel subject reaches Week 12 post-dose adjustment. 
p. In Section 9.3.8, Duration of Subject Participation, final follow-up visit for subjects 
who discontinue from the study has been changed from 2 weeks to 4 weeks after last 
dose to be consistent with the safety follow-up at 4 weeks in the Schedule of Events.  
q. In Section 9.4.1, Treatments Administered, text has been added to reiterate that 
sentinel subjects will be treated with BMN 111, versus randomized subjects who will 
receive either BMN 111 or placebo.  Additionally, the BMN 111 dose level is subject 
to potential per-protocol adjustment. 
r. Directions for subject observation following BMN 111 administration at study visits 
has been revised in Section 9.4.1.1, Study Drug Administration, for consistency with 
Section 9.4.4, Directions for Administration. 
s. Text in Section 9.4.1.1, Study Drug Administration now indicates that study drug 
injections will be administered at age-appropriate sites, determined at the discretion 
of the investigator. 
t. Text has been revised to indicate that in the hour prior to injection, all subjects should 
be well hydrated and fed.  Section 9.4.4, Directions for Administration; Section 9.6, 
Dietary or Other Protocol Restrictions. 
u. In Section 9.4.5, Method of Assigning Subjects to Treatment Groups, a note has been 
added that in Japan, subjects are randomized separately within each cohort. 


 
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v. Section 9.11.4.2, Imaging Assessment Procedures, has been corrected by removing 
lateral views from bilateral lower extremity x-rays, and clarified to state that bilateral 
lower extremity x-rays, anterior-posterior (AP) view, are done to assess growth plate 
morphology. Instruction has been added to contact the medical monitor to discuss 
alternate non-radiological methods for assessment if there are IRBs or IECs unwilling 
to allow x-rays in Cohort 3 subjects (also, Table 9.1.1, footnote t). Additionally, the 
list of DXA acquisitions has been clarified.   
w. Section 9.11.4.7.1, Bayley-III, has been revised to remove reference to the 
Social-Emotional and Adaptive Behavior Scale components because these scales will 
not be used in this study.  Additionally, the duration of the assessment has been 
clarified. 
x. In Section 9.11.4.7.4, Child Behavior Checklist, the duration of the assessment has 
been clarified. 
y. In Section 10.1.2, the statement that hospitalization for less than 24 hours will not be 
considered an SAE has been deleted to make the criterion consistent across all 
BioMarin protocols. Section 10.1.2, Serious Adverse Events.  
z. Error in Table 10.2.3.3.1 has been corrected to read “The AE could not be explained 
by factors or causes other than exposure to the IP” 
 
 


 
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2 
SYNOPSIS 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
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ONLY: 
TITLE OF STUDY:  A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial to 
Evaluate the Safety and Efficacy of BMN 111 in Infants and Young Children with Achondroplasia, 
Age 0 to < 60 Months 
PROTOCOL NUMBER:  111-206 
STUDY SITES:  Approximately 10-15 sites worldwide 
PHASE OF DEVELOPMENT:  Phase 2 
STUDY RATIONALE: 
BMN 111 is a recombinant CNP analogue that has been engineered to resist degradation by NEP, 
allowing for a longer half-life. 
The pharmacological activity of BMN 111 was explored in two mouse models of ACH, a severe, 
Fgfr3Y367C/+ (TD) model (Lorget, 2012), and a milder [Ach] /+ (Ach) model. These included 
studies in 7-day old TD mice given BMN 111 daily by SC administration for up to 20 days and a 
study in 3-week old Ach mice given BMN 111 daily by SC administration for 5 weeks. Partial or 
complete reversion of the ACH phenotype was observed in these mouse models after BMN 111 
administration. In wild-type mice, and normal rats and monkeys, BMN 111 administration resulted 
in growth plate expansion and dose-dependent skeletal growth at hemodynamically tolerated dose 
levels (Wendt, 2015). Additionally, the potential effect of age on BMN 111 PK was evaluated in 
normal rats aged between 7 days and 12-13 weeks.  
Infants and young children with ACH have a high incidence of medical complications and currently 
there is no approved pharmacological therapy for ACH in the US or EU. The most severe 
complication, cervicomedullary compression (CMC), occurs in a subset of subjects with ACH due 
to abnormal endochondral bone growth and narrowing of the foramen magnum (White, 2016). CMC 
has been linked to serious respiratory and neurological complications including hypotonia, apnea, 
ataxia, developmental delay, and respiratory arrest associated with sudden death (Mukherjee, 2014). 
Foramen magnum decompression surgery is currently the only treatment for this condition.   
Sleep apnea has also been extensively described in ACH, and sleep-disordered breathing may affect 
up to 85% of all children with ACH (Ireland, 2012). This is thought to be due to midface 
hypoplasia, relative adenotonsillar hypertrophy, and potential posterior cranial fossa compression 
secondary to abnormal endochondral bone growth. Sleep apnea in ACH not only results in the need 
for surgical intervention, but has also been linked to sudden death in rare cases (Pauli, 1984).   
Similarly, the dysregulation of endochondral bone growth in ACH leads to other medical 
complications which are prevalent in this subject population, such as the following: 


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
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Page:   
 
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• 
Spinal stenosis, kyphosis, and lordosis (secondary to altered growth plate ossification in the 
vertebrae and narrowing of the interpedicular distances) (Shirley, 2009) 
• 
Developmental delay of gross motor and ambulatory skills (associated with proximal limb 
shortening, macrocephaly, and hypotonia) (Ireland, 2010) 
• 
Delayed functional skills and increased need for caregiver assistance (eg, eating, bladder 
management, bowel management, transfer to chair, climbing stairs) (Ireland, 2011) 
Thus, BMN 111 may provide greater benefit when children begin treatment at a younger age, as 
earlier initiation of treatment allows a longer time window to improve growth and potential to 
improve medical complications of achondroplasia. This study (111-206) is being conducted to 
assess safety and the potential benefit of BMN 111 in infants and young children.   
BMN 111 was first tested in humans in Study 111-101, a Phase 1 double-blinded, placebo-
controlled clinical trial of the safety and tolerability of BMN 111 in healthy adult male volunteers 
without ACH. Part 1 examined a series of single subcutaneous doses (5 µg/kg, 10 µg/kg and 
15 µg/kg), and Part 2 included 10 days of either fixed dosing or dose escalation (0.5 µg/kg to 
8 µg/kg). BMN 111 was generally well tolerated at all doses. As expected, mild, transient, self-
limited hypotension was reported (refer to current Investigators Brochure for additional 
information). Following SC administration, BMN 111 was rapidly absorbed with maximal plasma 
concentrations achieved in less than 30 minutes. BMN 111 was rapidly cleared from the plasma 
with a mean t1/2 ranging from 40 to 55 minutes across dose levels. BMN 111 exposure (Cmax and 
AUC0-t) generally increased greater than proportional to the increase in dose across the 2.5-to-
15-µg/kg dose range. Exposure following multiple dosing was found to be similar to exposure 
following single doses, indicating no apparent accumulation or time-dependence with once-daily SC 
administration. 
Study 111-202, the second clinical trial in humans and the first in children with ACH, is an ongoing 
Phase 2, open-label, sequential-cohort, dose-escalation study that assesses daily SC BMN 111 in 
pediatric subjects with ACH aged 5-14 years with doses ranging from 2.5 µg/kg to 30 µg/kg. The 
primary objective of Study 111-202 is to evaluate the safety and tolerability of BMN 111 
administered for 6 months and up to 24 months; the secondary objectives are to determine change 
from baseline in annualized growth velocity (AGV), growth parameters, body proportions, and 
evaluate the pharmacokinetics (PK) of BMN 111 in children with ACH. 


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
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ONLY: 
Analysis of safety data from the 6-month initial phase of Study 111-202 showed that treatment with 
BMN 111 for 6 months at the doses of 2.5, 7.5, 15, and 30 µg/kg was generally well tolerated (refer 
to current Investigator’s Brochure for specific details). One subject (30 µg/kg) in 111-202 withdrew 
due to an AE. The subject developed non-serious, asymptomatic Grade 1 intermittent Wolff-
Parkinson-White pattern, which was discovered on a routine day 10-study monitoring ECG. The 
most common AEs across all cohorts were injection site reactions, asymptomatic hypotension, 
headache, and nasopharyngitis. Based on previous experience of the ongoing Phase 2 clinical trial, 
including the 24-month data cut at 15 µg/kg, injection site reactions have been identified as risks 
associated with BMN 111 injections. The majority of hypotension events were grade 1 and reported 
in the setting of routine BP measurement. All reported events of hypotension were transient and 
resolved without medical intervention. For a detailed summary of risks, please refer to the current 
version of the Investigator’s Brochure supplied by BioMarin.  
Analysis of efficacy data from the 6-month initial phase of Study 111-202 showed that subjects 
treated with BMN 111 for 6 months at doses ranging from 2.5-15 µg/kg daily had a dose-dependent 
improvement in AGV, with ~50% improvement in AGV seen at the 15 µg/kg dose. The data from 
Cohort 4 (30 µg/kg) show an apparent greater than dose-proportional increase in BMN 111 plasma 
exposure (Cmax and AUC0-t), with a marginal improvement in both absolute AGV and change from 
baseline AGV after 6 months of BMN 111 treatment when compared with Cohort 3 (15 µg/kg).    
Study 111-206 is a Phase 2 randomized, double-blind, placebo-controlled clinical trial of BMN 111 
in infants and younger children with a diagnosis of ACH who are 0 to < 60 months old. This 52-
week study will enable assessment of BMN 111 efficacy and safety, tolerability, pharmacodynamics 
biomarkers, and PK in this population. Additional exploratory endpoints pertaining to medical 
complications of ACH will also be evaluated.   
Efficacy/toxicity studies have been conducted in neonatal and very young animals (7-day 
postpartum mouse and rat) in both a disease (TD mouse) and non-disease (rat) model. Given that 
this is the first study in infants and young children, an age-based cohort study design is used to 
assess safety and PK in young children (Cohort 1, ≥ 24 to < 60 months) prior to dosing toddlers 
(Cohort 2, ≥ 6 to < 24 months) and infants (Cohort 3, 0 to < 6 months). PK will be monitored and 
evaluated; Day 1 PK data from the sentinel subjects will inform dose selection modification for the 
sentinel subjects and for the rest of the cohort to target the observed exposure of the 15-µg/kg dose 
group in Study 111-202. Safety, efficacy and PK data from Study 111-202, a Phase 2 study in 
children with ACH, where a dose of 15 µg/kg has been and continues to be studied, are expected to 
be the most relevant, and translatable to this study (111-206).  
   


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
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OBJECTIVES:  
The primary objectives of the study are to: 
• 
Evaluate the safety and tolerability of BMN 111 in children age 0 to < 60 months with ACH  
• 
Evaluate the effect of BMN 111 on change from baseline in length/height Z-score 
 
The secondary objectives of the study are to: 
• 
Evaluate the effect of BMN 111 on AGV throughout the 52 weeks of the study  
• 
Evaluate the effect of BMN 111 on bone morphology/quality by x-ray and dual x-ray 
absorptiometry (DXA) 
• 
Evaluate the PK of BMN 111 in children age 0 to < 60 months with ACH  
• 
Evaluate hip function 
• 
Evaluate for hip, thigh, or knee pain, or change in gait  
• 
Evaluate the effect of BMN 111 on developmental/functional/QOL status (Bayley-III, 
WeeFIM, Child Behavior Checklist [CBCL], ITQOL 
• 
Evaluate immunogenicity of BMN 111 and assess impact on safety, PK, and efficacy 
measures  
• 
Evaluate the effect of BMN 111 on bone metabolism and BMN 111 pharmacodynamic 
biomarkers 
The exploratory objectives of the study are to: 
• 
Evaluate the effect of BMN 111 on growth parameters and body proportions, including 
change from baseline in upper:lower segment body ratio 
• 
Evaluate the effect of BMN 111 on sleep apnea 
• 
Document physical and phenotypic changes with clinical photography (optional) 
• 
Evaluate the effect of BMN 111 on skull and brain morphology, including foramen 
magnum, ventricular and brain parenchymal dimensions 
• 
Describe the incidence of surgical interventions, including cervical decompression, 
adenotonsillectomy, and tympanostomy 
STUDY DESIGN AND PLAN:  
This study, 111-206, is a Phase 2 randomized, double-blind, placebo-controlled clinical trial of 
BMN 111 in infants and younger children with a diagnosis of ACH.  


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
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ONLY: 
Study 111-901 is an ongoing study to collect serial growth measurements on pediatric subjects with 
ACH who are being considered for subsequent enrollment in future BioMarin studies.  Subjects age 
≥ 6 months to < 60 months old who have documented ACH confirmed by genetic testing; at least a 
6-month period of pretreatment growth assessment in Study 111-901 immediately before study 
entry; and who meet the study eligibility criteria, will participate. Eligible subjects ranging from 0 
months to < 3 months old may enroll directly into 111-206 and have a minimum of 3 months of 
pre-treatment observation prior to commencing treatment with investigational product, or may 
enroll in 111-901 for a minimum of 3 months of pretreatment growth assessment immediately 
before roll-over to 111-206. 
Approximately 70 subjects will be enrolled at approximately 10-15 clinical centers worldwide.   
The primary objectives of this study are to assess the safety and tolerability of daily SC BMN 111 
administered to infants and young children with ACH, and to evaluate the effect of BMN 111 on 
length/height Z-score. Subjects will be enrolled into 3 age cohorts based on age at study screening 
starting with the eldest population.  Within Cohorts 1 and 2, subjects will be stratified by age: 
• 
Cohort 1 – children aged ≥ 24 to < 60 months (n ≥ 30 total: 3 sentinel subjects who receive 
BMN 111, and at least 27 additional subjects randomized 1:1 to treatment or placebo 
control), stratified by age (≥ 24 to < 36 months and ≥ 36 months to < 60 months)  
• 
Cohort 2 – children aged ≥ 6 to < 24 months (n ≥ 20 total: 3 sentinel subjects who receive 
BMN 111, and at least 17 additional subjects randomized 1:1 to treatment or placebo 
control), stratified by age (≥ 6 months to < 15 months and ≥ 15 months to < 24 months)  
• 
Cohort 3 – children aged 0 to < 6 months (n ≥ 20 total: 3 sentinel subjects who will be under 
observation or receive BMN 111, and at least 17 additional subjects randomized 1:1 to 
treatment or placebo control).  Treatment begins at ≥ 3 months to  < 6 months after 3 
months of observation. 
If subjects who enroll in Cohort 3 are not able to begin treatment by  < 6 months of age, they will 
continue in the pretreatment period for another 3 months before enrolling in Cohort 2 to fulfill the 
pretreatment requirement for Cohort 2. 
Sentinel subjects from each cohort will be enrolled, treated with BMN 111, and studied for short-
term safety and PK data, after which subjects will be randomized to receive BMN 111 or placebo 
SC daily (1:1 ratio) for up to 52 weeks. No two sentinel subjects will be dosed on the same day for 
any cohort. 


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
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At the start of the study, three sentinel subjects will be enrolled and monitored in Cohort 1. After all 
3 sentinel subjects reach Day 8, the Sponsor will review and evaluate all available safety data and 
Day 1 PK data. Based on PK data review, the weight-based dose may be adjusted for the sentinel 
subjects and the rest of the cohort, and will be the starting dose for the younger cohort sentinel 
subjects.  Upon review of the clinical and PK data, the remainder of Cohort 1 (≥ 27 additional 
subjects) will be enrolled and randomized to treatment with BMN 111 or placebo (1:1 ratio).  After 
the sentinel subjects complete 12 weeks of dosing, a DMC review will occur to evaluate all 
available safety and PK data.  Upon approval by the DMC, the next younger cohort (Cohort 2) will 
be opened and the 3 sentinel subjects will be enrolled. 
The same procedure will be followed for Cohort 2. After all 3 sentinel subjects reach Day 8, the 
Sponsor will review and evaluate all available safety data and Day 1 PK data. Based on PK data and 
criteria set in the protocol, the dose may be adjusted for the sentinel subjects and the rest of the 
cohort, and will be the starting dose for the younger cohort sentinel subjects.  Upon review of the 
clinical and PK data, the remainder of Cohort 2 (≥ 17 additional subjects) will be enrolled and 
randomized to treatment with BMN 111 or placebo (1:1 ratio). After the sentinel subjects complete 
12 weeks of dosing, a DMC review will occur to evaluate all available safety and PK data.  Upon 
approval by the DMC, the youngest cohort (Cohort 3) will be opened and the 3 sentinel subjects will 
be enrolled. 
The same procedure will be followed for Cohort 3. After all 3 sentinel subjects reach Day 8, the 
Sponsor will review and evaluate all available safety data and Day 1 PK data. Based on PK data and 
criteria set in the protocol, the dose may be adjusted for the sentinel subjects and the rest of the 
cohort, and will be the starting dose for the younger cohort sentinel subjects.  Upon review of the 
clinical and PK data, the remainder of Cohort 3 (≥ 17 additional subjects) will be enrolled and 
randomized to treatment with BMN 111 or placebo (1:1 ratio).  
Cohort 3 subjects must have a minimum of 3 months of observation prior to commencement of 
treatment.  These subjects will have the option to enroll in either 111-901 or 111-206, depending on 
age at enrollment: 
• 
Infants ≥ 3 months and  < 6 months old (≥ 13 weeks and  < 26 weeks) will enroll in 111-901 
for a 6-month period of pretreatment growth assessment prior to enrollment in 111-206 for 
treatment in Cohort 2. 
• 
Infants between birth and < 3 months old (0 weeks and < 13 weeks) will enroll into 111-206 
with a 3-month observational period prior to treatment. 
Additional sentinels may be added to any cohort if needed for additional safety and/or PK 
assessment. 


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
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As subjects age on study, they will be administered the dose determined to be appropriate for their 
current age.  For example, if a subject enrolls into Cohort 2 at age 20 months, they will receive the 
recommended dose for subjects aged ≥ 6 to < 24 months until they turn 24 months in age.  When 
they turn 24 months in age, they will begin to receive the recommended dose for subjects 
aged  ≥ 24 to  < 60 months.  Duration of the study is 52 weeks of treatment with a safety follow up at 
Week 56. Following completion of the study, subjects in all treatment groups may be eligible to 
receive BMN 111 in an open-label extension study, to assess safety and efficacy of BMN 111 over 
the longer term; and to study the long-term outcomes on sustained growth, proportionality, bone 
maturation and medical comorbidities.  
For subjects enrolling into the extension study, safety follow up visit at Week 56 will be waived.  
Data Monitoring Committee (DMC) 
In addition to safety and PK monitoring by BioMarin personnel, an independent DMC will act as an 
advisory body to BioMarin and will monitor the safety and PK of subjects in the study. After the 
sentinel subjects complete 12 weeks of dosing, a DMC review will occur to evaluate all available 
safety and PK data.  Upon approval by the DMC, the next younger cohort will be opened and the 
3 sentinel subjects will be enrolled. 
The DMC will make recommendations for stopping or continuing the study on an individual subject 
level and/or on a cohort level per the pre-specified stopping criteria. Based on criteria outlined in the 
protocol, the DMC may also make endorsements for dose adjustments if needed.  
Please see DMC Charter for further details. 
 
Individual Subject Stopping Criteria  
For individual subjects treated with BMN 111, DMC will be informed if any of the following 
individual subject stopping criteria should occur. Temporary dosing suspension, permanent 
discontinuation of dosing, or dose reduction for the individual subject will be considered. 
• 
Any treatment-emergent adverse event (AE) assessed as at least Grade 4 by the Investigator 
and/or Sponsor Medical Monitor  
• 
Any treatment-emergent AE of at least Grade 3 assessed as related to study drug by the 
Investigator and/or Sponsor Medical Monitor  
• 
Any two treatment-emergent Grade 2 symptomatic hypotension events within 7 days 
(non-urgent medical intervention indicated) or any Grade 3 hypotensive event (urgent 
medical intervention or hospitalization indicated) assessed by the Investigator and/or 
Sponsor’s Medical Monitor  


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
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Dossier: 
 
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• 
Clinically significant finding or arrhythmia on ECG that indicates abnormal cardiac 
function or conduction or prolongation of QTc-F >500 msec 
• 
Clinically significant new or worsening signs of cervicomedullary compression as 
determined by the Investigator and in consultation with Sponsor medical monitor and 
neurosurgical specialist (if needed) 
• 
Adverse findings on clinical hip exam or hip imaging assessments that are determined to be 
clinically significant as determined by the Investigator and in consultation with Sponsor 
Medical Monitor and orthopedic specialist (if needed)  
If the subject meets any stopping criterion, after Investigator consultation with the BioMarin 
Medical Monitor and DMC, the subject may be re-challenged at the same dose. If the subject meets 
stopping criteria on re-challenge or if re-challenge is not clinically indicated, other options that may 
be considered include:  
• 
Re-challenge at lower dose with consideration given to upward titration to tolerated dose  
• 
Permanent treatment discontinuation (with an option of ongoing assessment in the study)  
Cohort Stopping Criteria  
For each cohort, a DMC review will be conducted if any of the following cohort stopping criteria 
occur in subjects treated with BMN 111.  Temporary dosing suspension, permanent discontinuation 
of dosing, or dose reduction for the cohort(s) will be considered and the impact on all other age 
cohorts will be assessed.  
• 
Any treatment-emergent AE assessed as at least Grade 4 by the Investigator and/or Sponsor 
Medical Monitor  
• 
Any two subjects have a treatment-emergent AE of at least Grade 3 assessed as related to 
study drug by the Investigator and/or Sponsor Medical Monitor  
• 
Any two subjects have two treatment-emergent Grade 2 symptomatic hypotension events 
within 7 days (non-urgent medical intervention indicated) or any two subjects cohort have a 
Grade 3 hypotensive event (urgent medical intervention or hospitalization indicated) 
assessed by the Investigator and/or Sponsor’s Medical Monitor  
• 
Any two subjects have a clinically significant finding or arrhythmia on ECG that indicates 
abnormal cardiac function or conduction or prolongation of QTc-F >500 msec 


 
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Proprietary and Confidential 
16 August 2018 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
• 
Any two subjects have adverse findings on clinical hip exam or hip imaging assessments 
that are determined to be clinically significant as decided by principal investigator and in 
consultation with Sponsor medical monitor and orthopedic specialist (if needed)  
Dose Adjustments 
Analysis of available PK data from studies 111-101 and 111-202 indicated that differences in 
subject body weight did not directly translate to differences in total body clearance of BMN 111.  
The same weight-based dose in the pediatric population of Study 111-202 (5-12 years old) yielded 
lower exposure (Cmax and AUC) than that characterized in the adult population of Study 111-101.  
Therefore, the same weight-based dose in the young pediatric population in this study may yield 
exposure less than the target exposure range characterized to be safe and effective in Study 111-202 
at the 15-µg/kg dose. Since this is the first experience with BMN 111 in this young pediatric 
population, it is also possible the exposure at 15 μg/kg could be greater than the target exposure 
range, and dose adjustment may be warranted. Thus, an option for adjustment of the weight-based 
dose is provided to ensure that the appropriate target exposure for safety and efficacy is reached for 
the young subjects in this study.   
The need for dose adjustment will be evaluated as follows: three sentinel subjects in Cohort 1 will 
receive an initial dose of 15 µg/kg. After all three sentinel subjects reach Day 8, a review will occur 
to evaluate all available safety and PK data (at minimum). If the criteria for dose adjustment are 
met, the three sentinel subjects will be started on the new adjusted dose at their next scheduled visit, 
and vital signs will be obtained for at least 4 hours post-dose. 
The remainder of the subjects in the age cohort will also be enrolled starting at the new adjusted 
dose. After the third sentinel subject reaches Week 12 post-dose adjustment, a DMC review will 
occur to evaluate all safety and PK data and, upon endorsement, the three sentinel subjects from the 
next younger cohort will be enrolled starting at the new adjusted dose.  The three sentinel subjects 
for the second and third cohorts will be evaluated similarly to the sentinel subjects in the first cohort 
for potential dose adjustment. 
As subjects age on study, they will be administered the dose determined to be appropriate for their 
current age.  For example, if a subject enrolls into Cohort 2 at age 20 months, they will receive the 
recommended dose for subjects aged ≥ 6 to < 24 months until they turn 24 months in age.  When 
they turn 24 months in age, they will begin to receive the recommended dose for subjects aged ≥ 24 
to < 60 months. 


 
Study 111-206A1 
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Proprietary and Confidential 
16 August 2018 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
Safety and Efficacy Monitoring 
Each treated subject will have expanded outpatient safety monitoring for a minimum of 3 days of 
dosing, during which they will be closely observed and non-invasive hemodynamic monitoring will 
be conducted for at least 4-8 hours post-dosing. Because younger children may not be able to 
verbalize complaints of dizziness or lightheadedness that are potentially associated with 
hypotension, study personnel and caregivers will be trained to recognize the signs of hypotension in 
this population, which may include tachycardia, pallor, diaphoresis, lethargy, delayed capillary 
refill, and poor feeding. Appropriate rigorous training will be required for parents and caregivers 
prior to daily injections at home. Training includes the storage, reconstitution, and administration of 
BMN 111, as well as documentation/reporting of AEs and vigilance for signs of hypotension. 
It is generally expected that after subjects are tolerating the drug well and specified criteria have 
been met, caregivers will begin administering study drug. Home health care is not required at any 
point but may be provided if the caregiver is unable or unavailable to administer the study drug. A 
Home Healthcare nurse will train the caregiver(s) if training has not been completed by the Day 3 
visit. A phone call by the study staff member to the caregiver will be required weekly for 6 months 
and then every 2 weeks for the remainder of the study. During these contacts, study staff will ask the 
caregiver about dose administration and seek information on AEs and SAEs by specific questioning. 
If the caregiver cannot be contacted by phone after two attempts, contact can be made via email.   
Safety will be evaluated by the incidence of AEs, serious AEs (SAEs), laboratory test results 
(urinalysis, chemistry, and hematology), vital signs, physical examination, ECG and 
echocardiogram, hip clinical assessment, and anti-BMN 111 immunogenicity assessments.  Clinical 
laboratory tests, PK, immunogenicity and blood biomarker assessments will be limited to the 
minimum necessary for evaluation of safety and efficacy in order to minimize blood volume in the 
pediatric population. 
Efficacy will be assessed by change from baseline in AGV and length/height Z-score. Exploratory 
assessments will include change from baseline in growth parameters and body proportions by 
anthropometry. X-rays will be performed of the lower extremities and spine to evaluate for changes 
in bone morphology, quality, and growth. An MRI will be performed to assess the effect of BMN 
111 on skull and brain morphology, including foramen magnum, ventricular and brain parenchymal 
dimensions.  A board-certified, fellowship-trained (or equivalent) pediatric anesthesiologist will 
administer anesthesia during MRI measurements in the event that the subject is unable to remain 
still for the duration of the scan. Sleep studies will be conducted to evaluate sleep apnea. Additional 
assessments will be conducted to evaluate changes from baseline in bone metabolism and BMN111 
pharmacodynamic biomarkers, and developmental/functional status.   
NUMBER OF SUBJECTS PLANNED: Approximately 70 subjects, including at least 30 subjects 
in Cohort 1, at least 20 subjects in Cohort 2, and at least 20 subjects in Cohort 3. 


 
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Proprietary and Confidential 
16 August 2018 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:  
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Diagnosis of ACH, confirmed by genetic testing.  If subjects had previous genetic testing, 
subjects must have a lab report from a certified laboratory with the study specific mutation 
documented. 
2. Age   0 to < 60 months, at study entry (Day 1) 
3. Cohort 1 and 2 subjects must have at least a 6-month period of pretreatment growth 
assessment in Study 111-901 immediately before study entry and have one documented 
measurement of height/body length a minimum of 6 months (+/- 10 days) prior to the 
screening visit for 111-206.  Cohort 3 subjects must have a minimum of 3 months of 
observation prior to treatment.  This observational period can be obtained either (1) via prior 
enrollment in Study 111-901 or (2) via enrollment in this Study 111-206 for a minimum of 
3 months of non-treatment observation prior to commencement of treatment. 
4. Parent(s) or guardian(s) (and the subjects themselves, if required by local regulations or 
ethics committee) are willing and able to provide written, signed informed consent after the 
nature of the study has been explained and prior to performance of any research-related 
procedure 
5. Willing and able to perform all study procedures as physically possible 
6. Parent(s) or caregiver(s) are willing to administer daily injections to the subjects and 
complete the required training 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
1. Have hypochondroplasia or short-stature condition other than achondroplasia (e.g., 
trisomy 21, pseudoachondroplasia, etc.) 
2. Subject weighs < 5.0 kg (Cohorts 1 and 2) or <  4.0 kg (Cohort 3) 
3. Have any of the following: 
• 
Hypothyroidism or hyperthyroidism 
• 
Insulin-requiring diabetes mellitus 
• 
Autoimmune inflammatory disease (including celiac disease, systemic lupus 
erythematosus, juvenile dermatomyositis, scleroderma, etc.) 
• 
Inflammatory bowel disease 
• 
Autonomic neuropathy 


 
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Proprietary and Confidential 
16 August 2018 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
4. Have a history of any of the following: 
• 
Renal insufficiency defined as serum creatinine > 2 mg/dL 
• 
Chronic anemia or Hgb  < 10.0 g/dL (based on screening clinical laboratory testing) 
• 
Baseline systolic blood pressure (BP) below age and gender specified normal range 
or recurrent symptomatic hypotension (defined as episodes of low BP generally 
accompanied by symptoms e.g., dizziness, fainting) or recurrent symptomatic 
orthostatic hypotension 
• 
Cardiac or vascular disease, including the following: 
o Cardiac dysfunction (abnormal echocardiogram determined to be 
clinically significant by PI and medical monitor) at Screening Visit  
o Hypertrophic cardiomyopathy 
o Pulmonary hypertension 
o Congenital heart disease with ongoing cardiac dysfunction  
o Cerebrovascular disease 
o Aortic insufficiency or other clinically significant valvular dysfunction 
o Clinically significant atrial or ventricular arrhythmias 
5. Have a clinically significant finding or arrhythmia that indicates abnormal cardiac function 
or conduction or QTc-F  > 450 msec on screening ECG 
6. Have evidence of cervicomedullary compression (CMC) likely to require surgical 
intervention within 60 days of Screening as determined by the Investigator and informed by 
the following assessments: 
• 
Physical exam (eg, neurologic findings of clonus, opisthotonus, exaggerated 
reflexes, dilated facial veins) 
• 
Polysomnography (eg, severe central sleep apnea) 
• 
MRI indicating presence of severe CMC or spinal cord damage 
7. Have an unstable medical condition likely to require surgical intervention in the next 
6 months, or planned spine or long-bone surgery (i.e., surgery involving significant 
disruption of bone cortex) during the study period 
8. Have documented uncorrected Vitamin D deficiency: 25(OH)D   ≤ 15 ng/mL (37.5 nmol/L) 
9. Require any other investigational product prior to completion of the study period 
10. Have received another investigational product or investigational medical device within 
30 days prior to the Screening visit 


 
Study 111-206A1 
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Proprietary and Confidential 
16 August 2018 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
11. Have used any other investigational product or investigational medical device for the 
treatment of achondroplasia or short stature at any time  
12. Require current chronic therapy with antihypertensive medication or any medication that, in 
the investigator’s judgment, may compromise the safety or ability of the subject to 
participate in this clinical study (Table 9.3.5.1) 
13. Have been treated with growth hormone, insulin-like growth factor 1 (IGF-1), or anabolic 
steroids in the 6 months prior to screening, or long-term treatment ( > 3 months) at any time 
14. Have had regular long-term treatment (> 1 month) with oral corticosteroids (low-dose 
ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable) in the 12 months 
prior to screening 
15. Have ever had cervicomedullary decompression surgery (Cohorts 2 and 3 only), spine or 
long-bone surgery (ie, surgery involving disruption of bone cortex) or have ever had bone-
related surgery with chronic complications 
NOTE: Subjects with prior cervicomedullary decompression may be allowed into 
Cohort 1 only after discussion and agreement with Medical Monitor. 
16. Have ever had limb-lengthening surgery or plan to have limb-lengthening surgery during 
the study period 
17. Have had a fracture of the long bones or spine within 6 months prior to screening 
18. Have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or total bilirubin 
greater than upper limit of normal at screening (except for subjects with a known history of 
Gilberts or newborns entering screening in Cohort 3) 
19. Have evidence of severe untreated sleep apnea; or have newly initiated sleep apnea 
treatment (eg, CPAP or sleep apnea-mitigating surgery) in the 2 months prior to screening  
20. Have current malignancy, history of malignancy, or currently under work-up for suspected 
malignancy 
21. Have known hypersensitivity to BMN 111 or its excipients 
22. Have a history of hip surgery or severe hip dysplasia 
23. Have a history of clinically significant hip injury in the 30 days prior to screening  
24. Have a history of slipped capital femoral epiphysis or avascular necrosis of the femoral 
head  


 
Study 111-206A1 
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Proprietary and Confidential 
16 August 2018 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
25. Have abnormal findings on baseline clinical hip exam or imaging assessments that are 
determined to be clinically significant as determined by the Investigator 
26. Have a condition or circumstance that, in the view of the Investigator, places the subject at 
high risk for poor treatment compliance or for not completing the study 
27. Have any concurrent disease or condition that, in the view of the Investigator, would 
interfere with study participation or safety evaluations, for any reason 
Inclusion Criteria for Cohort 3 Observation Period 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Parent(s) or guardian(s) willing and able to provide signed informed consent after the nature 
of the study has been explained and prior to performance of any research-related procedure. 
Also, willing and able to provide written assent (if applicable) after the nature of the study 
has been explained and prior to performance of any research-related procedure. 
2. Birth to ≤ 3 months of age at study entry.  
3. Have ACH, documented by genetic testing 
4. Are willing and able to perform all study procedures as physically possible 
Exclusion Criteria for Cohort 3 Observation Period 
Individuals who meet any of the following exclusion criteria are not eligible to participate in the 
study: 
1. Have hypochondroplasia or short stature condition other than ACH (e.g., trisomy 21, 
pseudoachondroplasia) 
2. Have any of the following disorders: 
• 
Hypothyroidism 
• 
Insulin-requiring diabetes mellitus 
• 
Autoimmune inflammatory disease (including celiac disease, lupus (SLE), juvenile 
dermatomyositis, scleroderma, and others) 
• 
Inflammatory bowel disease 
• 
Autonomic neuropathy 
3. Have an unstable clinical condition likely to lead to intervention during the course of the 
study, including progressive cervical medullary compression  


 
Study 111-206A1 
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Proprietary and Confidential 
16 August 2018 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
4. Have a history of any of the following: 
• 
Renal insufficiency  
• 
Anemia  
5. Have a history of cardiac or vascular disease, including the following: 
• 
Cardiac dysfunction  
• 
Hypertrophic cardiomyopathy 
• 
Congenital heart disease 
• 
Cerebrovascular disease, aortic insufficiency 
• 
Clinically significant atrial or ventricular arrhythmias 
6. Current treatment with antihypertensive medications, ACE inhibitors, angiotensin II 
receptor blockers, diuretics, beta-blockers, calcium-channel blockers, cardiac glycosides, 
systemic anticholinergic agents, any medication that may impair or enhance compensatory 
tachycardia, drugs known to alter renal function that is expected to continue for the duration 
of the study 
7. Have had regular long-term treatment (> 1 month) with oral corticosteroids (low-dose 
ongoing inhaled steroid for asthma is acceptable) in the previous 3 months 
8. Concomitant medication that prolongs the QT/QTc interval within 14 days or 5 half-lives, 
whichever is longer, before the Screening visit 
9. Have used any other investigational product or investigational medical device for the 
treatment of ACH or short stature 
10. Planned or expected bone-related surgery (ie. surgery involving disruption of bone cortex), 
during the study period.  
11.  Planned or expected to have limb-lengthening surgery during the study period.   
12. Have any condition that, in the view of the Investigator, places the subject at high risk of 
poor compliance with the visit schedule or of not completing the study. 
13. Concurrent disease or condition that, in the view of the Investigator, would interfere with 
study participation 


 
Study 111-206A1 
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Proprietary and Confidential 
16 August 2018 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
INVESTIGATIONAL PRODUCT, DOSE, ROUTE, and REGIMEN: The clinical drug product 
will be supplied in sterile, single-dose, Type I glass vials with coated stopper and flip-off aluminum 
cap. BMN 111 drug product is supplied as a 0.8-mg or 2-mg lyophilized, preservative-free, white-
to-yellow powder for reconstitution with either a sterile diluent or sterile water for injection. The 
reconstituted solution is colorless to yellow and contains 0.8 mg/mL to 2 mg/mL of BMN 111, as 
well as citric acid, sodium citrate, trehalose, mannitol, methionine, polysorbate 80, and sterile water 
for injection. The target pH of the reconstituted solution is 5.5. Sterile water for injection will be 
commercially sourced and sterile diluent solution containing all of the above excipients will be 
supplied for reconstitution. All reconstitution and dose preparation steps will be performed as 
indicated in the BMN 111 Injection Guide and Injection video.  
BMN 111 will be administered as a single SC injection given daily at approximately the same time 
each day whenever possible. Following administration of each dose at clinic visits, subjects should 
be observed for 8 hours after the injection on Days 1 and 2; 4 hours on Days 3 and 8; and 1 hour on 
subsequent dosing visits. Subjects should be observed for 30 minutes after every injection that is not 
administered at the clinic. 
REFERENCE THERAPY, DOSE, ROUTE, and REGIMEN: BMN 111-placebo lyophilized 
product will be supplied in sterile, single-dose, Type I glass vials with coated stopper and flip-off 
aluminum cap. The placebo is designed to be comparable in appearance to the drug product and 
contains all of the components of the drug product except the drug substance.  
All reconstitution and dose preparation steps should be performed as indicated in the Study Drug 
Injection Guide and Injection instruction media. 
Placebo will be administered as a single SC injection given daily at approximately the same time 
each day whenever possible. Following administration of each dose at clinic visits, subjects should 
be observed for 8 hours after the injection on Days 1 and 2; 4 hours on Days 3 and 8; and 1 hour on 
subsequent dosing visits. Subjects should be observed for 30 minutes after every injection that is not 
administered at the clinic. 
DURATION OF TREATMENT: Up to 52 weeks 
CRITERIA FOR EVALUATION: 
Safety: The following safety outcome measurements will be assessed: 
• 
Incidence of AEs and SAEs 
• 
Vital signs (heart rate, blood pressure, respiratory rate, and temperature) 
• 
Physical examination (including neurological assessment) 
• 
Hip clinical assessment 
• 
Laboratory test results (urinalysis, chemistry, hematology) 
• 
Electrocardiogram (ECG) 


 
Study 111-206A1 
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Proprietary and Confidential 
16 August 2018 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
• 
Echocardiogram  
• 
Anti-BMN 111 immunogenicity assessments 
• 
Cortisol levels 
• 
Prolactin levels 
Efficacy: The following efficacy outcome measurements will be assessed: 
• 
Change from baseline in AGV  
• 
Change from baseline in length/height Z-score 
Pharmacokinetics: Whenever possible, the following PK parameters will be estimated by 
non-compartmental analysis: 
• 
Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞)  
• 
Area under the plasma concentration-time curve from 0 to the time of last measurable 
concentration (AUC0-t) 
• 
Maximum plasma concentration (Cmax)  
• 
Time to reach Cmax (Tmax)  
• 
Elimination half-life (t1/2)  
• 
Apparent clearance of drug (CL/F)  
• 
Apparent volume of distribution based upon the terminal phase (Vz/F)  
Drug accumulation after repeat-dose administration will also be evaluated. PK parameters at 
Week 13, 26, 39 and 52 will be compared to Day 1. The impact of immunogenicity (if present) on 
PK will also be evaluated. 
Bone metabolism and BMN 111 pharmacodynamic biomarkers:  
• 
Changes in bone and collagen metabolism and BMN 111 activity will be assessed.  
Clinical outcome assessments: 
• 
Bayley-III  
• 
WeeFIM  
• 
CBCL 
• 
ITQOL  
Exploratory: The following exploratory measurements will be assessed: 
• 
Upper:lower body segment ratio 
• 
Imaging assessments (X-rays of the spine and lower extremities) 
• 
MRI to define skull and brain morphology (including dimensions of foramen magnum, 
ventricular and brain parenchymal dimensions) 
• 
Sleep study 
• 
Clinical photography (optional) 


 
Study 111-206A1 
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Proprietary and Confidential 
16 August 2018 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
STATISTICAL METHODS:  
Sample Size Determination: Approximately 70 subjects age 0 to < 60 months at study entry will 
participate in this study. No formal sample size calculations were performed. The number of 
subjects is considered appropriate to evaluate the safety and efficacy of BMN 111 in the target 
population.    
Safety Analysis: All subjects who receive at least one dose of study treatment or who are 
randomized to the placebo-control group in this study will be included in the safety analysis. The 
safety analysis will be descriptive. 
All AEs will be coded using the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA) to assign system organ class and preferred term classification to event and 
disease, based on the original terms entered on the eCRF. The incidence of AEs will be summarized 
by system organ class, preferred term, relationship to study treatment as assessed by the 
investigator, seriousness, and severity. All AEs, including SAEs and AEs that lead to permanent 
discontinuation from the study and from the study treatment, will be listed. 
All other safety measures including laboratory tests, vital signs, ECG, echocardiogram, hip clinical 
assessment, and concomitant medication data will also be summarized descriptively. Data 
summaries will be presented by treatment group (when applicable) for each cohort and overall. All 
safety results will be listed.  
Efficacy Analysis: 
All randomized subjects who receive at least one dose of study treatment or placebo in the study 
will be included in the efficacy analysis.  
Efficacy variables, including AGV (based on length/height) and length/height Z-score according to 
normal reference standards (not ACH), along with their change from baseline will be summarized 
by treatment group and cohort. Comparisons between treatment groups by cohort on these variables 
will be carried out where appropriate. Statistical comparisons will be considered descriptive. 95% 
CIs will be provided along with p values for treatment group comparisons.  
Sentinel subjects will be summarized apart for both efficacy and safety. 


 
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16 August 2018 
3 TABLE OF CONTENTS 
TITLE PAGE.….……………………………………………………………………………...1 
1 RATIONALE AND SUMMARY OF CHANGES .............................................................2 
2 SYNOPSIS ...........................................................................................................................7 
3 TABLE OF CONTENTS ...................................................................................................25 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................31 
5 ETHICS..............................................................................................................................34 
5.1 Institutional Review Board or Independent Ethics Committee ................................34 
5.2 Ethical Conduct of Study ..........................................................................................35 
5.3 Subject Information and Informed Consent ..............................................................35 
6 INVESTIGATORS AND STUDY ADMINSTIRATIVE STRUCTURE ........................37 
7 INTRODUCTION .............................................................................................................38 
7.1 Nonclinical Studies ...................................................................................................39 
7.2 Previous Clinical Studies ..........................................................................................40 
7.2.1 
Study 111-101 .............................................................................................40 
7.3 Ongoing Clinical Studies ..........................................................................................41 
7.3.1 
Study 111-901 .............................................................................................41 
7.3.2 
Study 111-202 .............................................................................................41 
7.3.3 
Study 111-205 .............................................................................................42 
7.3.4 
Study 111-301 .............................................................................................42 
7.3.5 
Study 111-302 .............................................................................................42 
7.4 Study Rationale .........................................................................................................43 
7.5 Summary of Overall Risks and Benefits ...................................................................45 
7.5.1 
Summary of Risks from Nonclinical Studies ..............................................45 
7.5.2 
Summary of Risks from Clinical Studies ....................................................45 
7.5.2.1 
Study 111-101 ..............................................................................45 
7.5.2.2 
Ongoing Studies ...........................................................................46 
7.5.3 
Summary of Potential Benefits from Clinical Studies ................................46 
8 STUDY OBJECTIVES ......................................................................................................47 
9 INVESTIGATIONAL PLAN ............................................................................................48 


 
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16 August 2018 
9.1 Overall Study Design and Plan .................................................................................48 
9.1.1 
Dose Adjustments ........................................................................................60 
9.1.2 
Stopping Criteria .........................................................................................61 
9.2 Discussion of Study Design, Including Choice of Control Group ............................63 
9.3 Selection of Study Population ...................................................................................63 
9.3.1 
Inclusion Criteria .........................................................................................63 
9.3.2 
Exclusion Criteria ........................................................................................64 
9.3.3 
Inclusion Criteria for Cohort 3 Observation Period ....................................66 
9.3.4 
Exclusion Criteria for Cohort 3 Observation Period ...................................66 
9.3.5 
Current Chronic Therapy with Restricted Medications ..............................68 
9.3.6 
Removal of Subjects from Treatment or Assessment .................................68 
9.3.7 
Subject Identification ..................................................................................70 
9.3.8 
Duration of Subject Participation ................................................................70 
9.4 Treatments .................................................................................................................70 
9.4.1 
Treatments Administered ............................................................................70 
9.4.1.1 
Study Drug Administration ..........................................................71 
9.4.2 
Identity of BMN 111 ...................................................................................71 
9.4.2.1 
Product Characteristics and Labeling ..........................................71 
9.4.3 
Storage .........................................................................................................72 
9.4.4 
Directions for Administration .....................................................................72 
9.4.5 
Method of Assigning Subjects to Treatment Groups ..................................73 
9.4.6 
Selection of Dose and Dosing Schedule Used in the Study ........................73 
9.4.6.1 
Selection of Timing of Dose for Each Subject ............................74 
9.4.7 
Blinding .......................................................................................................74 
9.4.8 
Prior and Concomitant Medications ............................................................75 
9.4.9 
Treatment Compliance ................................................................................75 
9.5 Investigational Product Accountability (BMN 111 or Placebo) ...............................75 
9.5.1 
Return and Disposition of Clinical Supplies ...............................................76 
9.6 Dietary or Other Protocol Restrictions ......................................................................76 
9.7 Demographic Data and Medical History ..................................................................76 


 
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16 August 2018 
9.8 Biological Parental Standing Height .........................................................................77 
9.9 Physical Examination Findings .................................................................................77 
9.10 Echocardiogram ........................................................................................................77 
9.11 Efficacy and Safety Variables ...................................................................................77 
9.11.1 Efficacy and Safety Measurements Assessed .............................................77 
9.11.2 Primary Efficacy Variables .........................................................................77 
9.11.3 Secondary Efficacy Variables .....................................................................78 
9.11.4 Exploratory Efficacy Variables ...................................................................78 
9.11.4.1 
Body Proportion Ratios of the Extremities ..................................78 
9.11.4.2 
Imaging Assessment Procedures (per Schedule of Events) .........79 
9.11.4.3 
Exploratory Biomarker Research Sample Analyses ....................79 
9.11.4.4 
Genomic Biomarker Analysis ......................................................80 
9.11.4.5 
Sleep Study ..................................................................................80 
9.11.4.6 
Clinical Photography ...................................................................80 
9.11.4.7 
Clinical Outcome Assessments ....................................................80 
9.11.5 Pharmacokinetics Variables ........................................................................82 
9.11.6 Safety Variables ..........................................................................................83 
9.11.6.1 
Adverse Events ............................................................................83 
9.11.6.2 
Procedures During the Study .......................................................83 
9.11.6.3 
Clinical Laboratory Assessments .................................................84 
9.11.6.4 
Other Laboratory Assessments ....................................................85 
9.11.6.5 
Vital Signs, Physical Examinations and Other 
Observations Related to Safety ....................................................86 
9.11.6.6 
Mitigating the Risk of Potential Hypotension .............................87 
9.11.6.7 
Electrocardiography .....................................................................88 
9.11.6.8 
Hip Clinical Assessment ..............................................................88 
9.11.6.9 
Pediatric Blood Volume ...............................................................89 
9.11.6.10 Anti- BMN 111 Immunogenicity Assessments and IgE 
Testing..........................................................................................89 
9.11.6.11 HPA Axis Assessments................................................................89 
9.11.6.12 Ad Hoc Safety Assessments ........................................................90 


 
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9.11.6.13 Unscheduled Safety Visits ...........................................................90 
10 REPORTING ADVERSE EVENTS .................................................................................91 
10.1 Safety Parameters and Definitions ............................................................................91 
10.1.1 Adverse Events ............................................................................................91 
10.1.2 Serious Adverse Events ...............................................................................91 
10.1.3 Events of Special Interest (EOSI) ...............................................................92 
10.2 Methods and Timing for Capturing and Assessing Safety Parameters .....................92 
10.2.1 Adverse Event Reporting Period .................................................................92 
10.2.2 Eliciting Adverse Events .............................................................................92 
10.2.3 Assessment of Seriousness, Severity, and Causality ...................................92 
10.2.3.1 
Seriousness ...................................................................................93 
10.2.3.2 
Severity ........................................................................................93 
10.2.3.3 
Causality ......................................................................................94 
10.3 Procedures for Recording Adverse Events ...............................................................96 
10.3.1 Recording Adverse Events on a eCRF ........................................................96 
10.3.1.1 
Diagnosis versus Signs and Symptoms........................................96 
10.3.1.2 
Adverse Events Occurring Secondary to Other Events ...............96 
10.3.1.3 
Persistent or Recurrent Adverse Events .......................................96 
10.3.1.4 
Hypotension .................................................................................96 
10.3.1.5 
Injection Site Reactions ...............................................................97 
10.3.1.6 
Abnormal Laboratory Values ......................................................97 
10.3.1.7 
Pre-existing Conditions ................................................................98 
10.3.1.8 
General Physical Examination Findings ......................................98 
10.3.1.9 
Hospitalization, Prolonged Hospitalization, or Surgery ..............98 
10.3.1.10 Deaths ..........................................................................................99 
10.4 Reporting Requirements ...........................................................................................99 
10.4.1 Expedited Reporting Requirements .............................................................99 
10.4.2 IRB Reporting Requirements ....................................................................100 
10.5 Follow-up of Subjects after Adverse Events ...........................................................100 
10.6 Post-Study Adverse Events .....................................................................................100 


 
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10.7 Urgent Safety Measures ..........................................................................................100 
10.8 BioMarin Pharmacovigilance Contact Information ................................................102 
11 APPROPRIATENESS OF MEASUREMENTS .............................................................103 
12 STUDY PROCEDURES .................................................................................................104 
12.1 Treatment Visit(s) ...................................................................................................104 
12.1.1 Screening/Baseline Day -30 to Day -1 ......................................................104 
12.1.2 Day 1 and Week 13 (±7d) .........................................................................105 
12.1.3 Days 2 and 3 ..............................................................................................105 
12.1.4 Day 8 (±1d) and Week 20 (±7d) ................................................................106 
12.1.5 Week 3 (±7d) .............................................................................................106 
12.1.6 Week 6 (±7d) .............................................................................................107 
12.1.7 Week 26 (±7d) ...........................................................................................107 
12.1.8 Week 39 (±7d) ...........................................................................................108 
12.1.9 Week 52 (±7d) ...........................................................................................109 
12.1.10 Week 56 Safety Follow-up ( + 7d) ............................................................110 
12.1.11 Early Termination Visit .............................................................................110 
12.2 Observational Period for Cohort 3 (Infants between birth and  < 3 months 
old [0 days to   < 13 weeks]) ...................................................................................111 
12.2.1 Screening Visit ..........................................................................................111 
12.2.2 Day 1 (Month 0) ........................................................................................112 
12.2.3 3 Months (± 10 days) .................................................................................112 
13 DATA QUALITY ASSURANCE ...................................................................................113 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ................114 
14.1 Statistical and Analytical Plans ...............................................................................114 
14.1.1 Interim Analyses ........................................................................................114 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data ........114 
14.2 Safety Analysis .......................................................................................................114 
14.3 Efficacy Analysis ....................................................................................................115 
14.4 Pharmacokinetic Analyses ......................................................................................116 
14.5 Immunogenicity Analysis .......................................................................................116 
14.6 Determination of Sample Size ................................................................................116 


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14.7 Analysis Populations ...............................................................................................116 
14.7.1 Efficacy Population ...................................................................................116 
14.7.2 Safety Population ......................................................................................116 
15 DATA MONITORING COMMITTEE ...........................................................................117 
16 COSTS, COMPENSATION, AND SUBJECT INJURY ................................................118 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS ............................................119 
18 STUDY MONITORING AND AUDITING ...................................................................121 
19 RETENTION OF RECORDS..........................................................................................122 
20 USE OF INFORMATION AND PUBLICATION ..........................................................123 
21 REFERENCES ................................................................................................................124 
22 INVESTIGATOR RESPONSIBILITIES ........................................................................126 
22.1 Conduct of Study and Protection of Human Subjects .............................................126 
23 SIGNATURE PAGE .......................................................................................................127 
24 PROTOCOL AMENDMENT TEXT REVISIONS ........................................................128 
LIST OF TABLES 
Table 9.1.1:  Schedule of Events .............................................................................................52 
Table 9.1.2:  Schedule of Events Observational Period for Cohort 3 (infants between 
birth and < 3 months old) ..............................................................................58 
Table 9.3.5.1:  Current Chronic Therapy with Restricted Medications ...................................68 
Table 9.11.6.3.1:  Clinical Laboratory Tests ...........................................................................85 
Table 9.11.6.4.1:  Biomarkers and Anti-BMN 111 Antibodies ...............................................86 
Table 9.11.6.5.1:  Vital Sign Assessment Frequency ..............................................................87 
Table 10.2.3.2.1:  Adverse Event Grading (Severity) Scale ....................................................94 
Table 10.2.3.3.1:  Causality Attribution Guidance ..................................................................95 
 
LIST OF FIGURES 
Figure 9.1.1:  Study Design .....................................................................................................51 
Figure 9.11.4.7.1:  Clinical Outcomes Assessment Tools .......................................................81 


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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
°C 
degree Celsius 
ACE 
angiotensin-converting enzyme 
Ach 
Fgfr3G380R achondroplasia mouse model 
ACH 
achondroplasia 
ADL 
Activity of Daily Living 
ADR 
adverse drug reaction 
AE 
adverse event 
AGV 
annualized growth velocity 
ALT 
alanine aminotransaminase 
ANP 
atrial natriuretic peptide 
AP 
anterior-posterior 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve  
BMC 
bone mineral content 
BMD 
bone mineral density 
BNP 
B-type Natriuretic Peptide 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
cGMP 
cyclic guanosine monophosphate 
Cmax 
maximum observed plasma concentration 
CBCL 
Child Behavior Checklist 
CNP 
C-type natriuretic peptide 
CNP53 
C-type natriuretic peptide (53 amino acids in length) 
CRA 
clinical research associate 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
cardiovascular 
DCF 
data clarification form 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
FGF 
fibroblast growth factor 
G380R 
substitution in the transmembrane domain of the FGFR3 receptor at position 380 
GCP 
Good Clinical Practice 


 
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HIPAA 
Health Insurance Portability and Accountability Act 
HR 
heart rate 
HRQOL 
health-related quality of life 
IB 
investigator brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICH E6 [R2] 
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
IEC 
Independent ethics committee 
IgE 
immunoglobulin E 
IND 
Investigational New Drug (application) 
IP 
investigational product 
IRB 
institutional review board 
ITQOL 
Infant Toddler Quality of Life questionnaire 
LV 
left ventricular 
MAPK 
mitogen-activated protein kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mL 
milliliter 
msec 
millisecond 
NAb 
neutralizing antibodies 
NEP 
neutral endopeptidase 
NP 
natriuretic peptide 
NPR-B 
natriuretic peptide receptor type B 
PA 
posterior-anterior 
PD 
pharmacodynamics 
PI 
Principal Investigator 
PK 
pharmacokinetics 
QT 
a measure of the time between the start of the Q wave and the end of the T wave  
QTc-F 
Fridericia’s corrected QT interval 
REB 
research ethics board 
rhCNP  
recombinant C-type natriuretic peptide 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SOI 
Statement of Investigator Form 
t1/2 
elimination half-life 
TAb 
total antibody 


 
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Tmax 
time to reach Cmax 
ULN 
upper limit of normal 
US 
United States 
WeeFIM 
Functional independence measure for children 
WFI 
water for injection 
µg/kg 
microgram/kilogram 
 
Definition of Terms:  
Investigational Product (IP): 
“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use” 
(from International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline: 
Guideline for Good Clinical Practice E6 [ICH E6] (R2)]).  
The terms “IP” and “study drug” may be used interchangeably in the protocol. 
 


 
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5 
ETHICS 
BioMarin Pharmaceutical Inc. (hereafter referred to as BioMarin or the Sponsor) conducts its 
studies according to the highest ethical and scientific standards. The following sections 
articulate standards to which Investigators will be held accountable, as well as matters of 
compliance to document adherence to such standards. 
5.1 
Institutional Review Board or Independent Ethics Committee 
Investigators are expected to interact with independent Ethics Committees (IECs) promptly, 
as required, during the course of the study. This includes, but is not limited to, providing 
appropriate documentation to support study initiation and maintaining appropriate flow of 
safety and other information during the course of the study and for study close-out activities. 
BioMarin (or designee) will assist Investigators with access to timely and accurate 
information and with assurance of prompt resolution of any queries. 
Prior to initiating the study, the Investigator will obtain written confirmation that the 
institutional review board (IRB) or independent ethics committee (IEC), or Research Ethics 
Board (REB) is properly constituted and compliant with International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) and Good Clinical Practice (GCP) requirements, applicable laws, and local 
regulations. A copy of the confirmation from the IRB/IEC/REB will be provided to BioMarin 
Pharmaceutical Inc. (BioMarin) or its designee.  
The Investigator will provide the IRB/IEC/REB with all appropriate material, including the 
protocol, Investigator’s Brochure (IB), the Informed Consent Form (ICF) including 
compensation procedures, and any other written information provided to the subjects, 
including all ICFs translated for subjects who do not speak the local language at the clinical 
site. The study will not be initiated and Investigational Product (IP) supplies will not be 
shipped to the site until appropriate documents from the IRB/IEC/REB confirming 
unconditional approval of the protocol, the ICF and all subject recruitment materials are 
obtained in writing by the Investigator and copies are received at BioMarin or its designee. 
The approval document should refer to the study by protocol title and BioMarin protocol 
number (if possible), identify the documents reviewed, and include the date of the review and 
approval. BioMarin will ensure that the appropriate reports on the progress of the study are 
made to the IRB/IEC/REB and BioMarin by the Investigator in accordance with applicable 
guidance documents and governmental regulations. 


 
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5.2 
Ethical Conduct of Study 
It is expected that Investigators understand and comply with the protocol. This includes, but 
is not limited to: establishing and meeting enrollment commitments, including providing 
eligible subjects for study enrollment; adhering to adverse event reporting, diagnostic, or 
other procedures as specified in the protocol; and assuring appropriate compliance with study 
treatment administration and accountability. 
This study will be conducted in accordance with the following: 
• European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC, for studies conducted within any European country 
• US Code of Federal Regulations (CFR) sections that address clinical research studies, 
and/or other national and local regulations, as applicable 
• ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
(ICH E6) or E6(R2) (ICH E6R2) if adopted 
• The ethical principles established by the Declaration of Helsinki 
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB/IEC/REB and will be conducted by scientifically and medically qualified persons. 
The benefits of the study are in proportion to the risks. The rights and welfare of the subjects 
will be respected and the investigators conducting the study do not find the hazards to 
outweigh the potential benefits. Each subject, or his/her legally authorized representative will 
provide written, informed consent before any study-related tests or evaluations are 
performed. 
5.3 
Subject Information and Informed Consent 
A properly written and executed informed consent form (ICF), in compliance with the 
Declaration of Helsinki, ICH E6 (Section 4.8), United States Code of Federal Regulations 
(CFR) 21 CFR §50, European Clinical Trial Directive 2001/20/EC and Good Clinical 
Practice Directive 2005/28/EC, and other applicable local regulations, will be obtained for 
each subject prior to entering the subject into the study. The Investigator will prepare the ICF 
and provide the documents to BioMarin for approval prior to submission to the IRB/EC/REB 
approval. BioMarin and the IRB/IEC/REB must approve the documents before they are 
implemented. A copy of the approved ICF (minor assent form and parental ICF for studies 
involving minors), and if applicable, a copy of the approved subject information sheet and all 
ICFs translated to a language other than the native language of the clinical site must also be 
received by BioMarin or designee prior to any study-specific procedures being performed. 


 
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Subjects under the age of majority will provide written assent (if required), and his/her 
legally authorized representative (parent or legal guardian) will provide written informed 
consent for such subjects. The Investigator will provide copies of the signed ICF to each 
subject (or the legally authorized representative of the subject) and will maintain the original 
in the record file of the subject. 
 


 
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6 
INVESTIGATORS AND STUDY ADMINSTIRATIVE STRUCTURE  
During administration of informed consent, expectations regarding participation in the study 
should be made clear to subjects. Subjects who are not willing and/or are not able to comply 
with all aspects of the study should not be encouraged to participate. 
Prior to beginning the study, the Investigator at each site must provide to BioMarin or 
designee a fully executed and signed Statement of Investigator (SOI) form.  A US Food and 
Drug Administration (FDA) Form FDA 1572 serves as an acceptable SOI form.  If Form 
FDA 1572 may not be used in a particular region, the Investigator must provide a fully 
executed SOI on the form provided by the Sponsor.  All Investigators and Sub-Investigators 
must be listed on Form FDA 1672 or its equivalent SOI.  Financial Disclosure Forms must 
also be completed for all Investigators and Sub-Investigators listed on the Form FDA 1572 or 
SOI who will be directly involved in the treatment or evaluation of subjects in this study. 
The study will be administered by and monitored by employees or representatives of 
BioMarin. Clinical research associates (CRAs) or trained designees will monitor each site on 
a periodic basis and perform verification of source documentation for each subject as well as 
other required review processes. BioMarin’s Pharmacovigilance Department (or designee) 
will be responsible for the timely reporting of serious adverse events (SAEs) to appropriate 
regulatory authorities as required. 
In multicenter studies, a Coordinating Investigator will be identified who will be responsible 
for study overview. The Coordinating Investigator will read the clinical study report (CSR) 
and confirm that it accurately describes the conduct and results of the study, to the best of his 
or her knowledge. The Coordinating Investigator will be chosen on the basis of active 
participation in the study, ability to interpret data, and willingness to review and sign the 
report in a specified timeframe. The identity of the Coordinating Investigator and a list of all 
Investigators participating in the study will be provided in the CSR. 


 
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7 
INTRODUCTION 
BMN 111 is a proposed pharmacologic therapeutic option for ACH, the most common form 
of dwarfism. 
ACH is a rare disease with a prevalence of 1/25000 in the US (Wynn, 2007) The average 
adult heights for men and women with ACH are 131 cm and 124 cm, respectively 
(NIH, Genetics Home Reference, 2012).  Characteristic features include long and narrow 
trunk, a large head with frontal bossing, hypoplasia of the mid-face, bowed legs and stenosis 
of the foramen and spinal canals that can be life-threatening. Foramen magnum stenosis can 
lead to cervicomedullary compression in infants with complications including hydrocephalus, 
hypotonia, respiratory insufficiency, apnea, cyanotic episodes, feeding problems, 
quadriparesis, and sudden death.  
There is no approved pharmacological therapy for achondroplasia in the US or EU. Current 
treatments for achondroplasia are focused on neurosurgical interventions for foramen 
magnum stenosis or lumbar stenosis, thoracolumbar braces to help ameliorate the kyphosis, 
or limb lengthening requiring multiple operations over 2 to 3 years (Shirley, 2009), 
(Horton, 2007).  
ACH is caused by a gain-of-function mutation in FGFR3, a negative regulator of 
chondrocyte proliferation and differentiation.  The most common mutation (98%) in ACH 
patients is a G380R substitution in the transmembrane domain of FGFR3.  The majority of 
new cases (80%) originate from parents with normal stature.   
The extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) 
pathway mediates part of FGFR3 inhibition of chondrocyte proliferation and differentiation 
(Foldynova-Trantirkova, 2012).  The ERK MAPK pathway is modulated by CNP, a positive 
regulator of chondrocyte proliferation and differentiation.  Binding of CNP to the Natriuretic 
Peptide-Receptor B (NPR-B) antagonizes FGFR3 downstream signaling by inhibiting the 
MAPK (ERK1/2) pathway at the level of RAF-1 (Krejci, 2005); (Yasoda, 2004); 
(Yasoda, 2009); (Pejchalova, 2007).  This crosstalk was demonstrated in a mouse model of 
FGFR3-related chondrodysplasia (Yasoda, 2004); (Yasoda, 2009).  The dwarfism phenotype 
of mice harboring the FGFR3G380R mutation was rescued by expression of CNP in cartilage 
or by the continuous administration of CNP (infusion). 
CNP is a member of the natriuretic peptide (NP) family that includes Atrial Natriuretic 
Peptide (ANP) and B-type Natriuretic Peptide (BNP). These peptides are structurally related 
but are distinct paracrine/autocrine (CNP) or endocrine (ANP and BNP) factors that regulate 
the cardiovascular (CV), skeletal, nervous, reproductive and other systems. Synthetic analogs 


 
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of ANP (anaritide and carperitide) and BNP (nesiritide) have been investigated as potential 
therapies for the treatment of decompensated heart failure and cardiovascular-related 
diseases. 
BMN 111 is a 39-amino acid CNP analogue harboring the 37 amino acids of the human 
CNP53 C-terminal sequence and modified by the addition of two amino acids (Pro-Gly) on 
the N-terminus.  It is a recombinant human peptide fused to human transcription factor 
(TAF) and expressed as an inclusion body in E. coli.  BMN 111 is liberated and solubilized 
from the TAF-fusion protein by formic acid cleavage, and purified by column 
chromatography (Long, 2012).  BMN 111 was designed to 1) mimic CNP activities in terms 
of receptor binding and pharmacological activity and 2) be resistant to neutral endopeptidase 
(NEP) digestion in order to have an extended half-life in comparison to CNP that is 
presumed to increase exposure to the target growth plate (Wendt, 2015).  
A comprehensive review of BMN 111 is contained in the current version of the Investigator’s 
Brochure supplied by BioMarin.  Investigators are required to review the Investigator’s 
Brochure prior to initiating this study. 
7.1 
Nonclinical Studies 
The pharmacological activity of BMN 111 was explored in two mouse models of ACH, a 
severe, Fgfr3Y367C/+ model (Lorget, 2012), and a mild [Ach] /+ model.  Partial or complete 
reversion of the ACH phenotype was observed in these mouse models after BMN 111 
administration.  Additionally, in wild-type mice, and normal rats and monkeys, BMN 111 
administration resulted in growth plate expansion and dose-dependent skeletal growth at 
hemodynamically tolerated dose levels (Wendt, 2015).  
BMN 111-related adverse findings in nonclinical species (mice, rats, cynomolgus monkeys) 
were limited to the known mechanism of action of CNP on the growth plate and vasculature.  
Reversible subcutaneous injection site reactions were reported, including injection site 
discoloration and microscopic findings of perivascular mononuclear cell infiltrates that were 
seen with slightly higher incidence and severity in BMN 111-treated rats and monkeys 
compared to the vehicle control.  Adverse skeletal changes associated with exaggerated 
growth were seen in normal nonclinical species with open growth plates, and were dose-, 
exposure- and time-dependent. Decreases in blood pressure and compensatory increases in 
heart rate were detected in monkeys across multiple studies, with overt CV-related clinical 
signs observed in some animals at doses ≥ 236 µg/kg. These overt clinical signs consisted of 
transient, short and repeated bouts of sternal or lateral recumbency and/or reduced motor 
activity, typically within 1-hour post-dose administration.  Additional detailed information 


 
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about nonclinical studies of BMN 111 is provided in the current version of the Investigator’s 
Brochure supplied by BioMarin.   
7.2 
Previous Clinical Studies 
7.2.1 Study 111-101 
Study 111-101, “A Phase 1, Two Part, Double Blind, Placebo-Controlled Study to Evaluate 
the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Doses of BMN 111 
Administered to Healthy Adult Volunteers,” was a first-in-human study conducted in 2 parts 
to allow for assessment of the safety, tolerability, and PK of BMN 111 administered as a 
single dose and as a multiple dose to healthy adult male volunteers. 
Doses ranging from 5.0 µg/kg to 15.0 µg/kg were administered as a single daily SC dose; 
doses ranging from 0.5 µg/kg to 8.0 µg/kg were administered in the multiple ascending dose 
segment of the study. As expected, mild, transient, self-limited hypotension occurred. 
The majority of these cases were asymptomatic and observed upon assumption of an upright 
posture following recumbence. Hypotension events were reported in the BMN 111 treatment 
groups with higher frequency compared with placebo. All events were judged to be mild in 
severity and resolved spontaneously without an intervention. These events occurred across 
dose ranges.  Due to the limited number of events at each dose, it is unclear if symptomatic 
hypotension is dose related.  No dose limiting toxicities were identified outside of these 
cardiovascular events. The only AEs occurring in more than one subject receiving BMN 111 
were orthostatic hypotension, contact dermatitis, and back pain, and injection site reactions. 
Most AEs in the study were of mild severity, and no SAEs were reported. There were no AEs 
that led to premature discontinuation of study drug.   
The PK parameters for BMN 111 were obtained from Part 1 of the study and from the first 
dose on Day 1 of the multiple dose study in Part 2. The results demonstrate that BMN 111 
was rapidly absorbed in human, reaching a mean time to peak concentration (Tmax) between 
15-26 minutes. After reaching maximal plasma concentrations, BMN 111 levels rapidly 
declined, with a t1/2 of 40-55 minutes. Mean plasma concentration-time profiles indicate that 
exposure increased with dose from 2.5 to 15 µg/kg. The corresponding increases in plasma 
Cmax and area under the curve (AUC) exposure parameters were greater than dose 
proportional. The increase in Cmax with dose was linear over the dose range evaluated.  
In Part 2, with multiple dosing at 5 µg/kg for 10 days, the plasma concentration-time curves 
obtained on each of the three sampling days were nearly superimposable. Comparison of PK 
exposure parameters for AUC and Cmax indicate that Cmax is unchanged and AUC is 


 
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increased slightly by +33% over Day 1.  Overall the results indicate that changes in 
BMN 111 exposure are minimal with repeat dosing out to 10 days. 
7.3 
Ongoing Clinical Studies 
7.3.1 Study 111-901 
Study 111-901 is a multicenter, multinational study to collect serial growth measurements on 
pediatric subjects with ACH who are being considered for subsequent enrollment in future 
studies sponsored by BioMarin. To obtain accurate baseline measurements, at least 6 months 
of growth data are collected.  
Data gathered from this study are used to characterize baseline growth data in children or 
infants (defined as children < 2 years of age) who may subsequently be enrolled in future 
studies sponsored by BioMarin, and may also be used to establish historical control cohort 
for use in other BioMarin-sponsored studies, when appropriate. For that reason, data related 
to ACH symptoms, tests, and interventions are collected. 
7.3.2 Study 111-202 
Study 111-202 is an ongoing Phase 2, open-label, sequential cohort, dose escalation study 
that assesses daily SC administration of BMN 111 in pediatric subjects with ACH. 
The primary objective of Study 111-202 is to evaluate the safety and tolerability of BMN 111 
administered for 6 months and up to 24 months; the secondary objectives are to determine 
change from baseline in annualized growth velocity (AGV), growth parameters, body 
proportions, and evaluate the dose-exposure and PK profiles of BMN 111 in children with 
ACH.  
Analysis of safety data from the 6-month initial phase of Study 111-202 showed that 
treatment with BMN 111 for 6 months at dose cohorts of 2.5, 7.5, 15, and 30 µg/kg 
(Cohorts 1 to 4, respectively) was generally well tolerated. The most common AEs were mild 
injection site reactions, asymptomatic hypotension, headache, and nasopharyngitis. For a 
detailed summary of risks, please refer to the current version of the Investigator’s Brochure 
supplied by BioMarin.  
Analysis of efficacy data from the 6-month initial phase of Study 111-202 demonstrated that 
the mean (standard deviation) change from baseline AGV when BMN 111 is administered at 
2.5, 7.5, 15, and 30 µg/kg subcutaneously daily for 6 months is -0.37 (1.592), 1.28 (1.439), 
2.01 (1.999), and 2.08 (2.137) cm/year, respectively.  Thus, a positive dose-dependent 
response was observed in change from baseline AGV at doses ranging from 2.5-15 µg/kg 
daily.   


 
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For longer term follow up data from the 202 study, please refer to the current Investigator 
Brochure supplied by BioMarin. 
7.3.3 Study 111-205 
Study 111-205 is an ongoing open-label, Phase 2 extension study to assess long-term safety, 
tolerability, and efficacy of BMN 111 in children with ACH. Subjects continue receiving the 
same stable dose of BMN 111 received upon completion of the 111-202 study (up to 
30 µg/kg daily). This 5-year study allows for long-term assessment of the effect of daily 
BMN 111 administration on safety, tolerability, growth velocity, height, and body 
proportions in subject completing 2 years of BMN 111 treatment in Study 111-202 (7 years 
total BMN 111 treatment duration). Additional exploratory endpoints are being examined to 
determine long-term effects of BMN 111 on bone physiology and the medical complications 
of ACH. 
7.3.4 Study 111-301 
Study 111-301 is an ongoing Phase 3, double-blind, placebo-controlled multicenter study to 
further characterize and confirm efficacy and safety of BMN 111 at 15 µg/kg in a 58-week 
study (up to 4 weeks of screening, 52 weeks of treatment, plus an additional 2 weeks of 
safety follow up). The study assesses the effect of daily BMN 111 administration on change 
from baseline in AGV, height, and body proportions in subjects treated with BMN 111 
compared with control subjects in the placebo group; and further characterizes safety and 
tolerability of BMN 111 in children with ACH. Additional exploratory endpoints are being 
examined to determine the effect of BMN 111 on bone physiology and to assess quality of 
life and daily function of study subjects. 
7.3.5 Study 111-302 
Study 111-302 is an open-label Phase 3 extension study to further evaluate the efficacy and 
safety of BMN 111 either until subjects reach near-final adult height (defined as evidence of 
growth plate closure and < 1.5 cm/yr annualized growth velocity), or for 5 years if near-final 
adult height (NFAH) occurs prior to the end of the 5-year period.  All subjects will receive 
BMN 111 15 µg/kg. This study will allow for long-term assessment of the effect of daily 
BMN 111 administration on safety, tolerability, growth velocity, height, and body 
proportions in subjects who have completed 1 year of placebo or BMN 111 treatment in 
Study 111-301.   


 
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7.4 
Study Rationale 
BMN 111 is a recombinant CNP analogue that has been engineered to resist degradation by 
NEP, allowing for a longer half-life. 
The pharmacological activity of BMN 111 was explored in two mouse models of ACH, a 
severe, Fgfr3Y367C/+ (TD) model (Lorget, 2012), and a milder [Ach] /+ (Ach) model. These 
included studies in 7-day old TD mice given BMN 111 daily by SC administration for up to 
20 days and a study in 3 week old Ach mice given BMN 111 daily by SC administration for 
5 weeks. Partial or complete reversion of the ACH phenotype was observed in these mouse 
models after BMN 111 administration. In wild-type mice, and normal rats and monkeys, 
BMN 111 administration resulted in growth plate expansion and dose-dependent skeletal 
growth at hemodynamically tolerated dose levels (Wendt, 2015). Additionally, the potential 
effect of age on BMN 111 PK was evaluated in normal rats aged between 7 days and 
12-13 weeks. 
Infants and young children with ACH have a high incidence of medical complications and 
currently there is no approved pharmacological therapy for ACH in the US or EU. The most 
severe complication, cervicomedullary compression (CMC), occurs in a subset of subjects 
with ACH due to abnormal endochondral bone growth and narrowing of the foramen 
magnum (White, 2016). CMC has been linked to serious respiratory and neurological 
complications including hypotonia, apnea, ataxia, developmental delay, and respiratory arrest 
associated with sudden death (Mukherjee, 2014). Foramen magnum decompression surgery 
is currently the only treatment for this condition.   
Sleep apnea has also been extensively described in ACH, and sleep-disordered breathing may 
affect up to 85% of all children with ACH (Ireland, 2012). This is thought to be due to 
midface hypoplasia, relative adenotonsillar hypertrophy, and potential posterior cranial fossa 
compression secondary to abnormal endochondral bone growth. Sleep apnea in ACH not 
only results in the need for surgical intervention, but has also been linked to sudden death in 
rare cases (Pauli, 1984).   
Similarly, the dysregulation of endochondral bone growth in ACH leads to other medical 
complications which are prevalent in this subject population, such as the following: 
• Spinal stenosis, kyphosis, and lordosis (secondary to altered growth plate ossification 
in the vertebrae and narrowing of the interpedicular distances) (Shirley, 2009) 
• Developmental delay of gross motor and ambulatory skills (associated with proximal 
limb shortening, macrocephaly, and hypotonia) (Ireland, 2010) 


 
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• Delayed functional skills and increased need for caregiver assistance (eg, eating, 
bladder management, bowel management, transfer to chair, climbing stairs) 
(Ireland, 2011) 
Thus, BMN 111 may provide greater benefit when children begin treatment at a younger age, 
as earlier initiation of treatment allows a longer time window to improve growth and 
potential to improve medical complications of achondroplasia. This study (111-206) is being 
conducted to assess safety and the potential benefit of BMN 111 in infants and young 
children.   
BioMarin has engineered a CNP analog (BMN 111) that has a longer half-life than 
endogenous CNP, thereby allowing daily SC administration. Similar to CNP, BMN 111 
activates NPR-B signaling with subsequent inhibition of FGFR3 downstream signaling, 
leading to the promotion of chondrocyte proliferation and differentiation and subsequent 
increased endochondral bone formation. BMN 111 administration has been shown to 
promote endochondral bone formation at hemodynamically tolerated dose levels in both 
normal animals and mouse models of ACH reported (refer to current Investigator’s Brochure 
for additional information). 
Human studies to date have also demonstrated that BMN 111 is generally well tolerated at 
doses that result in improvements in growth velocity approaching that of children of average 
stature. 
Study 111-202 is an ongoing Phase 2, open-label, sequential cohort, dose escalation study 
that assesses daily SC administration of BMN 111 in pediatric subjects with ACH, in which 
the primary objective is to evaluate the safety and tolerability of BMN 111 administered for 
6 months and up to 24 months and includes secondary objectives consisting of determination 
of change from baseline in AGV, growth parameters, body proportions, and evaluation of the 
dose-exposure and PK profiles of BMN 111 in children with ACH.  
Analysis of safety data from the 6-month initial phase of Study 111-202 showed that 
treatment with BMN 111 was generally well tolerated at all dose levels (refer to current 
Investigators Brochure for specific details).  
Analysis of efficacy data from Study 111-202 demonstrated that that subjects given 
BMN 111 at the dose of 15 µg/kg daily had an improvement in AGV, with approximately 
~50% increase over baseline seen with treatment for 6 months which was sustained after 
continued treatment for 12 months.  
Subjects treated with 30 µg/kg daily also showed similar improvement in mean AGV after 
6 months and their mean changes from baseline in AGV were similar to subjects treated with 


 
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15 µg/kg daily. Safety data for the 30-µg/kg daily dose was also similar to the 15-µg/kg daily 
dose.  Given that no clinically significant difference could be identified between the 
15-µg/kg and 30-µg/kg daily dose in the Phase 2, 6-month safety and efficacy data, the lower 
of the two doses has been chosen for this Phase 2 study.  
Study 111-206 is a Phase 2 randomized, double-blind, placebo-controlled clinical trial of 
BMN 111 in infants and younger children with a diagnosis of ACH who are age 0 to 
< 60 months. This 52-week study will enable assessment of BMN 111 safety, tolerability, 
pharmacodynamics biomarkers, and PK in this population, and also allow for examination of 
potential impact on efficacy endpoints. Additional exploratory endpoints pertaining to 
medical complications of ACH will also be evaluated.  
7.5 
Summary of Overall Risks and Benefits 
7.5.1 Summary of Risks from Nonclinical Studies 
Individuals in this study will be exposed to a recombinant analogue of human C-type 
natriuretic peptide (CNP). Based on the results of experimentation in animals, the most 
relevant potential toxicities relate to the expected pharmacological effects of exogenous CNP 
administration, including hemodynamic changes, skeletal overgrowth, and injection site 
reactions. Transient and sporadic decreases in blood pressure and compensating increases in 
heart rate occurred within the first hour post-dose in cynomolgus monkeys; the effects were 
mainly asymptomatic with a subset of animals given doses ≥ 236 µg/kg observed with 
symptomatic effects consisting of transient, short and repeated bouts of sternal or lateral 
recumbency and/or reduced motor activity. These hemodynamic effects can be monitored, 
but have the potential to be an acute dose-limiting factor in patients.  Exaggerated 
appendicular bone responses to the drug included abnormally shaped femoral head, 
acetabular growth center/plate dysplasia and concomitant articular cartilage degeneration 
with clinical manifestations of restricted use of hips. Adverse skeletal changes associated 
with exaggerated growth were dose-, exposure- and time-dependent. Additional detailed 
information about risks identified in nonclinical studies of BMN 111 is provided in the 
current version of the Investigator’s Brochure supplied by BioMarin.   
7.5.2 Summary of Risks from Clinical Studies 
7.5.2.1 
Study 111-101 
Based on review of the first-in-human Phase 1 study of BMN 111 in healthy adult volunteers, 
Study 111-101, BMN 111 administered SC daily was well tolerated with doses ranging from 
0.5 µg/kg to 15 µg/kg. All AEs were of mild severity, and no SAEs were reported. The most 
common AE was mild, transient, self-limited orthostatic hypotension, of which the majority 


 
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of cases were asymptomatic and observed only upon assumption of an upright posture 
following recumbence. No dose-limiting toxicities were identified outside of these CV 
events. 
7.5.2.2 
Ongoing Studies 
Based on analysis of safety data from ongoing phase 2 and 3 studies, treatment with 
BMN 111 was generally well tolerated. Injection site reactions were the most common 
adverse events reported and are considered to be an identified risk. All injection site reactions 
events have been reported as non-serious, Grade 1 in severity, and transient. Hypotension and 
hypersensitivity reactions including development of BMN 111 antibodies are potential risks 
associated with BMN 111 injections. For a detailed summary of risks, please refer to the 
current version of the Investigator’s Brochure supplied by BioMarin. 
7.5.3 Summary of Potential Benefits from Clinical Studies 
For children with ACH who will receive BMN 111 as part of Study 111-206, potential 
benefits may include improvement of AGV rates such that their increase in growth velocity 
may approach that of children of average stature.  Additional potential benefits may include 
improvement of the disproportionate growth as well as improvement in quality of life, 
activities of daily living, and medical complications of ACH.  For example, improvement in 
height could have an impact on daily activity performance. 
 


 
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8 
STUDY OBJECTIVES 
The primary objectives of the study are to: 
• Evaluate the safety and tolerability of BMN 111 in children age 0 to < 60 months 
with ACH  
• Evaluate the effect of BMN 111 on change from baseline in length/height Z-score  
The secondary objectives of the study are to: 
• Evaluate the effect of BMN 111 on AGV throughout the 52 weeks of the study 
• Evaluate the effect of BMN 111 on bone morphology/quality by x-ray and dual x-ray 
absorptiometry (DXA) 
• Evaluate the PK of BMN 111 in children age 0 to < 60 months with ACH  
• Evaluate hip function 
• Evaluate for hip, thigh, or knee pain, or change in gait  
• Evaluate the effect of BMN 111 on developmental/functional/QOL status (Bayley-III, 
WeeFIM, Child Behavior Checklist [CBCL], ITQOL  
• Evaluate immunogenicity of BMN 111 and assess impact on safety, PK, and efficacy 
measures  
• Evaluate the effect of BMN 111 on bone metabolism and BMN 111 
pharmacodynamic biomarkers 
The exploratory objectives of the study are to: 
• Evaluate the effect of BMN 111 on growth parameters and body proportions, 
including change from baseline in upper:lower body segment ratio 
• Evaluate the effect of BMN 111 on sleep apnea 
• Document physical and phenotypic changes with clinical photography (optional)  
• Evaluate the effect of BMN 111 on skull and brain morphology, including foramen 
magnum, ventricular and brain parenchymal dimensions 
• Describe the incidence of surgical interventions, including cervical decompression, 
adenotonsillectomy, and tympanostomy 


 
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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a Phase 2 randomized, double-blind, placebo-controlled clinical trial of BMN 111 in 
infants and younger children with a diagnosis of ACH.  
Subjects age ≥ 6 months to < 60 months old who have documented ACH confirmed by 
genetic testing; at least a 6-month period of pretreatment growth assessment in Study 
111-901 immediately before study entry; and who meet the study eligibility criteria, will 
participate. Eligible subjects ranging from 0 months to < 3 months old may enroll directly 
into 111-206 and have a minimum of 3 months of pre-treatment observation prior to 
commencing treatment with investigational product, or may enroll in 111-901 for a minimum 
of 3 months of pretreatment growth assessment immediately before roll-over to 111-206. 
Approximately 70 subjects will be enrolled at approximately 10-15 clinical centers 
worldwide.   
The primary objectives of this study are to assess the safety and tolerability of daily SC 
BMN 111 administered to infants and young children with ACH, and evaluate the effect of 
BMN 111 on Z-scores. Subjects will be enrolled into 3 age cohorts based on age at study 
screening starting with the eldest population. Within Cohorts 1 and 2, subjects will be 
stratified by age: 
• Cohort 1 – children aged ≥ 24 to < 60 months (n ≥ 30 total: 3 sentinel subjects who 
receive BMN 111, and at least 27 additional subjects randomized 1:1 to treatment or 
placebo control), stratified by age (≥ 24 to < 36 months and ≥ 36 months to 
< 60 months)  
• Cohort 2 – children aged  ≥  6 to   < 24 months (n ≥ 20 total: 3 sentinel subjects who 
receive BMN 111, and at least 17 additional subjects randomized 1:1 to treatment or 
placebo control), stratified by age (≥ 6 months to < 15 months and ≥ 15 months to 
< 24 months)  
• Cohort 3 – children aged 0 to < 6 months (n ≥ 20 total: 3 sentinel subjects who 
receive BMN 111, and at least 17 additional subjects randomized 1:1 to treatment or 
placebo control).  Treatment begins at ≥ 3 months to < 6 months after 3 months of 
observation. 
If subjects who enroll in Cohort 3 are not able to begin treatment by < 6 months of age, they 
will continue in the pretreatment period for another 3 months before enrolling in Cohort 2 to 
fulfill the pretreatment requirement for Cohort 2.  
 


 
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Sentinel subjects from each cohort will be enrolled and studied for short-term safety and PK 
data, after which subjects in all 3 cohorts will be randomized to receive BMN 111 or placebo 
SC daily (1:1 ratio) for up to 52 weeks. No two sentinel subjects will be dosed on the same 
day for any cohort.  At the start of the study, 3 sentinel subjects will be enrolled and 
monitored in Cohort 1. After all 3 sentinel subjects reach Day 8, the Sponsor will review and 
evaluate all available safety data and Day 1 PK data. Based on PK data and criteria set in the 
protocol, the dose may be adjusted for the sentinel subjects and the rest of the cohort, and 
will be the starting dose for the younger cohort sentinel subjects.  Upon review of the clinical 
and PK data, the remainder of Cohort 1 (≥ 27 additional subjects) will be enrolled and 
randomized to treatment with BMN 111 or placebo (1:1 ratio).  After the sentinel subjects 
complete 12 weeks of dosing, a DMC review will occur to evaluate all available safety and 
PK data.  Upon approval by the DMC, the next younger cohort (Cohort 2) will be opened and 
the 3 sentinel subjects will be enrolled. 
The same procedure will be followed for Cohort 2. After all 3 sentinel subjects reach Day 8, 
the Sponsor will review and evaluate all available safety data and Day 1 PK data. Based on 
PK data and criteria set in the protocol, the dose may be adjusted for the sentinel subjects and 
the rest of the cohort, and will be the starting dose for the younger cohort sentinel subjects.  
Upon review of the clinical and PK data, the remainder of Cohort 2 (≥ 17 additional subjects) 
will be enrolled and randomized to treatment with BMN 111 or placebo (1:1 ratio). After the 
sentinel subjects complete 12 weeks of dosing, a DMC review will occur to evaluate all 
available safety and PK data.  Upon approval by the DMC, the youngest cohort (Cohort 3) 
will be opened and the 3 sentinel subjects will be enrolled.  
The same procedure will be followed for Cohort 3. After all 3 sentinel subjects reach Day 8, 
the Sponsor will review and evaluate all available safety data and Day 1 PK data. Based on 
PK data and criteria set in the protocol, the dose may be adjusted for the sentinel subjects and 
the rest of the cohort, and will be the starting dose for the younger cohort sentinel subjects.  
Upon review of the clinical and PK data, the remainder of Cohort 3 (≥ 17 additional subjects) 
will be enrolled and randomized to treatment with BMN 111 or placebo (1:1 ratio).  
Cohort 3 subjects must have a minimum of 3 months of observation prior to commencement 
of treatment.  These subjects will have the option to enroll in either 111-901 or 111-206, 
depending on age at enrollment: 
• Infants ≥ 3 months and  < 6 months old (≥ 13 weeks and < 26 weeks) will enroll in 
111-901 for a 6-month period of pretreatment growth assessment prior to enrollment 
in 111 206 for treatment in Cohort 2. 


 
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• Infants between birth and < 3 months old (0 weeks and < 13 weeks) will enroll into 
111-206 with a 3-month observational period prior to treatment. 
Additional sentinels may be added to any cohort if needed for additional safety and/or PK 
assessment. 
As subjects age on study, they will be administered the dose determined to be appropriate for 
their current age.  For example, if a subject enrolls into Cohort 2 at age 20 months, they will 
receive the recommended dose for subjects aged ≥ 6 to < 24 months until they turn 24 months 
in age.  When they turn 24 months in age, they will begin to receive the recommended dose 
for subjects aged ≥ 24 to < 60 months. 
Each treated subject will have expanded outpatient safety monitoring for a minimum of 
3 days of dosing, during which they will be closely observed and non-invasive hemodynamic 
monitoring will be conducted for at least 4-8 hours post-dosing. Because younger children 
may not be able to verbalize complaints of dizziness or lightheadedness that are potentially 
associated with hypotension, study personnel and caregivers will be trained to recognize the 
signs of hypotension in this population, which may include tachycardia, pallor, diaphoresis, 
lethargy, delayed capillary refill, and poor feeding. Appropriate rigorous training will be 
required for parents and caregivers prior to daily injections at home. Training includes the 
storage, reconstitution, and administration of BMN 111, as well as documentation/reporting 
of AEs and vigilance for signs of hypotension. 
It is generally expected that after subjects are tolerating the drug well and specified criteria 
have been met, caregivers will begin administering study drug. Home health care is not 
required at any point but may be provided if the caregiver is unable or unavailable to 
administer the study drug. A Home Healthcare nurse will train the caregiver(s) if training has 
not been completed by the Day 3 visit. A phone call by the study staff member to the 
caregiver will be required weekly for 6 months and then every 2 weeks for the remainder of 
the study. During these contacts, study staff will ask the caregiver about dose administration 
and seek information on AEs and SAEs by specific questioning. If the caregiver cannot be 
contacted by phone after two attempts, contact can be made via email.   
Duration of the study is 52 weeks of treatment with a safety follow up at Week 56. Following 
completion of the study, subjects in all treatments groups may be eligible to receive 
BMN 111 in an open-label extension study, to assess safety and efficacy of BMN 111 over 
the longer term.  For subjects enrolling into the extension study, safety follow up visit at 
Week 56 will be waived. 
A summary of events and assessments are provided by visit in Table 9.1.1 and Table 9.1.2. 


 
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For a discussion of efficacy assessments, see Section 9.11.2 and Section 9.11.3; exploratory 
efficacy assessments, Section 9.11.4; safety assessments, Section 9.11.6; and PK variables, 
Section 9.11.5. The 111-206 study design is presented in Figure 9.1.1.   
Figure 9.1.1:  Study Design 
 
 
 


 
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Table 9.1.1:  Schedule of Events 
Procedurea 
Screening/
Baseline 
Day -30 to 
Day -1b 
Day 
1u 
Day 
2 
Day 
3 
Day 
8 
(±1d) 
Week 
3 
(±7d) 
Week 
6 
(±7d) 
Week 
13 
(±7d) 
Week 
20 
(±7d) 
Week 
26 
(±7d) 
Week 
39 
(±7d) 
Week 
52 
(±7d) 
Week 56 
Safety 
Follow-Up 
( + 7d)z 
Early 
Term 
Visit 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parental heightd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnostic genetic testing 
to confirm achondroplasia 
(if needed)e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogramh 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Echocardiogrami 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Xi 
Anthropometric 
measurementsj 
X 
X 
 
 
 
 
X 
X 
 
X 
X 
X 
 
X 
Clinical laboratory 
assessments (hematology, 
chemistry, urinalysis)k 
X 
 
 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
Thyroid function tests 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Vitamin D, 25-hydroxy 
test 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Salivary cortisol 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Serum prolactin 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Plasma pharmacokinetics 
and cGMP assessmentsl 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
Anti-BMN 111 
immunogenicitym 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 


 
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Procedurea 
Screening/
Baseline 
Day -30 to 
Day -1b 
Day 
1u 
Day 
2 
Day 
3 
Day 
8 
(±1d) 
Week 
3 
(±7d) 
Week 
6 
(±7d) 
Week 
13 
(±7d) 
Week 
20 
(±7d) 
Week 
26 
(±7d) 
Week 
39 
(±7d) 
Week 
52 
(±7d) 
Week 56 
Safety 
Follow-Up 
( + 7d)z 
Early 
Term 
Visit 
Genomic biomarkers 
(optional) 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Bone metabolism blood 
biomarkersn 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Bone metabolism urine 
biomarkerso 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
BMN 111 
pharmacodynamic urine 
biomarkerso 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
Urine chemistryo 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
Screening baseline hip 
assessment with pelvis x-
ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hip monitoringp 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
MRI brain/skullq 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Sleep studyr 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Clinical outcome 
assessment: Bayley-III 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Clinical outcome 
assessment: WeeFIMs 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Clinical outcome 
assessment: ITQOL 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Clinical outcome 
assessment: CBCLs 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
DXA (BMD and BMC) of 
whole body [less head], 
spine and forearm 
(including ultra-
distal,mid-distal, and one 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 


 
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Procedurea 
Screening/
Baseline 
Day -30 to 
Day -1b 
Day 
1u 
Day 
2 
Day 
3 
Day 
8 
(±1d) 
Week 
3 
(±7d) 
Week 
6 
(±7d) 
Week 
13 
(±7d) 
Week 
20 
(±7d) 
Week 
26 
(±7d) 
Week 
39 
(±7d) 
Week 
52 
(±7d) 
Week 56 
Safety 
Follow-Up 
( + 7d)z 
Early 
Term 
Visit 
mid-distal, and one third 
radius regions of interest) 
AP and lateral X-rays of 
spinet 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
AP X-rays of lower 
extremitiest  
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Clinical photographs 
(optional)u   
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Capture all procedures in 
the Schedule of Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BMN 111 or placebo 
administrationv 
 
All visits 
 
 
BMN 111 or placebo 
accountability  
 
All visits 
 
X 
Adverse eventsw 
 
All visits 
X 
X 
Concomitant medicationsx 
X 
All visits 
X 
X 
Phone call or home health 
visity 
 
Weekly calls for 6 months and then every 2 weeks for the remainder of the study 
 
 
a Clinic visits (except Days 1, 2, 3, and 8) have a ± 7-day window.  Anthropometric measurement and imaging assessments can be conducted either pre-dose or 
post-dose. 
b If the 111-901 visit at which the subject enters Study 111-206 and the 111-206 Screening visit are on the same day, the procedures common to both visits will 
be performed one time only.  All blood tests at Screening visit should be obtained between Day -30 and Day -14. 
c Medical history, including growth history and ACH-related history, should elicit all major illnesses, diagnoses, and surgeries that the subject has ever had; any 
prior or existing medical conditions that might interfere with study participation or safety. 
d Standing height of the participant’s biological parents will be assessed.  Prior to the measurement being taken, each parent is required to complete an ICF 
specific to parent height assessment.  The ICF will be signed prior to the assessment, which can be done at any point in the study.  If biological parent is not 
available during the course of the study to take their standing height, the parent can provide their stated height instead if consent has been given. 
e If subjects had previous genetic testing, subjects must have a lab certification documenting the specific mutation required for the 111-206 study, including the 
identification of FGFR3 mutation (G346E, G375C, G380R, or “other”).  
f Complete physical exam includes major body systems, including assessment of general appearance; CV; dermatologic; head, eyes, ears, nose, and throat; 
lymphatic; respiratory; gastrointestinal (GI); musculoskeletal; and neurological/psychological and genitourinary. 


 
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g All treatment visits have pre-dose vital sign assessments.  Vital signs at pre-dose include: body temperature in degrees Celsius (°C), heart rate, BP, and 
respiratory rate.  Post-dose measurements include heart rate, BP, and respiratory rate. 
Vital Sign Assessment Frequency  
Screening 
After at least 5 min of rest, subject’s vital signs are taken, preferably in sitting or supine position.  Vital sign measurements 
should be repeated and documented 3 times with at least 5 min intervals between assessments.   
 
Assessment Frequency 
Dosing Visits 
0-1 hr post-dose 
0-2 hr post-dose 
2-4 hr post dose 
4-8 hr post-dose 
Days 1, 2 
 
q 15 min (± 5 min) 
q 30 min (± 5 min) 
q 60 min (± 10 min) 
Days 3, 8 
 
q 15 min (± 5 min) 
q 30 min (± 5 min) 
 
Subsequent dosing visits 
q 15 min (± 5 min); 
final assessment prior to end of 
visit (if longer than 1 hr) 
 
 
 
1. 
Vital sign measurements are taken once per time point, preferably in a sitting or supine position, after at least 5 minutes of rest.   
2. 
Heart rate, blood pressure, and respiratory rate should be taken and recorded at each indicated time point.   
3. 
When blood samples and vital sign assessments are scheduled at the same time or within the same time window, vital signs should be measured before blood samples are 
drawn.   
4. 
If a vital sign measurement must be taken after a blood draw, ensure adequate analgesia for the blood draw and wait several minutes before measuring vital signs.   
5. 
Vital signs may be monitored more frequently or for longer duration post-dose as clinically indicated. 
6. 
If a subject has a hypotensive event, or signs potentially consistent with hypotension, or a decrease of 20 mm Hg systolic BP or more from baseline (defined by pre-dose 
vitals collected that day), vital signs should be measured and recorded approximately every 15 minutes (± 5 minutes) for the first hour and every 30 minutes (± 5 minutes) 
thereafter until the BP returns to baseline (or within the normal range for this subject as defined by PI) and signs (if present) resolve.  
7. 
If the decision is made to adjust the dose, vital signs will be obtained for at least 4 hr following the first dose at the adjusted dose level, similar to the Day 3, 8 schedule. 
8. 
If a dose adjustment visit coincides with a visit at which a full PK is drawn, vital signs will be obtained for 8 hours, similar to the Day 1,2 schedule. 
h A standard 12-lead ECG will include heart rate, rhythm, intervals, axis, conduction defects, and anatomic abnormalities. The time of collection will be 
recorded. ECGs should be performed in triplicate with the subject supine at the visits indicated in the Schedule of Events.  ECGs will be performed post-dose 
on study day visits at which a dose is given; in addition, on Day 1, ECGs will be performed pre-dose.  On days when PK samples are being drawn, ECGs 
should be performed within a 5-minute window prior to 30-minute PK assessment. 
i Echocardiogram is obtained at the early termination visit only if the previous assessment was done more than 3 months prior to early termination. 
j Growth measures may be collected in triplicate approximately the same time each day (± 2 hr around the time when the first measurement assessment was 
taken at Screening). Measurements may include but are not limited to length, standing height (if able to stand unsupported), crown-to-rump length, head 
circumference, upper and lower arm and leg, and arm span. Measurements not taken in the midsagittal plane should be taken on the right side of the body if 
possible and should always be taken on the same side of the body throughout the study.  


 
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k Clinical labs (hematology, chemistry, and urinalysis) are all pre-dose draws samples and can be drawn anytime during the visit if there is no drug 
administration. 
l Plasma samples will be collected pre-dose and at 5 (± 2 min), 15 (± 2 min), 30 (± 5 min), 45 (± 5 min), 60 (± 5 min), 90 (± 5 min), and 120 (± 5 min) minutes 
post-dose. On Day 1, additional PK samples will be collected at 180 (± 5 min) and 240 (± 5 min) minutes. Samples with volume remaining after 
pharmacokinetic assessment will be used for cGMP pharmacodynamics assessment.  NOTE: In the event of interruption of study drug administration for a 
sentinel patient on Day 1 when PK samples are scheduled, the collection of PK samples should be delayed until the subsequent day and only performed after 
successful administration of study drug has been completed in a single injection. 
m Antibodies:  Total anti-BMN 111 (TAb), TAb cross-reacting with endogenous natriuretic peptides, and neutralizing antibody (NAb) samples (serum) will be 
drawn pre-dose at each time point listed on the SOE. TAb cross-reacting with endogenous natriuretic peptides and NAb testing will be performed only on 
baseline and TAb positive samples from subjects weighing ≥ 7.0 kg and waived for subjects < 7.0 kg. Drug-specific IgE will be drawn pre-dose on Day 1 for 
subjects weighing ≥ 7.0 kg and waived for subjects < 7.0 kg to stay within the limits of permitted blood volume collections in infants. Total immunoglobulin E 
(IgE) and drug-specific IgE will be drawn in the event of Grade 3 hypersensitivity adverse event) or at Investigator or Sponsor discretion. If such an event 
occurs, the drug-specific IgE sample should be drawn at least 8 hours after the event start time or before the next dose. A sample for total IgE and serum 
tryptase should be drawn within an hour of the start of the event when possible or during an unscheduled safety visit.  
n Bone metabolism blood biomarkers will be waived at screening for subjects weighing < 7.0 kg to limit the blood volume on the smallest subjects at this visit. 
Serum samples for bone metabolism biomarkers will be collected pre-dose on the indicated visits. Bone metabolism blood biomarkers include bone-specific 
alkaline phosphatase and collagen type X. 
o Urine biomarkers and urine chemistry (urine creatinine test) should be obtained pre- and post-dose (approximately 2-4 hours after study drug administration) 
for subjects when possible at the indicated visits. The time of collection will be recorded. Urine biomarkers include cGMP and C-terminal telopeptide of cross-
linked collagen type II (CTX-II). 
p Hip monitoring: this assessment will include medical history of the hip and physical exam to determine changes in hip function or pain with hip range of 
motion. Adverse changes from baseline will trigger further evaluation. 
q MRI is obtained at the early termination visit only if the previous assessment was done more than 3 months prior to early termination (unless additional study is 
recommended by Investigator, BioMarin, or DMC). Efforts to obtain a satisfactory image can be discontinued after 3 unsuccessful attempts.   
r If sleep study is uninterpretable, subject may need to repeat assessment.  Obtained at the early termination visit only if the previous assessment was done more 
than 3 months prior to early termination (unless additional study is recommended by Investigator, BioMarin, or DMC). 
s WeeFim is waived for children < 6 months old; CBCL is waived for children < 18 months old.  
t AP lumbar, lateral lumbar, and AP lower extremities are obtained at the early termination visit only if the previous assessment was done more than 6 months 
prior to early termination (unless additional study is recommended by Investigator, BioMarin, or DMC). AP lower extremities X-ray at the Week 52 visit is 
waived for subjects who cannot stand upright unsupported.  Although X-rays are preferable for consistency across the study population, if there are IRBs or 
IECs unwilling to allow x-rays in Cohort 3 subjects, contact the MM to discuss alternate non-radiological methods for assessment. 
u To document the physical and phenotypic findings of achondroplasia with and without treatment with study drug, clinical photography of the full body, face, 
spine, and extremities will be conducted. This assessment is optional. If the parents/caregivers decline clinical photography, the assessment will be waived for 
the duration of the study. 
v The injection site should be rotated as described in the BMN-111 Injection Guide. Following administration of each dose at clinic visits, subjects should be 
observed for 8 hours after the injection on Days 1 and 2; 4 hours on Days 3 and 8; and 1 hour on subsequent dosing visits. Subjects should be observed for 
30 minutes after every injection that is not administered at the clinic. If interruption of study drug injection occurs, the remainder of the assigned dose should be 


 
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administered immediately (and no later than within 5 minutes) in a different location. The same syringe should be used and newly reconstituted investigational 
drug should be used to draw the remainder of the dose. 
w After written informed consent but before study treatment initiation, only SAEs associated with protocol-imposed interventions will be recorded. After study 
drug initiation, all AEs and SAEs will be recorded until 4 weeks after either the last administration of study drug or the Early Termination visit. If a subject is 
discontinued from the study prematurely, AEs and SAEs will be recorded at the Early Termination visit.   
x All medications (prescription, over-the-counter, herbal, topical) and nutritional supplements taken 30 days prior to screening and throughout the study should 
be documented. 
y During the call study staff will ask the caregiver about correct administration procedures, record adverse events (AEs), record concomitant medications, and 
answer questions.  
z The 4-week safety follow up visit will be waived for subjects who enter another BMN 111 study or registry within the 4-week period following last dose of 
study drug. 
 


 
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Table 9.1.2:  Schedule of Events Observational Period for Cohort 3 (infants between birth and < 3 months old) 
Assessments  
Screeninga 
Day 1a 
(Month 0) 
3 Months (± 10 days) 
Medical history, including growth history and ACH related history 
X 
 
 
Concomitant medications 
X 
X 
X 
Physical examinationb 
X 
 
 
Vital signsc 
X 
X 
X 
Anthropometric measurementsd 
 
X 
X 
Vitamin D, 25-hydroxye 
X 
 
X 
Alkaline phosphatasee 
X 
 
X 
Bone metabolism blood biomarkers 
X 
 
X 
Bone metabolism urine biomarkers 
X 
 
X 
Genomic biomarkers (optional)f 
 
X 
 
Weight 
 
X 
X 
Body mass index (calculated) 
 
X 
X 
Clinical outcome assessment: Bayley-IIIg 
 
X 
 
Clinical outcome assessment: ITQOLg 
 
X 
 
Capture all procedures in the Schedule of Events 
 
X 
X 
Adverse eventsh 
X 
X 
X 
a Screening and Day 1 (Month 0) assessments may be performed on the same calendar day at the discretion of the investigator. If Screening and Day 1 (Month 0) 
are done on the same day, vital signs are taken only once. Please refer to eCRF Completion Instructions. 
b A complete physical examination will be performed at Screening. Complete physical exam includes major body systems, including assessment of general 
appearance; CV; dermatologic; head, eyes, ears, nose, and throat; lymphatic; respiratory; gastrointestinal (GI); musculoskeletal; and neurological/psychological 
and genitourinary. 
c Vital signs will be measured with appropriate blood pressure cuffs for achondroplasia children following detailed instructions in Study Reference Manual. At 
screening, blood pressure should be taken with subject in a supine position, after the subject has been resting for at least 5 minutes. At all other visits, blood 
pressure should be taken one time after at least 5 minutes of rest, with subject in a supine position. Heart rate should be taken at each time point that blood 
pressure is measured. Left brachial arm should be the first method of assessment considered, and the same site should be used for blood pressure measurement 
in each subject throughout the study. The method and site of blood pressure measurement will be recorded and should be utilized consistently throughout the 
remainder of the study. 


 
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d Growth parameters (anthropometric measurements) may include but are not limited to height, standing height, sitting or supine height, weight, upper and lower 
arm and leg length, and arm span. Body proportion measurements may include but are not limited to upper:lower body segment ratio, upper arm:forearm length 
ratio, upper leg:lower leg length ratio, and arm span:standing height ratio. Refer to the Anthropometric Measurement Guidelines for specific instructions 
regarding the collection of growth measurements. All age-appropriate physical measurements will be collected at approximately the same time each visit 
( ± 2 hours) by a trained study staff member; every effort will be made to have the measurements collected by the same study staff member, if possible, 
throughout the study. Each measurement will be taken in triplicate (excluding weight, taken once).  
e Vitamin D (25-hydroxy) and alkaline phosphatase will be measured during Screening and at the 3-month visit. 
f If sample is not collected at Day 1, it may be drawn at any time during the study. The sample will be used for exploratory genomics including, but not limited 
to, NPR-B, BRAF, and other genes associated with CNP signaling.  
g Bayley-III is waived for subjects < 1 month old; ITQOL is waived for subjects < 2 months old.  
h AEs will be collected at screening.  For subjects enrolled in Cohort 3 (0 to <  6 months old), the collection period for all AEs begins after informed consent is 
obtained. 
 


 
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9.1.1 Dose Adjustments 
Analysis of available PK data from studies 111-101 and 111-202 indicated that differences in 
subject body weight did not directly translate to differences in total body clearance of 
BMN 111.  The same weight-based dose in the pediatric population of Study 111-202 
(5-12 years old) yielded lower exposure (Cmax and AUC) than that characterized in the adult 
population of Study 111-101.  Therefore, the same weight-based dose in the young pediatric 
population in this study may yield exposure less than the target exposure range characterized 
to be safe and effective in Study 111-202 at the 15-µg/kg dose. Since this is the first 
experience with BMN 111 in this young pediatric population, it is also possible the exposure 
at 15 μg/kg could be greater than the target exposure range, and dose adjustment may be 
warranted. Thus, an option for adjustment of the weight-based dose is provided to ensure that 
the appropriate target exposure for safety and efficacy is reached for the young subjects in 
this study.   
The need for dose adjustment will be evaluated as follows: three sentinel subjects in Cohort 1 
will receive an initial dose of 15 µg/kg. After all three sentinel subjects reach Day 8, the 
Sponsor will review and evaluate all available safety and PK data (at minimum). If the 
criteria for dose adjustment are met, the three sentinel subjects will be started on the new 
adjusted dose at their next scheduled visit, and vital signs will be obtained for at least 4 hours 
post-dose. 
The remainder of the subjects in the age cohort will also be enrolled starting at the new 
adjusted dose. After the third sentinel subject reaches Week 12 post dose adjustment, a DMC 
review will occur to evaluate all safety and PK data and, upon endorsement, the three 
sentinel subjects from the next younger cohort will be enrolled starting at the new adjusted 
dose.  The three sentinel subjects for the second and third cohorts will be evaluated similarly 
to the sentinel subjects in the first cohort for potential dose adjustment. 
As subjects age on study, they will be administered the dose determined to be appropriate for 
their current age.  For example, if a subject enrolls into Cohort 2 at age 20 months, they will 
receive the recommended dose for subjects aged ≥ 6 to < 24 months until they turn 24 months 
in age.  When they turn 24 months in age, they will begin to receive the recommended dose 
for subjects aged ≥ 24 to < 60 months. 
Criteria for Dose Adjustment 
The criteria for dose adjustment are based on obtaining equivalent exposure characterized to 
be safe and effective with the 15-μg/kg dose in Study 111-202 in each of the age cohorts 
evaluated in this study. BMN 111 dose may be adjusted if the mean observed AUC0-120 from 


 
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sentinel subjects is less than the 25th percentile for AUC0-120 in Cohort 3 (15 μg/kg) of Study 
111-202 or greater than the 75th percentile in Cohort 3 of Study 111-202. If these criteria are 
met, an allometric scaling coefficient, α, for BMN 111 clearance by subject body weight will 
be determined using a population PK modelling approach and available data from this study 
and Studies 111-202 and 111-101. The recommended adjusted dose will be determined using 
the following expression: 
 
 
where WTref and Doseref are the typical (i.e., median) subject body weight and total dose, 
respectively, at the 15 μg/kg dose level in Cohort 3 of Study 111-202, and WTch is the 
anticipated median weight in the age cohort being studied. As such, the recommended 
adjusted dose will target the median AUC0-120 observed at the 15 μg/kg dose level of Study 
111-202. The recommended adjusted dose, Dosech, will be normalized by WTch, to provide 
the recommended adjusted weight-based dose. The following rules will be used for dose 
adjustment: 
• A maximum of a 2-fold increase in dose/kg will be permitted between dose 
adjustments regardless of exposure. 
• The total dose will not exceed the highest total dose administered in Study 111-202. 
9.1.2 Stopping Criteria 
Individual Subject Stopping Criteria  
For individual subjects treated with BMN 111, DMC will be informed if any of the following 
individual subject stopping criteria should occur. Temporary dosing suspension, permanent 
discontinuation of dosing, or dose reduction for the individual subject will be considered. 
• Any treatment-emergent adverse event (AE) assessed as at least Grade 4 by the 
Investigator and/or Sponsor Medical Monitor  
• Any treatment-emergent AE of at least Grade 3 assessed as related to study drug by 
the Investigator and/or Sponsor Medical Monitor  
• Any two treatment-emergent Grade 2 symptomatic hypotension events within 7 days 
(non-urgent medical intervention indicated) or any Grade 3 hypotensive event (urgent 
medical intervention or hospitalization indicated) assessed by the Investigator and/or 
Sponsor’s Medical Monitor  
• Clinically significant finding or arrhythmia on ECG that indicates abnormal cardiac 
function or conduction or prolongation of QTc-F >500 msec 


 
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• Clinically significant new or worsening signs of cervicomedullary compression as 
determined by the Investigator and in consultation with Sponsor medical monitor and 
neurosurgical specialist (if needed) 
• Adverse findings on clinical hip exam or hip imaging assessments that are determined 
to be clinically significant as determined by the Investigator and in consultation with 
Sponsor Medical Monitor and orthopedic specialist (if needed)  
If the subject meets any stopping criterion, after Investigator consultation with the BioMarin 
Medical Monitor and DMC, the subject may be re-challenged at the same dose. If the subject 
meets stopping criteria on re-challenge or if re-challenge at same dose is not clinically 
indicated, other options that may be considered include:  
• Re-challenge at lower dose with consideration given to upward titration to tolerated 
dose  
• Permanent treatment discontinuation (with an option of ongoing assessment in the 
study)  
Cohort Stopping Criteria  
For each cohort, a DMC review will be conducted if any of the following cohort stopping 
criteria occur in subjects treated with BMN 111.  Temporary dosing suspension, permanent 
discontinuation of dosing, or dose reduction for the cohort(s) will be considered and the 
impact on all other age cohorts will be assessed.  
• Any treatment-emergent AE assessed as at least Grade 4 by the Investigator and/or 
Sponsor Medical Monitor  
• Any two subjects have a treatment-emergent AE of at least Grade 3 assessed as 
related to study drug by the Investigator and/or Sponsor Medical Monitor  
• Any two subjects have two treatment-emergent Grade 2 symptomatic hypotension 
events within 7 days (non-urgent medical intervention indicated) or any two subjects 
cohort have a Grade 3 hypotensive event (urgent medical intervention or 
hospitalization indicated) assessed by the Investigator and/or Sponsor’s Medical 
Monitor  
• Any two subjects have a clinically significant finding or arrhythmia on ECG that 
indicates abnormal cardiac function or conduction or prolongation of 
QTc-F >500 msec 
• Any two subjects have adverse findings on clinical hip exam or hip imaging 
assessments that are determined to be clinically significant as decided by principal 
investigator and in consultation with Sponsor medical monitor and orthopedic 
specialist (if needed)  


 
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9.2 
Discussion of Study Design, Including Choice of Control Group 
Study 111-206 is a Phase 2 randomized, double-blind, placebo-controlled clinical trial of 
BMN 111 in infants and younger children with a diagnosis of ACH who are age 0 to 
< 60 months. Identification of efficacy at this age range is congruent with mechanism of 
action of BMN 111, because BMN 111 is expected to act at open epiphyseal growth plates. 
Therefore, to have a potential therapeutic benefit for subjects with ACH, treatment is 
expected to be required prior to epiphyseal growth plate closure. 
In terms of the study design, a randomized double-blind placebo control will be used to 
mitigate the risk of selection bias and any potential bias in data collection and study conduct.  
Additionally, this design provides a framework for interpretation of any endpoints with a 
subjective component, e.g. HRQOL and ADL questionnaires and any subjective assessment 
of safety. 
9.3 
Selection of Study Population 
Subjects age 0 months to < 60 months old, with documented ACH confirmed by genetic 
testing, and who meet the study eligibility criteria will participate. 
Additional criteria for participation in the study are provided in Sections 9.3.1 and 9.3.2. 
9.3.1 Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Diagnosis of ACH, confirmed by genetic testing.  If subjects had previous genetic 
testing, subjects must have a lab report from a certified laboratory with the study 
specific mutation documented. 
2. Age 0 to < 60 months, at study entry (Day 1) 
3. Cohort 1 and 2 subjects must have at least a 6-month period of pretreatment growth 
assessment in Study 111 901 immediately before study entry, and have one 
documented measurement of height/body length a minimum of 6 months 
(+/- 10 days) prior to the screening visit for 111-206.  Cohort 3 subjects must have a 
minimum of 3 months of observation prior to treatment.  This observational period 
can be obtained either (1) via prior enrollment in Study 111-901 or (2) via enrollment 
in this Study 111 206 for a minimum of 3 months of non-treatment observation prior 
to commencement of treatment.  
4. Parent(s) or guardian(s) (and the subjects themselves, if required by local regulations 
or ethics committee) are willing and able to provide written, signed informed consent 
after the nature of the study has been explained and prior to performance of any 
research-related procedure 
5. Willing and able to perform all study procedures as physically possible 


 
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6. Parent(s) or caregiver(s) are willing to administer daily injections to the subjects and 
complete the required training 
9.3.2 Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1. Have hypochondroplasia or short-stature condition other than achondroplasia 
(e.g., trisomy 21, pseudoachondroplasia, etc.) 
2. Subject weighs < 5.0 kg (Cohort 1 and 2) or < 4.0 kg (Cohort 3) 
3. Have any of the following: 
• Hypothyroidism or hyperthyroidism 
• Insulin-requiring diabetes mellitus 
• Autoimmune inflammatory disease (including celiac disease, systemic lupus 
erythematosus, juvenile dermatomyositis, scleroderma, etc.) 
• Inflammatory bowel disease 
• Autonomic neuropathy 
4. Have a history of any of the following: 
• Renal insufficiency defined as serum creatinine > 2 mg/dL 
• Chronic anemia or Hgb  < 10.0 g/dL (based on screening clinical laboratory 
testing) 
• Baseline systolic blood pressure (BP) below age and gender specified normal 
range or recurrent symptomatic hypotension (defined as episodes of low BP 
generally accompanied by symptoms e.g., dizziness, fainting) or recurrent 
symptomatic orthostatic hypotension 
• Cardiac or vascular disease, including the following 
o Cardiac dysfunction (abnormal echocardiogram determined to be 
clinically significant by PI and medical monitor) at Screening Visit  
o Hypertrophic cardiomyopathy 
o Pulmonary hypertension 
o Congenital heart disease with ongoing cardiac dysfunction  
o Cerebrovascular disease 
o Aortic insufficiency or other clinically significant valvular dysfunction 
o Clinically significant atrial or ventricular arrhythmias 
5. Have a clinically significant finding or arrhythmia that indicates abnormal cardiac 
function or conduction or QTc-F  > 450 msec on screening ECG 
6. Have evidence of cervicomedullary compression (CMC) likely to require surgical 
intervention within 60 days of Screening as determined by the Investigator and 
informed by the following assessments:  


 
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• Physical exam (e.g., neurologic findings of clonus, opisthotonus, exaggerated 
reflexes, dilated facial veins) 
• Polysomnography (e.g., severe central sleep apnea) 
• MRI indicating presence of severe CMC or spinal cord damage  
7. Have an unstable medical condition likely to require surgical intervention in the next 
6 months, or planned spine or long-bone surgery (i.e., surgery involving significant 
disruption of bone cortex) during the study period 
8. Have documented uncorrected Vitamin D deficiency: 25(OH)D   ≤ 15 ng/mL 
(37.5 nmol/L) 
9. Require any other investigational product prior to completion of the study period 
10. Have received another investigational product or investigational medical device 
within 30 days prior to the Screening visit 
11. Have used any other investigational product or investigational medical device for the 
treatment of achondroplasia or short stature at any time  
12. Require current chronic therapy with antihypertensive medication or any medication 
that, in the investigator’s judgment, may compromise the safety or ability of the 
subject to participate in this clinical study (Table 9.3.5.1) 
13. Have been treated with growth hormone, insulin-like growth factor 1 (IGF-1), or 
anabolic steroids in the 6 months prior to screening, or long-term treatment 
(> 3 months) at any time 
14. Have had regular long-term treatment (> 1 month) with oral corticosteroids (low-dose 
ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable) in the 
12 months prior to screening 
15. Have ever had cervicomedullary decompression surgery (Cohorts 2 and 3 only), spine 
or long-bone surgery (i.e., surgery involving disruption of bone cortex) or have ever 
had bone-related surgery with chronic complications 
NOTE: Subjects with prior cervicomedullary decompression may be allowed into 
Cohort 1 only after discussion and agreement with Medical Monitor. 
16. Have ever had limb-lengthening surgery or plan to have limb-lengthening surgery 
during the study period 
17. Have had a fracture of the long bones or spine within 6 months prior to screening 
18. Have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or total 
bilirubin greater than upper limit of normal (ULN) at screening (except for subjects 
with a known history of Gilberts or newborns entering screening in Cohort 3) 
19. Have evidence of severe untreated sleep apnea; or have newly initiated sleep apnea 
treatment (eg, CPAP or sleep apnea-mitigating surgery) in the 2 months prior to 
screening 


 
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20. Have current malignancy, history of malignancy, or currently under work-up for 
suspected malignancy 
21. Have known hypersensitivity to BMN 111 or its excipients 
22. Have a history of hip surgery or severe hip dysplasia 
23. Have a history of clinically significant hip injury in the 30 days prior to screening  
24. Have a history of slipped capital femoral epiphysis or avascular necrosis of the 
femoral head  
25. Have abnormal findings on baseline clinical hip exam or imaging assessments that are 
determined to be clinically significant as determined by the Investigator 
26. Have a condition or circumstance that, in the view of the Investigator, places the 
subject at high risk for poor treatment compliance or for not completing the study 
27. Have any concurrent disease or condition that, in the view of the Investigator, would 
interfere with study participation or safety evaluations, for any reason 
 
9.3.3 
Inclusion Criteria for Cohort 3 Observation Period 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Parent(s) or guardian(s) willing and able to provide signed informed consent after the 
nature of the study has been explained and prior to performance of any 
research-related procedure. Also, willing and able to provide written assent (if 
applicable) after the nature of the study has been explained and prior to performance 
of any research-related procedure. 
2. Birth to ≤ 3 months of age at study entry.  
3. Have ACH, documented by genetic testing 
4. Are willing and able to perform all study procedures as physically possible 
 
9.3.4 Exclusion Criteria for Cohort 3 Observation Period 
Individuals who meet any of the following exclusion criteria are not eligible to participate in 
the study: 
1. Have hypochondroplasia or short stature condition other than ACH (e.g., trisomy 21, 
pseudoachondroplasia) 
2. Have any of the following disorders: 
• Hypothyroidism 
• Insulin-requiring diabetes mellitus 


 
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• Autoimmune inflammatory disease (including celiac disease, lupus (SLE), 
juvenile dermatomyositis, scleroderma, and others) 
• Inflammatory bowel disease 
• Autonomic neuropathy 
3. Have an unstable clinical condition likely to lead to intervention during the course of 
the study, including progressive cervical medullary compression  
4. Have a history of any of the following: 
• Renal insufficiency  
• Anemia  
5. Have a history of cardiac or vascular disease, including the following: 
• Cardiac dysfunction  
• Hypertrophic cardiomyopathy 
• Congenital heart disease 
• Cerebrovascular disease, aortic insufficiency 
• Clinically significant atrial or ventricular arrhythmias 
6. Current treatment with antihypertensive medications, ACE inhibitors, angiotensin II 
receptor blockers, diuretics, beta-blockers, calcium-channel blockers, cardiac 
glycosides, systemic anticholinergic agents, any medication that may impair or 
enhance compensatory tachycardia, drugs known to alter renal function that is 
expected to continue for the duration of the study 
7. Have had regular long-term treatment (> 1 month) with oral corticosteroids (low-dose 
ongoing inhaled steroid for asthma is acceptable) in the previous 3 months 
8. Concomitant medication that prolongs the QT/QTc interval within 14 days or 
5 half-lives, whichever is longer, before the Screening visit 
9. Have used any other investigational product or investigational medical device for the 
treatment of ACH or short stature 
10. Planned or expected bone-related surgery (ie. surgery involving disruption of bone 
cortex), during the study period.  
11.  Planned or expected to have limb-lengthening surgery during the study period.   
12. Have any condition that, in the view of the Investigator, places the subject at high risk 
of poor compliance with the visit schedule or of not completing the study. 
13. Concurrent disease or condition that, in the view of the Investigator, would interfere 
with study participation 
 


 
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9.3.5 Current Chronic Therapy with Restricted Medications 
Table 9.3.5.1 lists the medications that are restricted in Study 111-206. 
Table 9.3.5.1:  Current Chronic Therapy with Restricted Medications 
Restricted Medications 
• 
Antihypertensive medications 
• 
Angiotensin-converting enzyme (ACE) inhibitors 
• 
Angiotensin II receptor blockers 
• 
Diuretics 
• 
Beta-blockers 
• 
Calcium-channel blockers 
• 
Cardiac glycosides 
• 
Systemic anticholinergic agents 
• 
GnRH agonists 
• 
Growth hormone (and analogs) 
• 
Any medication that may impair or enhance compensatory tachycardia, diuretics, or 
other drugs known to alter renal or tubular function 
• 
Any medication that in the investigator’s judgment, may compromise the safety or 
ability of the subject to participate in the clinical trial 
 
9.3.6 Removal of Subjects from Treatment or Assessment 
Subjects (or their legally authorized representative) may withdraw their consent to participate 
in the study at any time without prejudice. The Investigator must withdraw from the study 
any subject who requests to be withdrawn. A subject’s participation in the study may be 
discontinued at any time at the discretion of the Investigator and in accordance with his/her 
clinical judgment. When possible, the tests and evaluations listed for the termination visit 
should be carried out.  BioMarin must be notified of all subject withdrawals as soon as 
possible.  
Investigators may discontinue administration of BMN 111 or placebo at any time. Reasons 
for which the investigator or BioMarin will withdraw a subject from study treatment include, 
but are not limited to, the following:  
1. Subject experiences a serious or intolerable AE due to BMN 111 as determined by the 
subject, investigator, or sponsor 
2. Subject requires medication or medical procedure prohibited by the protocol 
3. Subject does not adhere to study requirements specified in the protocol 
4. Subject is lost to follow-up 


 
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If a subject fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the subject cannot be reached by telephone, a certified letter should 
be sent to the subject (or the subject’s legally authorized representative, if appropriate) 
requesting contact with the Investigator. This information should be recorded in the study 
records.  
The Investigator or designee must explain to each subject, before enrollment into the study, 
that for evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with the study sponsor, regulatory agencies, and IRB/IEC/REB. It is 
the Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as HIPAA in the US, from each 
subject, or if appropriate, the subject’s legally authorized representative. If permission to use 
protected health information is withdrawn, it is the Investigator’s responsibility to obtain a 
written request, to ensure that no further data will be collected from the subject and the 
subject will be removed from the study. 
It is a priority of the study to maximize study subject retention and adherence to 
study-specific procedures. The completeness of the study data may affect the integrity and 
accuracy of the study results.  Therefore, subjects who discontinue study treatment should be 
encouraged to continue to undergo as many of the protocol-specified procedures and 
assessments as possible for the remainder of the study, as long as such continued 
participation does not detrimentally affect the health, safety, or welfare of the subject.   
For subjects who discontinue BMN 111 or placebo but remain in the study, PK and 
BMN 111 activity assessments will be waived completely; vital signs and clinical 
labs/biomarkers will be obtained only once at each visit subsequent to BMN 111 or placebo 
discontinuation.  Pre-and post-dose designations will not apply as the subject has 
discontinued dosing and vital sign and clinical lab/biomarkers assessments previously 
designated as “post-dose” will be waived.  All other assessments at each visit should be 
completed if possible and the subject is willing.  Data from the study procedures and 
assessments may be used to further characterize the natural progression of ACH.  
BioMarin reserves the right to discontinue the study at any time.  Premature termination of 
the study may occur because of regulatory authority decision, a change in the opinion of the 
IRB/IEC/REB, clinical or safety reasons, or at the discretion of the Sponsor.  The Sponsor 
reserves the right to discontinue the development of BMN 111 at any time, or to discontinue 
participation by an individual Investigator or site for poor enrollment or 
noncompliance.  Any decision to terminate the study will be promptly communicated to 
Investigators, regulatory authorities, and IRB/IEC/REB.  The Investigator is responsible for 


 
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communicating any decision to terminate a study to hospital staff involved in the conduct of 
the study and the participating subjects (and their families). 
9.3.7 Subject Identification  
Each subject will be assigned a unique subject identifier. This unique identifier will be on all 
eCRF pages. In legal jurisdictions where use of initials is not permitted, a substitute identifier 
will be used. 
9.3.8 Duration of Subject Participation 
Duration of the study is 52 weeks of treatment with a safety follow up at Week 56. Following 
completion of the study, subjects in both treatments groups may be eligible to receive 
BMN 111 in an open-label extension study, to assess safety and efficacy of BMN 111 over 
the longer term.  For subjects enrolling into the extension study, safety follow up visit at 
Week 56 will be waived.  
Subjects who are not eligible to receive BMN 111 in a separate study will return at Week 56 
for the Safety Follow-Up visit to assess for any AEs that may have occurred following 
completion of dosing. 
Follow-up assessments and procedures should be performed as outlined in the Study 111-206 
Schedule of Events (Table 9.1.1 and Table 9.1.2).  
Subjects who discontinue from study treatment will be asked to complete study assessments 
and procedures for the remainder of the study.  If subjects discontinue from study treatment 
and decline to participate for the remainder of the study, they will be asked to return for a 
final follow-up visit 4 weeks after their last dose, and the agreement should be documented. 
Subjects will participate in the study until completion or until one of the following occurs: 
the subject withdraws consent and discontinues from the study, the subject is discontinued 
from the study at the discretion of the investigator or BioMarin (upon consultation and in 
agreement with the investigator) or the study is terminated. 
9.4 
Treatments 
9.4.1 Treatments Administered 
BioMarin and/or its designee will provide the study site with a supply of IP sufficient for the 
completion of the study. 
Sentinel subjects will receive BMN 111 at a daily dose of 15 µg/kg (subject to adjustment 
per protocol). Subjects will be randomized to BMN 111 at a daily dose of 15 µg/kg (subject 


 
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to adjustment per protocol) or placebo for the duration of the study. The normal dosing 
schedule is a single daily subcutaneous injection given 7 days a week.  
If a recent acute illness associated with volume depletion (e.g., nausea, vomiting, diarrhea) 
has not completely resolved prior to the first dose of BMN 111 or placebo, the dosing will be 
delayed until hydration status has improved (up to the maximum period allowed for the visit 
window). 
9.4.1.1 
Study Drug Administration 
During the study, BMN 111 or placebo will be administered as a single 15 µg/kg SC 
injection given daily at approximately the same time each day whenever possible.  
Determination of appropriate injection sites will be left to the discretion of the investigator.  
The same injection site should not be used 2 days in a row, and sites should be rotated.  
Study drug should be administered at age-appropriate locations (upper thigh, upper back of 
arm, abdomen or buttocks). Doses may be administered in any of the common SC areas 
(upper arm, thigh, abdomen, buttocks).  Following administration of each dose at clinic 
visits, subjects should be observed for 8 hours after the injection on Days 1 and 2; 4 hours on 
Days 3 and 8; and 1 hour on subsequent dosing visits. Subjects should be observed for 
30 minutes after every injection that is not administered at the clinic.  Instructions for home 
administration of BMN 111 or placebo for subjects who qualify for parent/caregiver 
administration are provided in the Study Drug Injection Guide and Injection media. 
9.4.2 Identity of BMN 111 
BMN 111 is cloned into the pJexpress401 vector, expressed in E. coli and then purified. 
The drug substance is a modified CNP peptide that retains wild-type activity and specificity. 
The modified CNP sequence is: 
PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC 
The amino acid sequence is an analogue of the naturally occurring tissue-expressed form of 
C-type natriuretic peptide (CNP-53). BMN 111 is a recombinant 39 amino acid peptide that 
includes the 37 C-terminal amino acids of the human CNP-53 sequence, and is engineered to 
include two additional amino acids (Pro-Gly) on the N-terminus, which renders the peptide 
more resistant to degradation. It is a cyclic peptide formed by an intramolecular disulfide 
bond. The molecular weight of the purified product is 4.1 kDa. 
9.4.2.1 
Product Characteristics and Labeling 
The clinical drug product will be supplied in sterile, single-dose, Type I glass vials with 
coated stopper and flip-off aluminum cap. BMN 111 drug product is supplied as a 0.8-mg or 


 
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2-mg lyophilized, preservative-free, white-to-yellow powder for reconstitution with either a 
sterile diluent or sterile water for injection. The reconstituted solution is colorless to yellow 
and contains 0.8 mg/mL to 2 mg/mL of BMN 111, as well as citric acid, sodium citrate, 
trehalose, mannitol, methionine, polysorbate 80, and sterile water for injection. The target pH 
of the reconstituted solution is 5.5. Sterile water for injection will be commercially sourced 
and sterile diluent solution containing all of the above excipients will be supplied for 
reconstitution. All reconstitution and dose preparation steps will be performed as indicated in 
the BMN 111 Injection Guide and Injection video. 
BMN 111-placebo lyophilized product will be supplied in sterile, single-dose, Type I glass 
vials with coated stopper and flip-off aluminum cap. The placebo is designed to be 
comparable in appearance to the drug product and contains all of the components of the drug 
product including commercially sourced sterile WFI except the drug substance. 
The BMN 111 or placebo kit label includes the following information: the contents, 
directions, lot number, quantity, subject ID, vial ID, investigator, the required storage 
conditions, a precautionary statement, the expiry date, the study number, and BioMarin 
Pharmaceutical name and location. This may vary based on country requirements. 
9.4.3 Storage 
At the study site, all IP must be stored under the conditions specified in the Investigator’s 
Brochure in a secure area accessible only to the designated pharmacists and clinical site 
personnel. All IP must be stored and inventoried and the inventories must be carefully and 
accurately documented according to applicable state, federal and local regulations, ICH GCP, 
and study procedures. 
Specific information for storage and return of BMN 111 or placebo is provided in the 
Pharmacy Binder, Study Drug Injection Guide, and Injection media. 
9.4.4 Directions for Administration 
Refer to the Study Drug Injection Guide for complete BMN 111 or placebo preparation 
instructions.  
The injection will be administered as a daily dose of BMN 111 15 µg/kg or placebo given as 
a single subcutaneous injection. The dose should be given at approximately the same time 
every day whenever possible.  Following administration of each dose at clinic visits, subjects 
should be observed for 8 hours after the injection on Days 1 and 2; 4 hours on Days 3 and 8; 
and 1 hour on subsequent dosing visits. Subjects should be observed for 30 minutes after 
every injection that is not administered at the clinic. Subjects should have adequate food 


 
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intake prior to dosing.  All subjects should have been well hydrated and fed in the hour prior 
to administration of BMN 111 or placebo. 
Caregivers will administer BMN 111 or placebo at home once approved by the investigator 
and adequate training is demonstrated. Instructions on how to complete and document the 
training can be found in the Study Reference Manual.   
A caregiver will be eligible to administer BMN 111 or placebo if he or she meets all of the 
following criteria: 
• The subject has been on a stable dosing regimen for a minimum of 3 days  
• PI has approved administration of BMN 111 or placebo by the caregiver 
• The caregiver has completed the Administration Training conducted by qualified 
study site personnel and has been observed by the study site personnel to be able to 
adequately prepare the proper dose and perform the injections safely 
For dosing between planned clinic visits prior to caregiver approval, a home health nurse 
may administer BMN 111 or placebo, or subjects may be administered BMN 111 or placebo 
in the clinic by study staff or trained caregiver.   
The caregiver will be provided with a study diary and will be asked to record daily dosing 
information, changes in health status, medications and injection sites used, date and time of 
the injection, and injection site reactions, if any. 
A subject’s suitability for continued at-home drug administration will be evaluated by the 
investigator and the Sponsor’s Medical Monitor if a subject experiences a CTCAE Grade 3 
or higher AE that is considered possibly or probably drug-related, and/or a hypersensitivity 
reaction during the study.   
9.4.5 Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized in a 1:1 ratio, i.e., injection with placebo:15 µg/kg of BMN 111, 
using IXRS.  An independent third-party vendor will develop the randomization schedule so 
that BioMarin and site personnel are blinded to treatment assignments.  NOTE: In Japan, 
subjects are randomized separately within each cohort. 
9.4.6 Selection of Dose and Dosing Schedule Used in the Study 
Study 111-202, the second clinical trial in humans and the first in children with ACH, is an 
ongoing Phase 2, open-label, sequential-cohort, dose-escalation study that assesses daily SC 
BMN 111 in pediatric subjects with ACH aged 5-14 years with doses ranging from 2.5 µg/kg 
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Analysis of safety data from the 6-month initial phase of Study 111-202 showed that 
treatment with BMN 111 for 6 months at the doses of 2.5, 7.5, 15, and 30 µg/kg was 
generally well tolerated. The most common AEs across all cohorts were injection site 
reactions, asymptomatic hypotension, headache, and nasopharyngitis. Based on previous 
experience of the ongoing Phase 2 clinical trial, including the 24-month data cut at 15 µg/kg, 
injection site reactions have been identified as risks associated with BMN 111 injections. For 
a detailed summary of risks, please refer to the current version of the Investigator’s Brochure 
supplied by BioMarin.  
Analysis of efficacy data from the 6-month initial phase of Study 111-202 showed that 
subjects treated with BMN 111 for 6 months at doses ranging from 2.5 to 15 µg/kg daily had 
a dose-dependent improvement in AGV, with ~50% improvement in AGV seen at the 
15 µg/kg dose. The data from Cohort 4 (30 µg/kg) show an apparent greater than dose-
proportional increase in BMN 111 plasma exposure (Cmax and AUC0-t), with a marginal 
improvement in both absolute AGV and change from baseline AGV after 6 months of 
BMN 111 treatment when compared with Cohort 3 (15 µg/kg). 
Efficacy/toxicity studies have been conducted in neonatal and very young animals (7-day 
postpartum mouse and rat) in both a disease (TD mouse) and non-disease (rat) model. 
Given that this is the first study in infants and young children, an age-based cohort study 
design is used to assess safety and PK in young children (Cohort 1, ≥ 24 to < 60 months) 
prior to dosing toddlers (Cohort 2, ≥ 6 to < 24 months) and infants (Cohort 3, 
0 to  <  6 months). PK will be monitored and evaluated; Day 1 PK data from the sentinel 
subjects will inform dose selection modification for the sentinel subjects and for the rest of 
the cohort to target the observed exposure of the 15-µg/kg dose group in Study 111-202. 
Safety, efficacy and PK data from Study 111-202, a Phase 2 study in children with ACH, 
where a dose of 15 µg/kg has been and continues to be studied, are expected to be the most 
relevant, and translatable to this study (111-206).   
9.4.6.1 
Selection of Timing of Dose for Each Subject 
9.4.7 Blinding 
An independent third-party vendor will develop the randomization schedule so that BioMarin 
and site personnel will not know treatment assignments. BMN 111 or placebo will be labeled 
with the study number and a unique identification number. Subjects and the participating site 
members will be blinded to the two study treatments (BMN 111 or placebo).  
The investigator and other members of staff involved with the study will remain blinded to 
the treatment randomization code during the assembly procedure. In the event of an 


 
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emergency medical situation where subject management would be determined or 
significantly altered by knowing the treatment assignment, the investigator may be unblinded 
without prior written approval from the Medical Monitor.  Following such an emergency 
unblinding, the investigator will contact the medical monitor and provide written rationale 
according to the unscheduled unblinding procedure set forth in the Study Manual.  
The Medical Monitor will review the rationale, evaluate whether there are any additional 
safety considerations that need to be implemented for the subject and/or the study, and 
determine whether the investigator requires further guidance on unblinding.  The Medical 
Monitor may also communicate with the investigator advice on the care of the subject and 
define the plan for the subject’s future participation in the study. 
9.4.8 Prior and Concomitant Medications 
All medications (prescription, over-the-counter [OTC] and herbal), and nutritional 
supplements 30 days prior to screening and throughout the study will be recorded on the 
designated eCRF.  The Investigator may prescribe additional medications during the study, as 
long as the prescribed medication is not prohibited by the protocol. In the event of an 
emergency, any needed medications may be prescribed without prior approval, but the 
medical monitor must be notified of the use of any contraindicated medications immediately 
thereafter. Any concomitant medications added or discontinued during the study should be 
recorded on the eCRF. 
9.4.9 Treatment Compliance 
Subjects will be instructed to return all used and unused BMN 111 or placebo kits at each 
study visit. Subject compliance with the dosing regimen will be assessed by reconciliation of 
the used and unused vials. The quantity dispensed, returned, used, lost, etc. must be recorded 
on the dispensing log provided for the study. 
The date, time, and volume of each dose of BMN 111 or placebo administered to each 
subject must be recorded. These data will be used to assess treatment compliance.  
9.5 
Investigational Product Accountability (BMN 111 or Placebo) 
The Investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of IP(s) received, subjects to whom IP is dispensed (subject-by-subject dose 
specific accounting), and IP lost or accidentally or deliberately destroyed. The Investigator or 
designee must retain all unused or expired study supplies until the study monitor (on-site 
CRA) has confirmed the accountability data. 


 
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9.5.1 Return and Disposition of Clinical Supplies 
Unused BMN 111 or placebo must be kept in a secure location for accountability and 
reconciliation by the study monitor. The Investigator or designee must provide an 
explanation for any destroyed or missing BMN 111 or placebo kits/vials. 
Unused BMN 111 or placebo may be destroyed on site, per the site’s standard operating 
procedures, but only after BioMarin has granted approval for destruction. The study monitor 
must account for all BMN 111 or placebo kits/vials in a formal reconciliation process prior to 
destruction. The site must document all BMN 111 or placebo destroyed on site, and 
documentation must be provided to BioMarin and retained in the investigator study files. If a 
site is unable to destroy BMN 111 or placebo appropriately, the site can, upon request, return 
unused BMN 111 or placebo to the BioMarin contracted facility. The return of all BMN 111 
or placebo kits/vials must also be documented and accounted for per instructions provided by 
BioMarin. 
All BMN 111 or placebo and related materials should be stored, inventoried, reconciled, and 
destroyed or returned according to applicable state and federal regulations and study 
procedures. 
9.6 
Dietary or Other Protocol Restrictions 
BMN 111 will be administered as a single daily dose of 15 µg/kg SC injection given daily at 
approximately the same time each day whenever possible. Placebo will be administered as a 
single SC injection given daily at approximately the same time each day whenever possible. 
Following administration of each dose, subjects will be observed for at least 2 hours after the 
injection for observation for Days 1 to 3, and 30 minutes for all other days of dose 
administration.  
Subjects should have adequate food intake prior to dosing.  All subjects should have been 
well hydrated and fed in the hour prior to administration of BMN 111 or placebo. 
9.7 
Demographic Data and Medical History  
Demographic data and a detailed medical history will be obtained at Screening. This medical 
history, including growth history and ACH-related history, should elicit all major illnesses, 
diagnoses, and surgeries that the subject has ever had; any prior or existing medical 
conditions that might interfere with study participation or safety; and evaluation for knee, 
thigh, hip or groin pain, or change in gait/activity.   


 
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9.8 
Biological Parental Standing Height 
Standing height of the subject’s biological parents may be assessed (optional) via height 
measurement or stated height. Height measurement can be done at any point in the study.  
Prior to the measurement being taken, each parent is required to complete an ICF specific to 
parent height assessment.  The ICF will be signed prior to the assessment, which can be done 
at any point in the study. If the biological parent is not available during the course of the 
study to take his/her standing height, if consented, the biological parent can provide his/her 
stated height.  
9.9 
Physical Examination Findings 
Physical examination will include assessment of general appearance; CV; dermatologic; 
head, eyes, ears, nose, and throat; lymphatic; respiratory; GI; musculoskeletal; and 
neurological/psychological and genitourinary. Other body systems may be examined. 
Screening results will be the baseline values and clinically significant changes from baseline 
will be recorded as an AE or SAE and study drug related or unrelated when appropriate 
based on the investigator’s clinical judgment. 
9.10 
Echocardiogram 
Cardiac anatomy and function will be evaluated by a standard 2-dimensional Doppler 
echocardiogram by a cardiologist. Echocardiograms will be performed at screening, and 
provide information regarding cardiac anatomy and function prior to enrollment in the study. 
9.11 
Efficacy and Safety Variables 
9.11.1 Efficacy and Safety Measurements Assessed 
The Schedule of Events (Table 9.1.1 and Table 9.1.2) describes the timing of required 
evaluations. 
9.11.2 Primary Efficacy Variables 
The primary efficacy endpoint is change from baseline in length/height Z-score. 
Growth measures may be collected approximately the same time each visit (± 2 hr from the 
time when the first measurement assessment was taken at Screening) by a study staff 
member, preferably the same person throughout the study, who has been trained by a 
BioMarin representative. Standardized measuring equipment and detailed measurement 
techniques are detailed in the Anthropometric Measurement Guidelines.  


 
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9.11.3 Secondary Efficacy Variables 
The secondary efficacy endpoints include change from baseline in AGV (annualized to 
cm/yr), biomarker samples to evaluate the effect of BMN 111 on bone metabolism, and 
BMN 111 pharmacodynamic biomarkers. 
Weight will be measured at Screening and at study visits as indicated on the Schedule of 
Events (Table 9.1.1 and Table 9.1.2). 
Biomarkers may include but are not limited to assessment of changes in bone and collagen 
metabolism (serum bone-specific alkaline phosphatase, serum collagen type X, and urine 
C-terminal telopeptide of collagen type II [CTX-II]) and BMN 111 bioactivity (plasma and 
urine cGMP). BioMarin or designee will perform analysis, and samples may also be used for 
assay development.   
Samples for blood and/or urine biomarkers will be collected at the time points presented in 
the Schedule of Events (Table 9.1.1 and Table 9.1.2). Refer to the Study Laboratory Manual 
for instructions regarding obtaining and shipping samples. The sample type will also be 
included in the Study Laboratory Manual. 
9.11.4 Exploratory Efficacy Variables 
9.11.4.1 
Body Proportion Ratios of the Extremities 
Change from baseline in body proportion ratios of the extremities will be evaluated using 
anthropometric measurements and measurement ratios.  Refer to the Anthropometric 
Measurement Guidelines for specific instructions regarding the collection of growth 
measurements. All age-appropriate physical measurements will be collected at approximately 
the same time each visit (±2 hours around the time when the first measurement assessment 
was taken at Screening) by a trained study staff member; every effort will be made to have 
the measurements collected by the same study staff member, if possible, throughout the 
study. Each measurement will be taken in triplicate (excluding weight, taken once). 
Anthropometric measurement can be conducted either pre-dose or post-dose. Measurements 
may include but are not limited to length, standing height (if able to stand unsupported), 
crown-to-rump length, head circumference, upper and lower arm and leg, and arm span. 
Measurements not taken in the midsagittal plane should be taken on the right side of the body 
if possible and should always be taken on the same side of the body throughout the study 
Body proportion measurements may include but are not limited to upper arm:forearm length 
ratio, upper leg:lower leg length ratio, and armspan:standing height ratio. 


 
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9.11.4.2 
Imaging Assessment Procedures (per Schedule of Events) 
Imaging assessment procedures for all visits must be performed using the same instruments.  
Imaging assessments can be conducted either pre-dose or post-dose. 
• Bilateral lower extremity x-rays, anterior-posterior (AP) view, to assess growth plate 
morphology. 
• Hip imaging via pelvis x-ray to identify hip pathology  
• Lumbar spine x-rays to measure changes from baseline in bone morphology and 
pathology.   
• MRI to evaluate the effect of BMN 111 on skull and brain morphology, including 
foramen magnum, ventricular and brain parenchymal dimensions.  
• DXA (BMD and BMC) of whole body [less head], spine, and forearm (including 
ultra-distal, mid-distal, and one third radius regions of interest) to assess bone mineral 
density (BMD) and bone mineral content (BMC). 
Although X-rays are preferable for consistency across the study population, if there are IRBs 
or IECs unwilling to allow x-rays in Cohort 3 subjects, contact the medical monitor to 
discuss alternate non-radiological methods for assessment.   
Additional imaging may be conducted should there be any issues or concerns with the 
subject’s imaging assessments. Imaging assessments will be collected and interpreted by a 
central reader. If clinically significant abnormalities are noted, the investigator or designee is 
required to assess whether it is appropriate to report an AE and if the subject should continue 
in the study. Refer to the vendor Imaging Guidelines for detailed imaging assessment 
requirements and procedures. 
9.11.4.3 
Exploratory Biomarker Research Sample Analyses 
All samples collected in this study may be used for on-study exploratory biomarker research 
once the primary use has been completed.  
For each portion of the blood and urine samples reserved for protocol-specified analyses, 
there may be multiple sample aliquots. Once samples have been successfully analyzed during 
the study, unused sample portions may be used during the study for assay development or 
other purposes stated in this section. No exploratory genomic research will be conducted 
without consent from the subject and his/her legally authorized representative (parent or legal 
guardian). 


 
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9.11.4.4 
Genomic Biomarker Analysis 
While the inherited FGFR3 mutations associated with achondroplasia are well characterized, 
disease phenotype in monogeneic diseases is often modified by variants in other genes. 
To identify and study genetic variants that may modify achondroplasia, a whole blood 
sample will be collected.  Exploratory genomics will include, but are not limited to NPR-B, 
BRAF, and other genes associated with CNP signaling.  Exploratory genomic analysis may 
inform understanding of the BMN 111 mechanism of action in achondroplasia.  Exploratory 
genomics will not be conducted without express consent from the subject and his/her legally 
authorized representative (parent or legal guardian).  
9.11.4.5 
Sleep Study 
Given that sleep apnea is a finding in children with ACH (Waters, 1993) and has implications 
on functional and health outcomes, a sleep study will be performed in a limited number of 
qualified sleep centers.  A sleep-testing device will be used to assess the presence and 
severity of sleep-disordered breathing by measurement of blood oxygen saturation, pulse 
rate, and airflow during overnight monitoring. Assessment of episodes of sleep apnea will 
include, but may not be limited to, the number of episodes of apnea and hypopnea per hour 
(Apnea/Hypopnea Index).   
9.11.4.6 
Clinical Photography 
To document the physical and phenotypic findings of achondroplasia with and without 
treatment with study drug, clinical photography of the full body, face, spine, and extremities 
will be conducted. This assessment is optional. If the parents/caregivers decline clinical 
photography, the assessment will be waived for the duration of the study. 
9.11.4.7 
Clinical Outcome Assessments 
Clinical outcome assessments will be administered to assess the health-related quality of life 
of study subjects. ADL questionnaires will be performed in study subjects to assess 
functional performance. Clinical outcome assessments will be performed at the time points 
indicated in the Schedules of Events (Table 9.1.1 and Table 9.1.2). The age ranges for 
clinical outcome assessment tools are shown in Figure 9.11.4.7.1. 
 
 
 
 


 
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Figure 9.11.4.7.1:  Clinical Outcomes Assessment Tools 
 
 
9.11.4.7.1 Bayley-III 
The Bayley-III is a performance-based outcome assessment for use in children from 1 to 
42 months. It is individually administered by the trained clinician to the subject/child. 
The time required varies from 15-60 minutes depending on the child’s developmental level 
and cooperation.  
Scales include Cognitive subscale, Receptive and Expressive subscales, and Gross and Fine 
Motor subscales. The two language scales make up a composite Language Scale score and 
the Gross and Fine Motor subscales yield a composite Motor Scale score.  
The scales have clinical and research utility as a diagnostic assessment for young children 
with varied disorders and disabilities, and reflect current professional standards for early 
childhood assessment (Bayley, 2006).  
In addition to its use for subjects ranging from 1 to 42 months old, the Bayley-III assessment 
will be administered to those entering the study between 42 and 60 months old 
(Figure 9.11.4.7.1) and for the remainder of the duration of this study, as this assessment can 
capture ongoing developmental issues associated with Achondroplasia.  Bayley-III is waived 
for subjects  < 1 month old. 
9.11.4.7.2 Activity of Daily Living and Functional Independence Measure (Wee-FIM) 
The Wee-FIM instrument is an ADL assessment tool that measures functional performance 
across three domains (self-care, mobility and cognition) (Ireland, 2011; Ireland, 2012). 


 
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The Wee-FIM instrument has been used in previous research in children with ACH, and has 
identified ongoing limitations in functional performance across these domains extending 
beyond the age of 7 years (Ireland, 2011). Because the WeeFIM considers the child’s 
performance from a caregiver’s perspective (Ireland, 2012), this tool in turn gives an 
indication of “burden of care” for families and caregivers of children with ACH.  WeeFIM is 
waived for children < 6 months old. 
9.11.4.7.3 ITQOL 
The ITQOL is an observer-reported outcome tool developed for use in children from 
2 months to 5 years old that attempts to capture physical, mental and social well-being. 
The ITQOL adopts the World Health Organization’s definition of health as a state of 
complete physical, mental and social well-being, and not merely the absence of disease. 
The ITQOL also assesses the quality of the parent/guardians life.  The 97-item full-length 
version (ITQOL) will be used for this study. Completion time varies.  ITQOL is waived for 
subjects < 2 months old. 
9.11.4.7.4 Child Behavior Checklist  
The Child Behavior Checklist (CBCL) is for use in children from 1.5-5 years old, and will be 
administered for those entering the study at less than 5 years old and for the remainder of the 
duration of the study.  The CBCL comprises 99 questions addressing symptoms related to 
mood, behavior issues, and sleep disturbance.  It is completed by the parent or primary 
caregiver.  
The form requires approximately 15 minutes to complete. The checklist yields scores in the 
following areas: reactivity, anxiety, depression, somatic complaints, withdrawal, sleep 
problems, attention problems, and aggressive behavior. CBCL is waived for 
children < 18 months old. 
9.11.5 Pharmacokinetics Variables 
PK plasma samples will be collected pre-dose and at 5 (± 2 min), 15 (± 2 min), 30 (± 5 min), 
45 (± 5 min), 60 (± 5 min), 90 (± 5 min), and 120 (± 5 min) minutes post-dose. On Day 1, 
additional PK samples will be collected at 180 (± 5 min) and 240 (± 5 min) minutes.  In the 
event of interruption of study drug administration for a sentinel patient on Day 1 when PK 
samples are scheduled, the collection of PK samples should be delayed until the subsequent 
day and only performed after successful administration of study drug has been completed in a 
single injection. 


 
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Whenever possible, the following PK parameters will be estimated by non-compartmental 
analysis: 
• Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) 
• Area under the plasma concentration-time curve from 0 to the time of last measurable 
concentration (AUC0-t) 
• Cmax 
• tmax 
• Elimination half-life (t1/2) 
• Apparent clearance of drug (CL/F) 
• Apparent volume of distribution based upon the terminal phase (Vz/F) 
Refer to the Study Laboratory Manual for additional instructions regarding obtaining and 
shipping samples. BioMarin will perform sample analysis, and samples may also be used for 
assay development.  
9.11.6 Safety Variables 
Safety will be evaluated by the incidence of AEs, SAEs, and clinically significant changes in 
vital signs, physical examination, ECG, imaging, and laboratory test results (urinalysis, 
chemistry, hematology). Additionally, imaging, hip monitoring, biomarker, immunogenicity, 
cortisol and prolactin levels, and physical measurement data will be utilized for safety-related 
reviews and analysis.  
9.11.6.1 
Adverse Events 
The occurrence of AEs will be assessed continuously from the time the subject receives study 
drug. The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10.2.1. Assessments of AEs will occur at the time points shown in the Schedule of 
Events (Table 9.1.1 and Table 9.1.2). Additionally, contact by a study staff member to the 
caregiver will be required every week for 6 months, and then every 2 weeks for the 
remainder of the study. During these contacts, study staff will ask the caregiver about dose 
administration and seek information on AEs and SAEs by specific questioning. Information 
on all AEs and SAEs should be recorded in the subject’s medical record and on the AE 
eCRF.  
9.11.6.2 
Procedures During the Study 
All procedures/intervention/surgery will be recorded after informed consent is obtained and 
after the first administration of study drug, until end of study. 


 
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9.11.6.3 
Clinical Laboratory Assessments 
Specific visits for obtaining clinical laboratory assessment samples are provided in 
Table 9.1.1 and Table 9.1.2. The scheduled clinical laboratory tests are listed in 
Table 9.11.6.3.1. Refer to the Study Reference Manual for instructions on obtaining and 
shipping samples. 
Any abnormal test results determined to be clinically significant by the Investigator should 
be repeated (at the Investigator’s discretion) until the cause of the abnormality is determined, 
the value returns to baseline or to within normal limits, or the Investigator determines that the 
abnormal value is no longer clinically significant. 
The investigator should assess all abnormal clinical results and include a comment on 
whether or not the result is clinically significant. Each clinically significant laboratory result 
should be recorded as an adverse event. 
The diagnosis, if known, associated with abnormalities in clinical laboratory tests that are 
considered clinically significant by the Investigator will be recorded on the AE eCRF. 


 
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Table 9.11.6.3.1:  Clinical Laboratory Tests 
Blood Chemistry 
Hematology 
Urinalysis 
Albumin 
Hemoglobin 
Appearance 
Alkaline phosphatase, total 
Hematocrit 
Color 
ALT (SGPT) 
WBC count 
pH 
AST (SGOT) 
RBC count 
Specific gravity 
Direct bilirubin 
Platelet count 
Ketones 
Total bilirubin 
Differential cell count 
Protein 
BUN 
 
Glucose 
Calcium 
 
Bilirubin 
Chloride 
 
Nitrite 
Potassium 
 
Urobilinogen 
Sodium 
 
Hemoglobin 
Glucose 
 
 
Bicarbonate 
 
Urine Chemistry  
Urine creatinine 
Urine sodium 
Urine potassium 
LDH 
Phosphorus 
 
 
Total protein 
25-hydroxy Vitamin D  
 
 
Creatinine 
Thyroid function (TSH, FT4; if either TSH and 
FT4 are abnormal then T3 may be measured in 
addition) 
 
 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; FT4, free thyroxine; LDH, 
lactate dehydrogenase; RBC, red blood cell; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-
pyruvic transaminase; T3, triiodothyronine; TSH, thyroid stimulating hormone; WBC, white blood cell. 
 
9.11.6.4 
Other Laboratory Assessments  
Subjects will be asked to provide blood and urine at the times indicated in the Schedule of 
Events (Table 9.1.1 and Table 9.1.2).  Blood volume for testing has been reduced to the 
minimum necessary for adequate evaluation of efficacy and safety of BMN 111. 
For subjects who have not previously had genetic testing confirming diagnosis of ACH, 
molecular genetic diagnosis to identify the FGFR3 mutation (G346E, G375C, G380R, or 
“other”) will be performed.  If subjects had previous genetic testing, subjects must have a lab 
report from a certified laboratory with the study specific mutation documented. 
Salivary cortisol and serum prolactin will be collected at the times indicated in the Schedule 
of Events (Table 9.1.1). 
Scheduled biomarker and anti-BMN 111 antibody tests are listed in Table 9.11.6.4.1. 


 
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Table 9.11.6.4.1:  Biomarkers and Anti-BMN 111 Antibodies 
Blood Special Chemistry 
Urine Biomarkers 
Exploratory bone metabolism biomarkers: 
bone-specific alkaline phosphatase and collagen type 
X 
Exploratory bone metabolism urine biomarkers: 
C-terminal telopeptide of collagen type II 
Genomic biomarkers 
BMN 111 pharmacodynamics biomarkers (cGMP) 
Anti-BMN 111 antibodies 
 
BMN 111 pharmacodynamics biomarker (cGMP) 
BMN 111 pharmacodynamics biomarker (cGMP) 
cGMP, cyclic guanosine monophosphate 
 
9.11.6.5 
Vital Signs, Physical Examinations and Other Observations Related to Safety 
Vital signs assessed pre-dose will include seated or supine systolic blood pressure (SBP) and 
diastolic blood pressure (DBP) measured in mm Hg, heart rate in beats per minute, 
respiration rate in breaths per minute, and temperature in degrees Celsius (°C). All treatment 
visits have pre-dose vital sign assessments. Post-dose measurements include heart rate and 
BP. For all dosing visits, assessment frequency is detailed in Table 9.11.6.5.1 (Schedule of 
Events, Table 9.1.1 and Table 9.1.2). 
At Screening, after at least 5 minutes of rest, subject’s BP is taken in sitting or supine 
position. Vital sign measurements should be repeated and documented 3 times, with at least 
5-minute intervals between assessments.  Left brachial arm should be the first method of 
assessment considered, and the same site should be used for blood pressure measurement in 
each subject throughout the study. The method and site of blood pressure measurement will 
be recorded and should be utilized consistently throughout the remainder of the study. 
At other visits, vital sign measurements are taken once per time point in a sitting or supine 
position after at least 5 minutes of rest. Heart rate should be taken at each time point that BP 
is measured. When blood samples and BP assessments are scheduled at the same time or 
within the same time window, BP should be measured before blood samples are drawn. If a 
BP measurement must be taken after a blood draw, ensure adequate analgesia for the blood 
draw and wait several minutes before measuring BP. Pre-dose vital signs should always be 
taken and recorded prior to pre-dose blood draw. Vital signs may be monitored more 
frequently or for longer duration post-dose as clinically indicated.   
If a subject has signs potentially consistent with hypotension or a decrease in systolic BP of 
20 mm Hg or more from pre-dose systolic BP, blood pressure and heart rate (BP/HR) should 
be measured and recorded approximately every 15 minutes for the first hour and every 
30 minutes thereafter until the systolic BP returns to pre-dose systolic BP (or within the 


 
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normal range for this subject as defined by PI) and signs (if present) resolve.  If the 
hypotension resolves within the first hour and returns to the normal range, additional BP 
monitoring as described above is not required. Detailed guidance for blood pressure 
measurements is provided in the Blood Pressure Instrument and Technique Guidelines.  
Table 9.11.6.5.1:  Vital Sign Assessment Frequency  
Vital Sign Assessment Frequency  
Screening 
After at least 5 min of rest, subject’s vital signs are taken, preferably in sitting or supine 
position.  Vital sign measurements should be repeated and documented 3 times with at 
least 5 min intervals between assessments.   
 
Assessment Frequency 
Dosing Visits 
0-1 hr post-dose 
0-2 hr post-dose 
2-4 hr post dose 
4-8 hr post-dose 
Days 1, 2 
 
q 15 min (± 5 min) 
q 30 min (± 5 min) 
q 60 min (± 10 min) 
Days 3, 8 
 
q 15 min (± 5 min) 
q 30 min (± 5 min) 
 
Subsequent dosing 
visits 
q 15 min (± 5 min); 
final assessment prior 
to end of visit (if 
longer than 1 hr) 
 
 
 
1. Vital sign measurements are taken once per time point, preferably in a sitting or supine position, after at 
least 5 minutes of rest.   
2. Heart rate, blood pressure, and respiratory rate should be taken and recorded at each indicated time 
point.   
3. When blood samples and vital sign assessments are scheduled at the same time or within the same time 
window, vital signs should be measured before blood samples are drawn.   
4. If a vital sign measurement must be taken after a blood draw, ensure adequate analgesia for the blood 
draw and wait several minutes before measuring vital signs.   
5. Vital signs may be monitored more frequently or for longer duration post-dose as clinically indicated. 
6. If a subject has a hypotensive event, or signs potentially consistent with hypotension, or a decrease of 20 
mm Hg systolic BP or more from baseline (defined by pre-dose vitals collected that day), vital signs 
should be measured and recorded approximately every 15 minutes (± 5 minutes) for the first hour and 
every 30 minutes (± 5 minutes) thereafter until the BP returns to baseline (or within the normal range for 
this subject as defined by PI) and signs (if present) resolve.  
7. If the decision is made to adjust the dose, vital signs will be obtained for at least 4 hr following the first 
dose at the adjusted dose level, similar to the Day 3, 8 schedule. 
8. If a dose adjustment visit coincides with a visit at which a full PK is drawn, vital signs will be obtained 
for 8 hours, similar to the Day 1,2 schedule. 
 
9.11.6.6 
Mitigating the Risk of Potential Hypotension  
Study personnel and caregivers should be made aware of the potential risk of hypotension 
with BMN 111 administration.  Subjects must be well hydrated and at a minimum be fed 


 
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prior to administration of BMN 111 or placebo.  If a recent acute illness associated with 
volume depletion (e.g., nausea, vomiting, diarrhea) has not completely resolved prior to the 
first dose of BMN 111 or placebo, BMN 111 or placebo dosing may be delayed until 
hydration status has improved (up to the maximum period allowed for the screening 
window). 
Caregivers should be trained to observe and recognize the signs of dehydration (e.g. from 
fever, vomiting, diarrhea, etc.) and contact the investigator prior to BMN 111 or placebo 
administration if dehydration is suspected. Site personnel and caregivers should be trained to 
identify the signs of hypotension and, if they occur, should implement first-aid strategies at 
the discretion of the investigator such as having the subject lie down supine, elevating the 
lower extremities, and administering fluids. For guidelines on how to report adverse events 
associated with hypotension, refer to Section 10.3.1.4. 
9.11.6.7 
Electrocardiography 
A standard 12-lead ECG will include heart rate, rhythm, intervals, axis, conduction defects, 
and anatomic abnormalities. The time of collection will be recorded. ECGs should be 
performed in triplicate with the subject supine at the visits indicated in the Schedule of 
Events (Table 9.1.1 and Table 9.1.2).  ECGs will be performed post-dose on study day visits 
at which a dose is given; in addition, on Day 1, ECGs will be performed pre-dose.  On days 
when PK samples are being drawn, ECGs should be performed within a 5-minute window 
prior to 30-minute PK assessment.  If clinically significant abnormalities are noted, the 
investigator or designee is required to assess whether it is appropriate for the subject to 
continue in the study. 
9.11.6.8 
Hip Clinical Assessment 
The hip clinical assessment should be completed by an appropriately qualified physical 
therapist or a physician (MD) i.e., the investigator or the sub-investigator at the time points 
indicated in the Schedule of Events (Table 9.1.1 and Table 9.1.2). Medical history will be 
obtained to evaluate for hip, thigh, or knee pain, or change in gait. The physical exam 
(including observation of gait when possible) identifies and evaluates any changes in hip 
function or pain with assessment of active and passive range of motion. Changes from 
baseline may trigger further evaluation based on the investigator’s clinical assessment, which 
may include hip imaging and/or orthopedic consultation. If findings on clinical hip exam are 
determined to be clinically significant by the investigator and in consultation with Sponsor’s 
Medical Monitor and orthopedic specialist (if needed), the DMC will be notified of AEs 
resulting from clinically significant abnormal hip monitoring assessments. DMC may 


 
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provide recommendations as to if/when BMN 111 or placebo treatment should be 
temporarily or permanently discontinued.  
9.11.6.9 
Pediatric Blood Volume 
Clinical labs and immunogenicity samples are necessary to perform to adequate safety 
assessment in this study.  The objectives of testing pharmacodynamics biomarkers are to 
demonstrate biologic activity of BMN 111 and to understand the impact of immune 
responses on drug activity; and for blood biomarkers, to investigate the effects of treatment 
on changes in bone metabolism and endogenous CNP production. 
To minimize blood collection volumes, assay technologies were chosen that are capable of 
sensitively detecting analytes using the lowest possible volume of blood for analysis.  
Additionally, assays capable of detecting analytes in urine rather than blood have been 
selected where possible. 
9.11.6.10 Anti- BMN 111 Immunogenicity Assessments and IgE Testing 
Subjects randomized to receive BMN 111 or placebo will undergo immunogenicity testing. 
Blood (serum) samples for immunogenicity assessments will be collected at the time points 
indicated in the Schedule of Events (Table 9.1.1), and testing performed using validated 
assays. Neutralizing antibody (NAb) testing will be performed on Baseline and TAb positive 
samples drawn from subjects weighing ≥ 7.0 kg and waived for subjects < 7.0 kg.  
Scheduled samples will be tested in one or more of the following assessments: 
• Anti- BMN 111 total antibody (TAb) 
• Anti-BMN 111 antibody cross-reactive with endogenous CNP, ANP, and BNP (TAb) 
• Anti- BMN 111 NAb 
Testing for the presence of cross-reactive antibodies that bind to endogenous CNP, ANP, or 
BNP and for the presence of BMN 111 NAbs will be performed on baseline samples and 
anti- BMN 111 TAb-positive samples. Baseline NAb sample and cross-reactive TAb sample 
testing will be done at any time prior to the end of study. 
9.11.6.11 HPA Axis Assessments 
To address potential effects of BMN 111 on activation of the hypothalamic pituitary adrenal 
(HPA) axis, assessment of salivary cortisol and serum Prolactin levels will be analyzed at the 
time points indicated in the Schedule of Events (Table 9.1.1). Both tests will be done at 
Baseline, Week 26, and Week 52.  


 
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9.11.6.12 Ad Hoc Safety Assessments 
Samples for total IgE and drug-specific IgE testing will be drawn on Day 1 and in the event 
of a significant hypersensitivity AE, or at the discretion of the investigator and/or BioMarin. 
A significant hypersensitivity AE is defined as an event that is grade 3 or higher, requires 
temporary or permanent cessation of BMN 111, or is determined to be significant at the 
discretion of investigator and/or BioMarin (excluding reactions that are solely a localized 
injection site reaction). If a hypersensitivity AE occurs, an unscheduled safety visit should 
occur no later than 48 hours of the start of the reaction, including inspection of the injection 
site and clinical laboratory tests.  
Blood (serum) samples should be collected and tested in one or more of the following 
assessments: 
•  Drug-specific IgE 
• Total IgE 
• Serum tryptase 
If feasible, a sample for drug-specific IgE should be drawn no sooner than 8 hours after the 
event start time or before the next dose. A sample for total IgE and serum tryptase should 
also be drawn within 1 hour of the start of the event when possible or during the unscheduled 
safety visit.  
A localized injection site reaction is defined as skin signs or signs restricted to one affected 
primary location, i.e., hives, wheals, or swelling or an area of erythema, redness, induration, 
pain, or itching at or near the site of injection. Management of such localized reactions 
should be determined by the investigator’s clinical judgment in consultation with the 
Sponsor’s Medical Monitor (if warranted). 
9.11.6.13 Unscheduled Safety Visits 
Unforeseen circumstances may arise in which an unscheduled visit may be needed. In such a 
case, the procedures performed at the unscheduled visit will be completed on a case-by-case 
basis. 


 
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10 
REPORTING ADVERSE EVENTS 
10.1 
Safety Parameters and Definitions 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified hematology, clinical chemistry, and urinalysis variables; 
measurement of protocol-specified vital signs; and other protocol-defined events of special 
interest that are deemed critical to the safety evaluation of the study drug. 
10.1.1 Adverse Events 
For this protocol, a reportable adverse event (AE) is any untoward medical occurrence 
(e.g., sign, symptom, illness, disease or injury) in a subject administered the study drug or 
other protocol-imposed intervention, regardless of attribution. This includes the following: 
• AEs not previously observed in the subject that emerge during the course of the 
study. 
• Pre-existing medical conditions judged by the Investigator to have worsened in 
severity or frequency or changed in character during the study. 
• Complications that occur as a result of non-drug protocol-imposed interventions 
(eg, AEs related to screening procedures, medication washout, or no-treatment 
run-in). 
An adverse drug reaction is any AE for which there is a reasonable possibility that the 
study-drug caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the study-drug and the AE. 
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series 
of terms relating to a diagnosis. 
10.1.2 Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose meets 
1 or more of the following criteria: 
• Is fatal 
• Is life threatening  
Note: Life-threatening refers to an event that places the subject at immediate risk of 
death. This definition does not include a reaction that, had it occurred in a more 
severe form, might have caused death. 
• Requires or prolongs inpatient hospitalization   
• Results in persistent or significant disability or incapacity 


 
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• Is a congenital anomaly or birth defect in the child or fetus of a subject exposed to IP 
prior to conception or during pregnancy 
• 
Is an important medical event or reaction – that, based on medical judgment, may 
jeopardize the subject or require intervention to prevent one of the above 
consequences (e.g. anaphylaxis) 
All adverse events that do not meet any of the criteria for SAEs should be regarded as 
non-serious AEs. 
10.1.3 Events of Special Interest (EOSI)  
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, 
irrespective of seriousness, severity or causality:  
• 
Fracture 
• 
Slipped Capital Femoral Epiphysis (SCFE) 
• 
Avascular necrosis or Osteonecrosis 
10.2 
Methods and Timing for Capturing and Assessing Safety Parameters 
10.2.1 Adverse Event Reporting Period 
For subjects enrolled in Cohort 1 ( ≥  24 to < 60 months old) and Cohort 2 ( ≥ 6 to   < 24 months 
old), the study AE reporting period is as follows: after informed consent but prior to initiation 
of study treatment, only SAEs associated with any protocol-imposed interventions will be 
reported.  After informed consent is obtained and the first administration of study drug, all 
non-serious AEs and SAEs reporting period begins and continues until 4 weeks following 
either the last administration of study drug or the early termination visit, whichever is longer 
(refer to Section 12.1.11). The criteria for determining, and the reporting of, SAEs is 
provided in Section 10.1.2.  For subjects enrolled in Cohort 3 (0 to <  6 months old), the 
collection period for all AEs begins after informed consent is obtained. 
10.2.2 Eliciting Adverse Events 
Investigators will seek information on AEs and SAEs and EOSI, if applicable at each subject 
contact by specific questioning and, as appropriate, by examination.  Information on all AEs 
and SAEs and EOSI, if applicable should be recorded in the subject’s medical record and on 
the AE Electronic Case Report Form (eCRF). 
10.2.3 Assessment of Seriousness, Severity, and Causality 
The Investigator or qualified designee responsible for the care of the subject will assess AEs 
for severity, relationship to study drug, and seriousness (refer to Section 10.1.2 for SAE 


 
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definitions).  These assessments should be made by a study clinician with the training and 
authority to make a diagnosis (e.g., MD/DO, physician’s assistant, nurse practitioner, or 
DDS). 
10.2.3.1 
Seriousness 
The investigator will assess if an AE should be classified as “serious” based on the 
seriousness criteria enumerated in Section 10.1.2.  Seriousness serves as a guide for defining 
regulatory reporting obligations. 
10.2.3.2 
Severity 
Severity (as in mild, moderate, or severe headache) is not equivalent to seriousness, which is 
based on subject/event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning.  The severity of each will be assessed using the 
defined categories in Table 10.2.3.2.1. 
The Investigator or qualified designee will determine the severity of each AE and SAE, and 
EOSI using the NCI CTCAE v4. Adverse events that do not have a corresponding CTCAE 
term will be assessed according to the general guidelines for grading used in the CTCAE v4 
as stated below. 


 
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Table 10.2.3.2.1:  Adverse Event Grading (Severity) Scale 
Grade 
Description 
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
2 
Moderate: minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)a 
3 
Severe or medically significant but not immediately life-threatening: hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADLb 
4 
Life threatening or debilitating: consequences; urgent 
intervention indicated 
Grade 4 and 5 AEs 
should always be 
reported as SAEs 
5 
Death related to AE 
a Instrumental ADL refer to the following examples: preparing meals, shopping for groceries or clothes, using the 
telephone, managing money. 
b Self-care ADL refer to the following examples: bathing, dressing and undressing, feeding oneself, using the toilet, 
taking medications, not bedridden. 
 
10.2.3.3 
Causality 
The Investigator will determine the relationship of an AE to the study drug and will record it 
on the source documents and AE eCRF.  To ensure consistency of causality assessments, 
Investigators should apply the guidance in Table 10.2.3.3.1. 


 
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Table 10.2.3.3.1:  Causality Attribution Guidance 
Relationshipa 
Description 
Not Related 
• 
Exposure to the IP has not occurred 
OR 
• 
The administration of the IP and the occurrence of the AE are not 
reasonably related in time  
OR 
• 
The AE is considered likely to be related to an etiology other than the use 
of the IP; that is, there are no facts, evidence, or arguments to suggest a 
causal relationship to the IP. 
Related 
• 
The administration of the IP and the occurrence of the AE are reasonably 
related in time 
AND 
• 
The AE could not be explained by factors or causes other than exposure 
to the IP 
                                                  OR 
 
• 
The administration of IP and the occurrence of the AE are reasonably 
related in time  
AND 
• 
The AE is more likely explained by exposure to the IP than by other factors 
or causes. 
 
Factors suggestive of a causal relationship could include (but are not limited to): 
• Plausible temporal relationship 
• Absence of alternative explanations 
• Rarity of event in a given subject or disease state 
• Absence of event prior to study drug exposure 
• Consistency with study product pharmacology 
• Known relationship to underlying mechanism of study drug action 
• Similarity to adverse reactions seen with related drug products 
• Abatement of AE with discontinuation of study drug, and/or recurrence of AE with 
reintroduction of study drug 
The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the Investigator’s assessment of causality for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 


 
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cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities. 
10.3 
Procedures for Recording Adverse Events 
10.3.1 Recording Adverse Events on a eCRF 
Investigators should use precise medical terminology when recording AEs or SAEs on an 
eCRF.  Avoid colloquialisms and abbreviations. 
Record only one diagnosis, sign, or symptom per event field on the AE eCRF (e.g., nausea 
and vomiting should not be recorded in the same entry, but as 2 separate entries). 
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor to the 
original terms entered on the eCRF, using MedDRA (Medical Dictionary for Regulatory 
Activities) terminology. 
10.3.1.1 
Diagnosis versus Signs and Symptoms 
Using accepted medical terminology, enter the diagnosis (if known).  If not known, enter 
sign(s) and/or symptom(s).  If a diagnosis subsequently becomes available, then this 
diagnosis should be entered on the AE form, replacing the original entries where appropriate. 
10.3.1.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events) should be 
identified by their primary cause.  For example, if severe diarrhea is known to have resulted 
in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the eCRF.  
However, medically important events that may be linked and/or separated in time should be 
recorded as independent events on the eCRF.  For example, if severe hemorrhage leads to 
renal failure, both events should be recorded separately on the eCRF. 
10.3.1.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between subject 
evaluation time points.  Such an event should be recorded only once on the eCRF unless its 
severity increases or decreases (in which case it should be recorded again on the AE eCRF). 
A recurrent AE is one that occurs and resolves between subject evaluation time points, but 
then subsequently recurs.  All recurrences of the AE should be recorded on the AE eCRF. 
10.3.1.4 
Hypotension 
If an asymptomatic drop in blood pressure meets the protocol definition of AE per clinical 
judgment of the reporter, report the event as “blood pressure decreased.”  If the drop in blood 


 
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pressure is associated with signs or symptoms, complete the symptomatic hypotension eCRF 
and use the following guidance to report the corresponding AE eCRF: If a unifying diagnosis 
is available to explain the event of hypotension, report the diagnosis as an AE and capture 
signs and symptoms on the symptomatic hypotension eCRF page. If no other unifying 
diagnosis is available, report “hypotension” as the event and capture signs and symptoms on 
the symptomatic hypotension eCRF page.  
10.3.1.5 
Injection Site Reactions 
If an injection site reaction is associated with a single sign or symptom, report the event on 
AE eCRF page (e.g., redness at injection site, AE is injection site redness). If the injection 
site reaction is associated with multiple signs or symptoms, report injection site reaction as 
the adverse event on the AE page, and individual signs and symptoms will be reported on the 
ISR eCRF page (e.g., if the subject experiences redness and induration, report “Injection site 
reaction” on the AE page, and in the corresponding Injection eCRF page, report erythema 
and induration).  If the injection site reaction appears after 24 hours, add “delayed” to the 
term used to describe the event. 
10.3.1.6 
Abnormal Laboratory Values 
Laboratory test results will be recorded on the laboratory results pages of the eCRF, or 
appear on electronically produced laboratory reports submitted directly from the central 
laboratory, if applicable. 
Any laboratory result abnormality fulfilling the criteria for a SAE should be reported as such, 
in addition to being recorded as an AE in the eCRF. 
A clinical laboratory abnormality should be documented as AE if it is not otherwise refuted 
by a repeat test to confirm the abnormality and any one or more of the following conditions 
is met: 
• Accompanied by clinical symptoms 
• Leading to a change in study medication (e.g. dose modification, interruption or 
permanent discontinuation)  
• Requiring a change in concomitant therapy (e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment). 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management (e.g., change of dose, 
discontinuation of study drug, more frequent follow-up assessments, further 
diagnostic investigation, etc.) 


 
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This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria. 
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 
explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported.  
10.3.1.7 
Pre-existing Conditions 
A pre-existing condition is one that is present at the start of the study.  Such conditions 
should be recorded as medical history on the appropriate eCRF. 
A pre-existing condition should be recorded as an AE or SAE during the study only if the 
frequency, intensity, or character of the condition worsens during the study period.  It is 
important to convey the concept that a pre-existing condition has changed by including 
applicable language in the verbatim description of the event (e.g., more frequent headaches). 
10.3.1.8 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition (refer to Section 10.3.1.7).  During the study, any new clinically significant 
findings and/or abnormalities discovered on physical examination that meet the definition of 
an AE (or an SAE) must be recorded and document as an AE or SAE on the AE eCRF. 
10.3.1.9 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol (refer to 
Section 10.1.2). 
There are some hospitalization scenarios that do not require reporting as an SAE when there 
is no occurrence of an AE.  These scenarios include planned hospitalizations or prolonged 
hospitalizations to: 
• Perform a protocol-mandated efficacy measurement 
• Undergo a diagnostic procedure 
• Elective surgical procedure for a pre-existing medical condition that has not changed 
• Receive scheduled therapy (study drug or otherwise) for the study indication 


 
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10.3.1.10 Deaths 
All deaths that occur during the AE reporting period (refer to Section 10.2.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the Sponsor as an 
SAE. 
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF.  If the cause of death 
is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the eCRF.  If the death is attributed to progression of the 
disease or condition being studies, record “-” as the SAE term on the eCRF. 
10.4 
Reporting Requirements 
The Sponsor is responsible for identifying, preparing, and reporting all suspected unexpected 
serious adverse reactions (SUSARs) to the relevant competent authorities, ethics committees, 
and investigators in accordance with requirements identified in the Clinical Trials 
Regulations. 
10.4.1 Expedited Reporting Requirements 
All SAEs and EOSI, if applicable that occur during the course of the AE Reporting Period 
(refer to Section 10.2.1), whether or not considered related to study drug, must be reported by 
entering the information in the AE eCRF and submitting to BPV within 24 hours of the site 
becoming aware of the event.  Each SAE must also be reported on the appropriate eCRF.  
Investigators should not wait to collect information that fully documents the event before 
notifying BPV of an SAE.  BioMarin may be required to report certain SAEs to regulatory 
authorities within 7 calendar days of being notified about the event; therefore, it is important 
that Investigators submit any information requested by BioMarin as soon as it becomes 
available. 
If the electronic data capture (EDC) is unavailable, all SAEs should be reported to BPV by 
completing the SAE Report Form and faxing or emailing the completed form to BPV within 
24 hours of the site becoming aware of the event. Once the EDC is available, the information 
should be entered in the AE eCRF.  
The reporting period for SAEs begins after informed consent is obtained and continues until 
4 weeks following either the last administration of study drug or study 
discontinuation/termination, whichever is longer.  


 
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10.4.2 IRB Reporting Requirements 
Reporting of SAEs to the IRB will be done in compliance with the standard operating 
procedures and policies of the IRB and with applicable regulatory requirements. Adequate 
documentation must be obtained by BioMarin showing that the IRB was properly and 
promptly notified as required. 
10.5 
Follow-up of Subjects after Adverse Events 
The Investigator should follow all unresolved AEs/SAEs until the events are resolved or have 
stabilized, the subject is lost to follow-up, or it has been determined that the study treatment 
or participation is not the cause of the AE/SAE.  Resolution of AEs and SAEs (with dates) 
should be documented on the AE eCRF and in the subject’s medical record to facilitate 
source data verification. 
For some SAEs, the Sponsor may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details (eg, hospital discharge summary, consultant 
report, or autopsy report) deemed necessary to appropriately evaluate the SAE report. 
10.6 
Post-Study Adverse Events 
At the last scheduled visit, the Investigator should instruct each subject to report, to the 
Investigator and/or to BPV directly, any subsequent SAEs that the subject’s personal 
physician(s) believes might be related to prior study treatment. 
The Investigator should notify the study Sponsor of any death or SAE occurring at any time 
after a subject has discontinued or terminated study participation, if the Investigator believes 
that the death or SAE may have been related to prior study treatment. The Sponsor should 
also be notified if the Investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a subject who participated in 
this study.  
10.7 
Urgent Safety Measures 
The regulations governing clinical trials state that the sponsor and Investigator are required to 
take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
subjects, the sponsor and the Investigator shall take appropriate urgent safety measures to 


 
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protect the subjects against any immediate hazard. The sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
IRB/EC/REB is notified at the same time.”  
The Sponsor is responsible for identifying, preparing and reporting all SUSARs to the 
relevant competent authorities, ethics committees and investigators in accordance with the 
requirements identified in the Clinical Trials Regulations. 
The reporting period for these events which may require the implementation of urgent safety 
measures is the period from the time of signing of the ICF through the completion of the last 
study visit or at the Early Termination Visit (ETV). Investigators are required to report any 
events which may require the implementation of urgent safety measures to BioMarin within 
24 hours. 
Examples of situations that may require urgent safety measures include discovery of the 
following: 
• 
Immediate need to revise the IP administration (eg, modified dose amount or frequency 
not defined in protocol) 
• 
Lack of study scientific value, or detrimental study conduct or management 
• 
Discovery that the quality or safety of the IP does not meet established safety 
requirements 


 
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10.8 
BioMarin Pharmacovigilance Contact Information 
Contact information for BioMarin Pharmacovigilance is as follows: 
BioMarin Pharmaceutical Inc. 
Address 
105 Digital Drive 
 
 
Novato, CA 94949 
Phone:  
 
Fax: 
 
 
E-mail: 
drugsafety@bmrn.com 
The Investigator is encouraged to discuss with the medical monitor any AEs for which the 
issue of seriousness is unclear or questioned. Contact information for the medical monitor is 
as follows: 
Name:  
 MD, PhD 
Address: 
10 Bloomsbury Way 
 
 
London WC1A 2SL 
Phone:  
 
Fax: 
 
 
E-mail: 
 
 
PI
PI
PI
PI
PI
PI


 
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11 
APPROPRIATENESS OF MEASUREMENTS 
The parameters to be evaluated in this study reflect the combined experience in the clinical 
study 111-202 and reflect the need to further define the efficacy and safety profile of 
BMN 111 in the context of achondroplasia (ACH), a complex skeletal dysplasia disorder 
with multiple clinical manifestations. 
The efficacy parameters to be evaluated in this study reflect the sponsor’s experience in the 
clinical study 111-202 and of previous studies of approved growth products (Kemp, 2009; 
Bright, 2009).  Evaluation of the parameters proposed in this study will document the effect 
of BMN 111 treatment on AGV in young children with ACH and are relevant to assessing 
the medical complications of ACH in this patient population.   
The PK assessments in this study are generally recognized as reliable, accurate, and relevant. 
Bone-related biomarkers and other biochemical markers of the pharmacological activity of 
BMN 111 in the blood or urine are secondary assessments.  Genomic biomarkers are 
exploratory assessments. 
 
 


 
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12 
STUDY PROCEDURES 
An ICF must be signed and dated by subject’s legally authorized, the investigator or 
designee, and witness (if required) before any study-related procedures are performed. 
12.1 
Treatment Visit(s) 
12.1.1 Screening/Baseline Day -30 to Day -1  
• Medical history 
• Parental height 
• Diagnostic genetic testing to confirm achondroplasia (if needed) 
• Physical examination 
• Weight 
• Vital signs 
• Electrocardiogram 
• Echocardiogram 
• Anthropometric measurements 
• Clinical laboratory assessments (hematology, chemistry, urinalysis) 
• Thyroid function tests 
• Vitamin D, 25-hydroxy test 
• Salivary cortisol 
• Serum prolactin 
• Bone metabolism blood biomarkers 
• Screening baseline hip assessment with pelvis x-ray 
• MRI brain/skull 
• Sleep study 
• Clinical outcome assessment: Bayley-III  
• Clinical outcome assessment: WeeFIM  
• Clinical outcome assessment: ITQOL 
• Clinical outcome assessment: CBCL 
• DXA 
• AP and lateral X-rays of spine 


 
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• AP X-rays of lower extremities  
• Clinical photographs (optional)  
• Concomitant medications 
12.1.2 Day 1 and Week 13 (±7d) 
• Physical examination 
• Weight 
• Vital signs 
• Electrocardiogram 
• Anthropometric measurements 
• Plasma pharmacokinetics and cGMP assessments 
• Anti-BMN 111 immunogenicity 
• Bone metabolism urine biomarkers 
• BMN 111 pharmacodynamic urine biomarkers 
• Urine chemistry 
• Capture all procedures 
• BMN 111 or placebo administration 
• BMN 111 or placebo accountability  
• Adverse events 
• Concomitant medications 
• Phone call or home health visit 
12.1.3 Days 2 and 3 
• Physical examination 
• Weight 
• Vital signs 
• Bone metabolism urine biomarkers 
• BMN 111 pharmacodynamic urine biomarkers 
• Urine chemistry 
• Capture all procedures  
• BMN 111 or placebo administration 


 
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• BMN 111 or placebo accountability  
• Adverse events 
• Concomitant medications 
• Phone call or home health visit 
12.1.4 Day 8 (±1d) and Week 20 (±7d) 
• Physical examination 
• Weight 
• Vital signs 
• Electrocardiogram 
• Clinical laboratory assessments (hematology, chemistry, urinalysis) 
• Bone metabolism blood biomarkers 
• Capture all procedures  
• BMN 111 or placebo administration 
• BMN 111 or placebo accountability  
• Adverse events 
• Concomitant medications 
• Phone call or home health visit 
12.1.5 Week 3 (±7d) 
• Physical examination 
• Weight 
• Vital signs 
• Clinical laboratory assessments (hematology, chemistry, urinalysis) 
• Anti-BMN 111 immunogenicity 
• Bone metabolism urine biomarkers 
• BMN 111 pharmacodynamic urine biomarkers 
• Urine chemistry 
• Capture all procedures  
• BMN 111 or placebo administration 
• BMN 111 or placebo accountability  


 
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• Adverse events 
• Concomitant medications 
• Phone call or home health visit 
12.1.6 Week 6 (±7d) 
• Physical examination 
• Weight 
• Vital signs 
• Electrocardiogram 
• Anthropometric measurements 
• Clinical laboratory assessments (hematology, chemistry, urinalysis) 
• Genomic biomarkers (optional) 
• Bone metabolism blood biomarkers 
• Capture all procedures  
• BMN 111 or placebo administration 
• BMN 111 or placebo accountability  
• Adverse events 
• Concomitant medications 
• Phone call or home health visit 
12.1.7 Week 26 (±7d) 
• Physical examination 
• Weight 
• Vital signs 
• Electrocardiogram 
• Anthropometric measurements 
• Salivary cortisol 
• Serum prolactin  
• Plasma pharmacokinetics and cGMP assessments 
• Anti-BMN 111 immunogenicity 
• Bone metabolism urine biomarkers 


 
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• BMN 111 pharmacodynamic biomarkers 
• Urine chemistry 
• Hip monitoring 
• Clinical outcome assessment: Bayley-III  
• Clinical outcome assessment: WeeFIM  
• Clinical outcome assessment: ITQOL 
• Clinical outcome assessment: CBCL 
• Capture all procedures  
• BMN 111 or placebo administration 
• BMN 111 or placebo accountability  
• Adverse events 
• Concomitant medications 
• Phone call or home health visit 
12.1.8 Week 39 (±7d) 
• Physical examination 
• Weight 
• Vital signs 
• Electrocardiogram 
• Anthropometric measurements 
• Clinical laboratory assessments (hematology, chemistry, urinalysis) 
• Plasma pharmacokinetics and cGMP assessments 
• Bone metabolism blood biomarkers 
• Bone metabolism urine biomarkers 
• BMN 111 pharmacodynamic urine biomarkers 
• Urine chemistry 
• Capture all procedures  
• BMN 111 or placebo administration 
• BMN 111 or placebo accountability  
• Adverse events 


 
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• Concomitant medications 
• Phone call or home health visit 
12.1.9 Week 52 (±7d) 
• Physical examination 
• Weight 
• Vital signs 
• Electrocardiogram 
• Anthropometric measurements 
• Clinical laboratory assessments (hematology, chemistry, urinalysis) 
• Thyroid function tests 
• Vitamin D, 25-hydroxy test 
• Salivary cortisol 
• Serum prolactin  
• Plasma pharmacokinetics and cGMP assessments 
• Anti-BMN 111 immunogenicity 
• Genomic biomarkers (optional) 
• Bone metabolism urine biomarkers 
• BMN 111 pharmacodynamic urine biomarkers 
• Urine chemistry 
• Hip monitoring 
• MRI brain/skull 
• Sleep study 
• Clinical outcome assessment: Bayley-III  
• Clinical outcome assessment: WeeFIM  
• Clinical outcome assessment: ITQOL 
• Clinical outcome assessment: CBCL 
• DXA 
• AP and lateral X-rays of spine 
• AP X-rays of lower extremities  


 
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• Clinical photographs (optional)  
• Capture all procedures  
• BMN 111 or placebo administration 
• BMN 111 or placebo accountability  
• Adverse events 
• Concomitant medications 
• Phone call or home health visit 
12.1.10  Week 56 Safety Follow-up ( + 7d) 
• Physical examination 
• Vital signs 
• Electrocardiogram 
• Echocardiogram 
• Capture all procedures  
• Adverse events 
• Concomitant medications 
12.1.11  Early Termination Visit 
• Physical examination 
• Weight 
• Vital signs 
• Electrocardiogram 
• Echocardiogram (obtained at the early termination visit only if the previous 
assessment was done more than 3 months prior to early termination) 
• Anthropometric measurements 
• Clinical laboratory assessments (hematology, chemistry, urinalysis) 
• Salivary cortisol 
• Serum prolactin  
• Anti-BMN 111 immunogenicity 
• Bone metabolism blood biomarkers 
• Bone metabolism urine biomarkers 


 
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• BMN 111 pharmacodynamic urine biomarkers 
• Urine chemistry 
• Hip monitoring 
• MRI brain/skull (obtained at the early termination visit only if the previous 
assessment was done more than 3 months prior to early termination) 
• Sleep study (obtained at the early termination visit only if the previous assessment 
was done more than 3 months prior to early termination) 
• Clinical outcome assessment: Bayley-III  
• Clinical outcome assessment: WeeFIM  
• Clinical outcome assessment: ITQOL 
• Clinical outcome assessment: CBCL 
• DXA 
• AP and lateral X-rays of spine (obtained at the early termination visit only if the 
previous assessment was done more than 6 months prior to early termination) 
• AP X-rays of lower extremities (obtained at the early termination visit only if the 
previous assessment was done more than 6 months prior to early termination) 
• Clinical photographs (optional)  
• Capture all procedures  
• BMN 111 or placebo accountability  
• Adverse events 
• Concomitant medications 
12.2 
Observational Period for Cohort 3 (Infants between birth and  < 3 months old 
[0 days to   < 13 weeks]) 
12.2.1 Screening Visit 
• Medical history, including growth history and ACH-related history 
• Concomitant medications 
• Physical examination 
• Vital signs 
• Vitamin D, 25-hydroxy 
• Alkaline phosphatase 


 
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• Bone metabolism blood biomarkers 
• Bone metabolism urine biomarkers 
• Adverse events 
12.2.2 Day 1 (Month 0) 
• Concomitant medications 
• Vital signs 
• Anthropometric measurements 
• Genomic biomarkers (optional) 
• Weight 
• Body mass index (calculated) 
• Clinical outcome assessment: Bayley-III  
• Clinical outcome assessment: ITQOL  
• Capture all procedures 
• Adverse events 
12.2.3 3 Months (± 10 days) 
• Concomitant medications 
• Vital signs 
• Anthropometric measurements 
• Vitamin D, 25-hydroxy 
• Alkaline phosphatase 
• Bone metabolism blood biomarkers 
• Bone metabolism urine biomarkers 
• Weight 
• Body mass index (calculated) 
• Capture all procedures 
• Adverse events 


 
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13 
DATA QUALITY ASSURANCE 
BioMarin personnel or designees will visit the study site prior to initiation of the study to 
review with the site personnel information about the IP, protocol and other regulatory 
document requirements, any applicable randomization procedures, source document 
requirements, eCRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs.  
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on eCRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records.  
Sites will enter study data into eCRFs into the study EDC system.  Data Quality Control will 
be performed by BioMarin Clinical Data Management or designee through implementation 
of quality control checks specified in the study data management plan and edit check 
specifications.  


 
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14 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE  
14.1 
Statistical and Analytical Plans 
The statistical analysis plan (SAP) will provide additional details on the planned statistical 
analysis. Unless otherwise stated, all analyses will be performed using SAS v. 9.4. 
14.1.1 Interim Analyses 
An interim analysis will be carried out to support NDA/MAA filing. The report will be 
provided by a third party to assure that the study team, subjects, and investigators have no 
access to the individual subject treatment allocation. 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data 
Because the completeness of the data affects the integrity and accuracy of the final study 
analysis, every effort will be made to ensure complete, accurate and timely data collection 
and, therefore, avoid missing data. In addition, a subject who prematurely discontinues study 
drug should be asked if they are willing to continue to participate in the study assessments for 
remaining duration of the study, as long as in the judgment of the investigator such continued 
participation would not detrimentally affect the health, safety, or welfare of the subject. 
No missing data will be imputed for any analysis, except for unless otherwise specified for 
the efficacy analyses or for the missing dates for AEs and concomitant medications. Missing 
dates or partially missing dates will be imputed conservatively to ensure that an AE is 
considered treatment emergent and has the longest possible duration, if the partial 
information available indicates that the AE is likely treatment emergent.  
Additional details regarding the handling of missing data will be provided in the SAP. 
14.2 
Safety Analysis 
The safety analysis will be performed on safety population as defined in Section 14.7.2 and 
will be considered descriptive. 
All AEs will be coded using the most current version of MedDRA will be used by the 
Sponsor to assign system organ class and preferred term classification to events and diseases, 
based on the original terms entered on the CRF. 
All AEs will be coded using MedDRA. The incidence of AEs will be summarized by system 
organ class, preferred term, relationship to study treatment (as assessed by investigator), and 
severity. All AEs, including SAEs and AEs that lead to permanent discontinuation from the 
study and from the study treatment, will be listed. Hypersensitivity reactions and 


 
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symptomatic hypotension are of interest, and the percentage of subjects who report these AEs 
will be presented. Hypersensitivity reactions will be defined in the SAP. 
Clinical laboratory data will be summarized by the type of laboratory test. For each clinical 
laboratory test, descriptive statistics will be provided on baseline as well as all subsequent 
visits. 
All other safety measures including laboratory tests, vital signs, ECG, echocardiogram, hip 
clinical assessment, and concomitant medication data will also be summarized descriptively. 
Data summaries will be presented by treatment group (when applicable) for each cohort and 
overall. All safety results will be listed. 
14.3 
Efficacy Analysis 
Efficacy analysis will be performed on the efficacy population as defined in Section 14.7.1. 
Efficacy endpoints include length/height AGV and length/height standard score (Z-score) at 
Week 52.  
For a given interval [Date1, Date2], the AGV is defined as follows: 
AGV = Length/standing height at Day 2 − Length/standing height at Day 1
Interval Length (Days)
 × 365.25 
 
where the interval length in days is calculated as Date2 – Date1. AGV will be calculated for 
the following visits/intervals: 
• Baseline: [Date of last length/height measurement in study 901 at least 6 months prior 
to screening visit in study 206, Date of Day 1] 
• Week 13: [Date of Day 1, Date of Week 13] 
• Week 26: [Date of Day 1, Date of Week 26] 
• Week 39: [Date of Day 1, Date of Week 39] 
• Week 52 (12-month): [Date of Day 1, Date of Week 52] 
The baseline of the AGV is established in the natural history study of Study111-901, based 
on the standing height measurements in the last 6 months prior to enrollment to Study 
111-206. AGV will be summarized using descriptive statistics (mean, SD, median, minimum, 
and maximum). Results will be summarized by treatment group and cohort. 


 
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The measurement of length/standing height will be converted to age-and sex-appropriate 
standard score (SDS), also referred to as Z-score, by comparison with normal reference 
standards (not ACH). The Z-score will be summarized similarly to growth velocity. 
Comparisons between treatment groups by cohort on these variables will be carried out 
where appropriate. Statistical comparisons will be considered descriptive. Additional details 
regarding efficacy analysis will be provided in the SAP. 
14.4 
Pharmacokinetic Analyses  
Subjects randomized to receive BMN 111 or placebo will undergo pharmacokinetic testing. 
For subjects randomized to BMN 111, PK parameters generated over the course of the study 
will be evaluated and summarized with descriptive statistical measures (mean, standard 
deviation, CV%, min, median and max). Correlative analyses of some of the PK parameters 
with efficacy, safety and immunogenicity measures may be conducted. 
14.5 
Immunogenicity Analysis 
Immunogenicity will be summarized as change from baseline as well as by study time point 
in subjects randomized to receive BMN 111 or placebo.  Results will be summarized as 
incidence and titer for all cohorts. Additionally, immunogenicity may be assessed for 
correlations with measures of safety, PK, and efficacy. 
14.6 
Determination of Sample Size 
Approximately 70 subjects age 0 to < 60 months at study entry will participate in this study. 
No formal sample size calculations were performed. The number of subjects is considered 
appropriate to evaluate the safety and efficacy of BMN 111 in the target population.  
14.7 
Analysis Populations 
14.7.1 Efficacy Population 
All randomized subjects who receive at least one dose of double-blinded BMN 111 or 
placebo in this study. 
14.7.2 Safety Population   
All subjects who receive at least one dose of double-blinded BMN 111 or placebo in this 
study.  
 
 


 
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15 
DATA MONITORING COMMITTEE 
In addition to safety and PK monitoring by BioMarin personnel, an independent DMC will 
act as an advisory body to BioMarin and will monitor the safety and PK of subjects in the 
study. After the sentinel subjects complete 12 weeks of dosing, a DMC review will occur to 
evaluate all available safety and PK data.  Upon approval by the DMC, the next younger 
cohort will be opened and the 3 sentinel subjects will be enrolled. 
The DMC will make recommendations for stopping or continuing the study on an individual 
subject level and/or on a cohort level per the pre-specified stopping criteria. Based on criteria 
outlined in the protocol, the DMC may also make endorsements for dose adjustments if 
needed.  
Please see DMC Charter for further details. 
 


 
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16 
COSTS, COMPENSATION, AND SUBJECT INJURY 
There will be no charge to study subjects to be in this study. BioMarin will pay all costs of 
tests, procedures, and treatments that are part of this study. In addition, after IRB/IEC/REB 
approval, BioMarin may reimburse the reasonable cost of travel for study-related visits in 
accordance with BioMarin’s study-specific travel and reimbursement policy. BioMarin will 
not pay for any hospitalizations, tests, or treatments for medical problems of any sort related 
solely to the study subject’s disease. Costs associated with such hospitalizations, tests, and 
treatments should be billed and collected in the way that such costs are usually billed and 
collected outside the study. 
The Investigator should contact BioMarin immediately upon notification that a study subject 
has been injured by the study drug or by procedures performed as part of the study. 
Any subject who experiences a study-related injury should be instructed by the Investigator 
to seek immediate medical treatment at a pre-specified medical institution if possible, or at 
the closest medical treatment facility if necessary. The subject should be given the name of a 
person to contact to seek further information about, and assistance with, treatment for 
study-related injuries. The treating physician should bill the subject’s health insurance 
company or other third party payer for the cost of this medical treatment. If the cost of the 
medical treatment is not covered by health insurance or another third party that usually pays 
these costs, then either BioMarin or the institution may pay for reasonable and necessary 
medical services to treat the injuries caused by the study drug or study procedures. In some 
jurisdictions, BioMarin is obligated by law to pay for study-related injuries without prior 
recourse to third party payer billing and/or regardless of fault. If this is the case, BioMarin 
will comply with the law. 


 
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17 
CASE REPORT FORMS AND SOURCE DOCUMENTS 
Electronic case report forms will be provided for each subject. The Investigator must review 
and electronically sign the completed eCRF casebook to verify its accuracy. 
eCRFs must be completed using a validated web-based application. Study site personnel will 
be trained on the application and will enter the clinical data from source documentation. 
Unless explicitly allowed in the eCRF instructions, blank data fields are not acceptable.  
In the event of an entry error, or if new information becomes available, the value will be 
corrected by deselecting the erroneous response and then selecting or entering the factual 
response. In compliance with 21 CFR Part 11, the system will require the personnel making 
the correction to enter a reason for changing the value. The documented audit trail will 
include the reason for the change, the original value, the new value, the time of the correction 
and the identity of the operator. 
BioMarin’s policy is that study data on the eCRFs must be verifiable to the source data, 
which necessitates access to all original recordings, laboratory reports, and subject records. 
In addition, all source data should be attributable (signed and dated). The Investigator must 
therefore agree to allow direct access to all source data. Subjects (or their legally authorized 
representative) must also allow access to their medical records, and subjects will be informed 
of this and will confirm their agreement when giving informed consent. If direct source 
document verification of study data by the site monitor is prohibited by institutional policy or 
local law, then the Investigator must make available facilities and/or personnel to allow 
GCP-compliant source verification to occur. Examples of such methods include certified 
copies of records which have study data visible but sensitive information redacted, or other 
GCP-compliant means agreed between the Investigator and the Sponsor. 
A CRA designated by BioMarin will compare the eCRFs with the original source documents 
at the study site and evaluate them for completeness and accuracy before designating them as 
“Source Data Verified” (SDV). If an error is discovered at any time or a clarification is 
needed, the CRA, or designee, will create an electronic query on the associated field. Site 
personnel will then answer the query by either correcting the data or responding to the query. 
The CRA will then review the response and determine either to close the query or re–query 
the site if the response does not fully address the question. This process is repeated until all 
open queries have been answered and closed.  
Before a subject’s eCRF casebook can be locked, data fields must be source data verified and 
all queries closed. Refer to the Study Monitoring Plan for details on which fields must be 
source data verified.  The Investigator will then electronically sign the casebook, specifying 


 
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that the information on the eCRFs is accurate and complete. The Data Manager, or designee, 
will then set the status of the forms, visits, and the entire casebook to Locked. Upon 
completion of the CSR, an electronic copy of each site’s casebooks will be copied to a 
compact disk (CD) and sent to each site for retention with other study documents. 


 
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STUDY MONITORING AND AUDITING 
Qualified individuals designated by BioMarin will monitor all aspects of the study according 
to GCP and standard operating procedures for compliance with applicable government 
regulations. The Investigator agrees to allow these monitors direct access to the clinical 
supplies, dispensing, and storage areas and to the clinical files, including original medical 
records, of the study subjects, and, if requested, agrees to assist the monitors. The 
Investigator and staff are responsible for being present or available for consultation during 
routinely scheduled site visits conducted by BioMarin or its designees. 
Members of BioMarin’s GCP Compliance Department or designees may conduct an audit of 
a clinical site at any time before, during, or after completion of the study. The Investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Representatives of the FDA or other Regulatory Agencies may also conduct an audit of the 
study. If informed of such an inspection, the Investigator should notify BioMarin 
immediately. The Investigator will ensure that the auditors have access to the clinical 
supplies, study site facilities, original source documentation, and all study files. 


 
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RETENTION OF RECORDS  
The Investigator must retain all study records required by BioMarin and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a BioMarin 
representative before disposal of any study records, and must notify BioMarin of any change 
in the location, disposition or custody of the study files. The Investigator /institution must 
take measures to prevent accidental or premature destruction of essential documents, that is, 
documents that individually and collectively permit evaluation of the conduct of a study and 
the quality of the data produced, including paper copies of study records (e.g., subject charts) 
as well as any original source documents that are electronic as required by applicable 
regulatory requirements.  
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the U.S. or an ICH region or (2) at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP. The Investigator /institution 
should retain subject identifiers for at least 15 years after the completion or discontinuation 
of the study. Subject files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution or private practice, but not less than 15 years. 
These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirements or by a BioMarin agreement. BioMarin must be notified 
and will assist with retention should Investigator /institution be unable to continue 
maintenance of subject files for the full 15 years. It is the responsibility of BioMarin to 
inform the Investigator /institution as to when these documents no longer need to be retained. 


 
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USE OF INFORMATION AND PUBLICATION 
BioMarin recognizes the importance of communicating medical study data and therefore 
encourages the publication of these data in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, manuscripts, 
and presentations based on the data from this study will be described in the Clinical Trial 
Agreement between BioMarin and the Investigator/Institution. Consideration for authorship 
of all publications will be based on compliance with the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals (“Uniform Requirements”) of the 
International Committee of Medical Journal Editors (ICMJE) (http://www.icmje.org/about-
icmje/faqs/icmje-recommendations/) and good publication practices (GPP).  


 
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REFERENCES 
Bartels, CF, Bukulmez, H, Padayatti, P, Rhee, DK et. al. Mutations in the transmembrane natriuretic 
peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. 
Am J Hum Genet 75[1], 27-34. 2004. 
Bayley, N. Bayley Scales of Infant Development, Third Ed. Psychological Corporation, New York, 
NY. 2006. 
Bocciardi, R, Giorda, R, Buttgereit, J, Gimelli, S et. al. Overexpression of the C-type natriuretic 
peptide (CNP) is associated with overgrowth and bone anomalies in an individual with balanced 
t(2;7) translocation. Hum Mutat 28[7], 724-731. 2007. 
Bright, GM, Mendoza, JR, Rosenfeld, RG. Recombinant human insulin-like growth factor-1 
treatment: ready for primetime. Endocrinol Metab Clin North Am. 38[3]:625-38. 2009. 
Chusho, H, Tamura, N, Ogawa, Y, Yasoda, A et. al. Dwarfism and early death in mice lacking C-type 
natriuretic peptide. Proc Natl Acad Sci U S A 98[7], 4016-4021. 2001. 
Foldynova-Trantirkova, S, Wilcox, WR, Krejci, P. Sixteen years and counting: the current 
understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias. Hum 
Mutat 33[1], 29-41. 2012. 
National Institutes of Health. Genetics Home Reference Achondroplasia 2012.  Available at: 
https://ghr.nlm.nih.gov/condition/achondroplasia. 
Horton, WA, Hall, JG, Hecht, JT. Achondroplasia. Lancet 370[9582], 162-172. 2007. 
Ireland PJ, Johnson S, Donaghey S, Johnston L, McGill J, Zankl A, Ware RS, Pacey V, Ault J, 
Savarirayan R, Sillence D, Thompson E, Townshend S. Developmental milestones in infants and 
young Australasian children with achondroplasia. J Dev Behav Pediatr. Jan;31(1):41-7. 2010. 
Ireland PJ, McGill J, Zankl A, Ware RS, Pacey V, Ault J, Savarirayan R, Sillence D, Thompson EM, 
Townshend S, Johnston  LM. Functional performance in young Australian children with 
achondroplasia. Dev Med Child Neurol. Oct;53(10):944-50. 2011. 
Ireland P, Johnston LM. Measures of self-care independence for children with osteochondrodysplasia: 
a clinimetric review. Phys Occup Ther Pediatr. 32(1):80-96. 2012. 
Kemp, SF. Insulin-like growth factor-I deficiency in children with growth hormone insensitivity: 
current and future treatment options. BioDrugs 23[3]:155-63. 2009. 
Krejci, P, Masri, B, Fontaine, V, Mekikian, PB et. al. Interaction of fibroblast growth factor and C-
natriuretic peptide signaling in regulation of chondrocyte proliferation and extracellular matrix 
homeostasis. J Cell Sci 118[Pt 21], 5089-5100. 2005. 
Little, R. J. A. (1993), “Pattern-Mixture Models for Multivariate Incomplete Data,” Journal of the 
American Statistical Association, 88, 125–134. 


 
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Long, S, Wendt, D, Bell, S. A novel method for the large-scale production of PG-CNP37, a C-type 
natriuretic peptide analogue. J Biotechnol 162[2], 196-201. 2012. 
Lorget, F, Kaci, N, Peng, J, Benoist-Lasselin, C et. al. Evaluation of the therapeutic potential of a 
CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet 91[6], 1108-
1114. 2012. 
Mukherjee D, Pressman BD, Krakow D, Rimoin DL, Danielpour M. Dynamic cervicomedullary cord 
compression and alterations in cerebrospinal fluid dynamics in children with achondroplasia: review 
of an 11-year surgical case series. J Neurosurg Pediatr.  Sep;14(3):238-44. 2014. 
Molenberghs, G. and Kenward, M. G. (2007), Missing Data in Clinical Studies, New York: John 
Wiley & Sons. 
Pauli RM, Scott CI, Wassman ER Jr, Gilbert EF, Leavitt LA, Ver Hoeve J, Hall JG, Partington MW, 
Jones KL, Sommer A, et al. Apnea and sudden unexpected death in infants with achondroplasia. J 
Pediatr. 1984 Mar;104(3):342-8. 
Pejchalova, K, Krejci, P, Wilcox, WR. C-natriuretic peptide: an important regulator of cartilage. Mol 
Genet Metab 92[3], 210-215. 2007. 
Shirley, ED, Ain, MC. Achondroplasia: manifestations and treatment. J Am Acad Orthop Surg 17[4], 
231-241. 2009. 
Waters, KA, Everett, F, Sillence, D, Fagan, E et. al. Breathing abnormalities in sleep in 
achondroplasia. Arch Dis Child 69[2], 191-196. 1993. 
Wendt, DJ, Dvorak-Ewell, M, Bullens, S, Lorget, F et. al. Neutral endopeptidase-resistant C-type 
natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth 
factor receptor 3-related dwarfism. J Pharmacol Exp Ther 353[1], 132-149. 2015. 
White KK, Parnell SE, Kifle Y, Blackledge M, Bompadre V. Is there a correlation between sleep 
disordered breathing and foramen magnum stenosis in children with achondroplasia? Am J Med 
Genet A. Jan;170A(1):32-41. 2016. 
 Wynn, J, King, TM, Gambello, MJ, Waller, DK et. al. Mortality in achondroplasia study: a 42-year 
follow-up. Am J Med Genet A 143A[21], 2502-2511. 2007. 
Yasoda, A, Kitamura, H, Fujii, T, Kondo, E et. al. Systemic administration of C-type natriuretic 
peptide as a novel therapeutic strategy for skeletal dysplasias. Endocrinology . 2009. 
Yasoda, A, Komatsu, Y, Chusho, H, Miyazawa, T et. al. Overexpression of CNP in chondrocytes 
rescues achondroplasia through a MAPK-dependent pathway. Nat Med 10[1], 80-86. 2004. 


 
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INVESTIGATOR RESPONSIBILITIES 
22.1 
Conduct of Study and Protection of Human Subjects  
In accordance with FDA Form 1572 and/or principles of ICH E6 GCP, the Investigator will 
ensure that: 
• He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of subjects. 
• He or she will personally conduct or supervise the study. 
• He or she will inform any potential subjects, or any persons used as controls, that the 
drugs are being used for investigational purposes.  He or she will ensure that the 
requirements relating to obtaining informed consent in 21 CFR Part 50 and/or ICH E6 
Sections 2.9 and 4.8 are met, as well as IRB/IEC review and approval requirements in 
21 CFR Part 56 and/or ICH E6 GCP Section 2.6.  
• He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with 21 CFR 312.64 and/or ICH E6 GCP Section 
4.11. 
• He or she has read and understands the information in the Investigator’s Brochure, 
including potential risks and side effects of the drug. 
• His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments 
• He or she will ensure that adequate and accurate records are in accordance with 
21 CFR 312.62 and/or ICH E6 Section 4.9, and will make those records available for 
inspection in accordance with 21 CFR 312.68 and/or ICH Section 4.9.7. 
• He or she will ensure that the IRB/IEC/REB complies with the requirements of 
21 CFR Part 56, ICH Section 3.0 and other applicable regulations, and conducts 
initial and ongoing reviews and approvals of the study. He or she will also ensure that 
any change in research activity and all problems involving risks to human subjects or 
others are reported to the IRB/IEC/REB. Additionally, he or she will not make any 
changes in the research without IRB/IEC/REB approval, except where necessary to 
eliminate apparent immediate hazards to human subjects. 
• He or she agrees to comply with all other requirements regarding the obligations of 
clinical Investigators and all other pertinent requirements in 21 CFR Part 312 and/or 
ICH E6 R2. 


PI
PI
PI


 
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PROTOCOL AMENDMENT TEXT REVISIONS 
The following table summarizes the major revisions and administrative changes made to the 
protocol body (corresponding changes have been applied in the synopsis but are not shown 
here) in Amendment 1, and relates the changes to the appropriate rationale (see pages 2-5).  
Text that has been added or inserted is indicated by underlined font, and deleted text is 
indicated by strikethrough font. 
Section No./Title 
Text Revisions 
Rationale #1: 
The lower age range of participating subjects who have a  ≥  6-month period of pretreatment growth 
assessment in Study 111-901 immediately before study entry has been revised from  ≥ 3 months 
to  ≥ 6 months 
Section 9.1 Overall 
Study Design and Plan 
Subjects age≥ 3  ≥ 6 months to < 60 months old who have documented ACH 
confirmed by genetic testing; at least a 6-month period of pretreatment growth 
assessment in Study 111-901 immediately before study entry; and who meet the 
study eligibility criteria, will participate. Eligible subjects ranging from 0 months 
to<  < 3 months old may enroll directly into 111-206 and have a minimum of 3 
months of pre-treatment observation prior to commencing treatment with 
investigational product, or may enroll in 111-901 for a minimum of 3 months of 
pretreatment growth assessment immediately before roll-over to 111-206. 
Rationale #2: 
No two sentinel subjects will be dosed on the same day for any cohort 
Section 9.1 Overall 
Study Design and Plan 
No two sentinel subjects will be dosed on the same day for any cohort. 
Rationale #3: 
Echocardiogram will be performed at the Week 56 Safety Follow-up and Early Termination visits 
Table 9.1.1 
Section 12.1.10 Week 56 
Safety Follow-up 
• 
Echocardiogram 
 
Section 12.1.11 Early 
Termination Visit 
• 
Echocardiogram (obtained at the early termination visit only if the 
previous assessment was done more than 3 months prior to early 
termination) 
Rationale #4: 
Use of residual plasma samples for cGMP PD biomarker assessment in all age groups has been added 
to procedures 
Table 9.1.1 
Pharmacokinetics assessments Plasma pharmacokinetics and cGMP assessmentsl 
Table 9.11.6.4.1 
Blood Special Chemistry 
Urine Biomarkers 


 
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Section No./Title 
Text Revisions 
Exploratory bone metabolism 
biomarkers: bone-specific alkaline 
phosphatase and collagen type X 
Exploratory bone metabolism urine 
biomarkers: C-terminal telopeptide of 
collagen type II 
Genomic biomarkers 
BMN 111 pharmacodynamics 
biomarkers (cGMP) 
Anti-BMN 111 antibodies 
 
BMN 111 pharmacodynamics 
biomarker (cGMP) 
BMN 111 pharmacodynamics 
biomarker (cGMP) 
cGMP, cyclic guanosine monophosphate 
 
Sections:  
12.1.2 Day 1 and Week 
13 
12.1.7 Week 26 
12.1.8 Week 39 
12.1.9 week 52 
 
• 
Pharmacokinetics Plasma pharmacokinetics and cGMP assessments 
 
Rationale #5: 
An anti-BMN 111 immunogenicity assessment has been added at Week 3 
Table 9.1.1 
Section 12.1.5 Week 3 
• 
Anti-BMN 111 immunogenicity 
 
Rationale #6: 
Bone metabolism urine biomarkers, BMN 111 pharmacodynamic urine biomarkers, and urine 
chemistry assessments have been added at Week 39 
Table 9.1.1 
Section 12.1.8 Week 39 
• 
Bone metabolism urine biomarkers 
• 
BMN 111 pharmacodynamic urine biomarkers 
• 
Urine chemistry 
Rationale #7: 
The sleep study scheduled at the Week 26 visit has been removed 
Table 9.1.1 
Section 12.1.7 Week 26 
• 
Sleep study 
 
Rationale #8: 
DXA scans will no longer include tibia scans 
Table 9.1.1 
Section 9.11.4.2 Imaging 
• 
DXA scan ( (BMD and BMC) of whole body [less head], including 
spine, one third and forearm and tibia, (including ultra-distal, mid-distal, 
and one third radius regions of interest) to assess bone mineral density 
(BMD) and bone mineral content (BMC). 


 
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Section No./Title 
Text Revisions 
Rationale #9: 
If the 111-901 visit at which the subject chooses to enter Study 111-206 and the 111-206 Screening visit 
are on the same day, the procedures common to both visits will be performed one time only 
Table 9.1.1, footnote b 
If the 111-901 visit at which the subject chooses to enter Study 111-206 and the 
111-206 Screening visit are on the same day, the procedures common to both 
visits will be performed one time only. 
Rationale #10: 
On days when PK samples are being drawn, ECG will be performed within a 5 minute window prior 
to the 30-minute PK assessment 
Table 9.1.1, footnote h 
Section 9.11.6.7  
On days when PK samples are being drawn, ECGs should be performed within a 
5-minute window prior to 30-minute PK assessment. 
Rationale #11: 
Exclusion criterion #6 has been revised from “…as determined by the Investigator based on the 
following assessments…) to (…as determined by the Investigator and informed by the following 
assessments…)   
Section 9.3.2 Exclusion 
Criteria 
Have evidence of cervicomedullary compression (CMC) likely to require 
surgical intervention within 60 days of Screening as determined by the 
Investigator based on and informed by the following assessments 
Rationale #12: 
Exclusion criterion #15 has been revised to include cervicomedullary decompression surgery (Cohorts 
2 and 3 only) 
Section 9.3.2 Exclusion 
Criteria 
Have ever had cervicomedullary decompression surgery (Cohorts 2 and 3 only), 
spine or long-bone surgery (i.e., surgery involving disruption of bone cortex) or 
have ever had bone-related surgery with chronic complications 
NOTE: Subjects with prior cervicomedullary decompression may be allowed 
into Cohort 1 only after discussion and agreement with Medical Monitor. 
Rationale #13: 
Inclusion/exclusion criteria have been added for Cohort 3 subjects enrolling in the observational 
period 


 
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Section 9.3.3 Inclusion 
Criteria for Cohort 3 
Observation Period; 
Section 9.3.4 Exclusion 
Criteria for Cohort 3 
Observation Period 
9.3.3 Inclusion Criteria for Cohort 3 Observation Period 
Individuals eligible to participate in this study must meet all of the following 
criteria: 
1. Parent(s) or guardian(s) willing and able to provide signed informed 
consent after the nature of the study has been explained and prior to 
performance of any research-related procedure. Also, willing and able 
to provide written assent (if applicable) after the nature of the study has 
been explained and prior to performance of any research-related 
procedure. 
2. Birth to ≤ 3 months of age at study entry.  
3. Have ACH, documented by genetic testing 
4. Are willing and able to perform all study procedures as physically 
possible 
 
9.3.4 Exclusion Criteria for Cohort 3 Observation Period 
Individuals who meet any of the following exclusion criteria are not eligible to 
participate in the study: 
1. Have hypochondroplasia or short stature condition other than ACH 
(e.g., trisomy 21, pseudoachondroplasia) 
2. Have any of the following disorders: 
• 
Hypothyroidism 
• 
Insulin-requiring diabetes mellitus 
• 
Autoimmune inflammatory disease (including celiac disease, lupus 
(SLE), juvenile dermatomyositis, scleroderma, and others) 
• 
Inflammatory bowel disease 
• 
Autonomic neuropathy 
3. Have an unstable clinical condition likely to lead to intervention during 
the course of the study, including progressive cervical medullary 
compression  
4. Have a history of any of the following: 
• 
Renal insufficiency  
• 
Anemia  
5. Have a history of cardiac or vascular disease, including the following: 
• 
Cardiac dysfunction  
• 
Hypertrophic cardiomyopathy 
• 
Congenital heart disease 
• 
Cerebrovascular disease, aortic insufficiency 
• 
Clinically significant atrial or ventricular arrhythmias 
6. Current treatment with antihypertensive medications, ACE inhibitors, 
angiotensin II receptor blockers, diuretics, beta-blockers, calcium-
channel blockers, cardiac glycosides, systemic anticholinergic agents, 
any medication that may impair or enhance compensatory tachycardia, 


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Section No./Title 
Text Revisions 
drugs known to alter renal function that is expected to continue for the 
duration of the study 
7.
Have had regular long-term treatment (> 1 month) with oral
corticosteroids (low-dose ongoing inhaled steroid for asthma is
acceptable) in the previous 3 months
8.
Concomitant medication that prolongs the QT/QTc interval within
14 days or 5 half-lives, whichever is longer, before the Screening visit
9.
Have used any other investigational product or investigational medical
device for the treatment of ACH or short stature
10. Planned or expected bone-related surgery (ie. surgery involving
disruption of bone cortex), during the study period.
11. Planned or expected to have limb-lengthening surgery during the study
period.
12. Have any condition that, in the view of the Investigator, places the
subject at high risk of poor compliance with the visit schedule or of not
completing the study.
13. Concurrent disease or condition that, in the view of the Investigator,
would interfere with study participation
Rationale #14: 
A table of restricted medications, including growth hormone, has been added 
Section 9.3.5 Current 
Chronic Therapy with 
Restricted Medications 
9.3.5 Current Chronic Therapy with Restricted Medications 
Table 9.3.5.1 lists the medications that are restricted in Study 111-206. 
Current Chronic Therapy with Restricted Medications 
Restricted Medications 
•
Antihypertensive medications
•
Angiotensin-converting enzyme (ACE) inhibitors
•
Angiotensin II receptor blockers
•
Diuretics
•
Beta-blockers
•
Calcium-channel blockers
•
Cardiac glycosides
•
Systemic anticholinergic agents
•
GnRH agonists
•
Growth hormone (and analogs)
•
Any medication that may impair or enhance compensatory
tachycardia, diuretics, or other drugs known to alter renal or tubular
function


 
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Section No./Title 
Text Revisions 
• 
Any medication that in the investigator’s judgment, may compromise 
the safety or ability of the subject to participate in the clinical trial 
Rationale #15: 
Genomic Biomarker Analysis, the text “of plasma DNA” has been removed from “Exploratory 
genomic analysis of plasma DNA may inform understanding of the BMN 111 mechanism of action…” 
Section 9.11.4.4 
Genomic Biomarker 
Analysis 
Exploratory genomic analysis of plasma DNA may inform understanding of the 
BMN 111 mechanism of action in achondroplasia. 
Rationale #16: 
For subjects enrolled in Cohort 3 (0 to < 6 months old), the collection period for all AEs begins after 
informed consent is obtained 
Table 9.1.2 footnote h 
Section 10.2.1 Adverse 
Event Reporting Period 
For subjects enrolled in Cohort 3 (0 to  < 6 months old), AE the collection period 
for all AEs begins after screening informed consent is obtained. 
Rationale #17: 
Administrative updates have been made to improve consistency and clarity 
#17a: 
Text has been changed to reflect the age of majority rather than age 18, as the age of majority varies 
between countries 
Section 5.3 Subject 
Information and 
Informed Consent 
Subjects under the age of 18 years majority will provide written assent (if 
required), and his/her legally authorized representative (parent or legal guardian) 
will provide written informed consent for such subjects. The Investigator will 
provide copies of the signed ICF to 
#17b: 
Section 7.3 has been updated to include a description of Study 111-302 
Section 7.3.5 Study 111-
302 
7.3.5 
Study 111-302 
Study 111-302 is an open-label Phase 3 extension study to further evaluate the 
efficacy and safety of BMN 111 either until subjects reach near-final adult height 
(defined as evidence of growth plate closure and < 1.5 cm/yr annualized growth 
velocity), or for 5 years if near final adult height (NFAH) occurs prior to the end 
of the 5-year period.  All subjects will receive BMN 111 15 µg/kg. This study 
will allow for long term assessment of the effect of daily BMN 111 
administration on safety, tolerability, growth velocity, height, and body 
proportions in subjects who have completed 1 year of placebo or BMN 111 
treatment in Study 111-301.   
#17c: 
The secondary objective addressing evaluation for hip, thigh, or knee pain, or change in gait has been 


 
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Section No./Title 
Text Revisions 
revised to clarify that hip assessments are performed at screening, and these measures serve as a 
baseline for future assessments 
Section 8 Study 
Objectives 
• 
Evaluate for hip, thigh, or knee pain, or change in gait from medical 
history 
#17d: 
Error in Section 9.1, description of Cohort 3 has been corrected to state that at least 17 additional 
subjects will be randomized 
Section 9.1 Overall 
Study Design and Plan 
Cohort 3 – children aged 0 to < 6 months (n ≥ 20 total: 3 sentinel subjects who 
receive BMN 111, and at least 20 17 additional subjects randomized 1:1 to 
treatment or placebo control).  Treatment begins at ≥ 3 months to < 6 months 
after 3 months of observation 
#17e: 
Clarification about age-appropriate dose adjustment has been added to indicate that subjects will be 
administered the recommended dose appropriate to their current age 
Section 9.1.1 Overall 
Study Design and Plan 
Section 9.1.1 Dose 
Adjustments 
As subjects age on study, they will be administered the dose determined to be 
appropriate for their current age.  For example, if a subject enrolls into Cohort 2 
at age 20 months, they will receive the recommended dose for subjects aged ≥ 6 
to < 24 months until they turn 24 months in age.  When they turn 24 months in 
age, they will begin to receive the recommended dose for subjects aged ≥ 24 to < 
60 months. 
#17f: 
The time window for the Week 56 safety follow-up visit has been changed from ± to + 7 days to allow a 
full 4 weeks between the last dose of study drug and the safety follow-up visit 
Table 9.1.1 
 
Section 12.1.10 Week 56 
Safety Follow-up 
Week 56 Safety 
Follow-Up (± ( + 7d) 
12.1.10 Week 56 Safety Follow-up (± ( + 7d) 
#17g: 
Clarified that the screening/baseline hip assessment includes a pelvis x-ray 
Table 9.1.1 
Section 12.1.1 
Screening/Baseline Day 
-30 to Day -1 
Screening baseline hip assessment with pelvis x-ray 
 
#17h: 
Because the definition of ACH-related events differed between sites, capture of ACH-related events 


 
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Section No./Title 
Text Revisions 
has been changed to capture all procedures listed in the Schedule of Events to ensure all procedures 
are collected and analyzed 
Tables 9.1.1 and 9.1.2 
Section 9.11.6.2 
 
Capture achondroplasia-related all procedures in the Schedule of Events 
9.11.6.2 Procedures due to Achondroplasia During the Study 
Sections 12.1.2-12.1.11; 
Sections 12.2.2-12.2.3 
• 
Capture all procedures 
 
#17i: 
Vital signs instructions now include sitting or supine positions to account for subjects who are too 
young to sit. The duration of vital signs assessments in Section 9.11.6.5 and Table 9.11.6.5.1 has been 
extended to align with the assessments presented in the SOE.  Additionally, if a dose adjustment visit 
coincides with a visit at which a full PK is drawn, vital signs will be obtained for 8 hours, similar to the 
Day 1,2 schedule.   
Table 9.1. Vital Sign 
Frequency Table 
After at least 5 min of rest, subject’s vital signs are taken, preferably in sitting or 
supine position.   
1. Vital sign measurements are taken once per time point, preferably in a sitting 
or supine position, after at least 5 minutes of rest.   
8. If a dose adjustment visit coincides with a visit at which a full PK is drawn, 
vital signs will be obtained for 8 hours, similar to the Day 1,2 schedule. 
Section 99.11.6.5 Vital 
Signs, Physical 
Examinations and Other 
Observations Related to 
Safety 
 
Vital signs assessed pre-dose will include seated or supine systolic blood 
pressure (SBP) and diastolic blood pressure (DBP) measured in mm Hg, heart 
rate in beats per minute, respiration rate in breaths per minute, and temperature in 
degrees Celsius (°C)… 
At Screening, after at least 5 minutes of rest, subject’s BP is taken in sitting 
position. Then the subject will stand and BP will be taken again at approximately 
1 and 3 minutes after standing. or supine position. Vital sign measurements 
should be repeated and documented 3 times, with at least 5-minute intervals 
between assessments… 
At other visits, vital sign measurements are taken once per time point in a sitting 
or supine position after at least 5 minutes of rest. 
Table 9.11.6.5.1 Vital 
Sign Frequency Table 
Please see tracked change version of Table 9.11.6.5.1 at the end the document. 
#17j: 
In the event that a sentinel subject has an interrupted dose of study drug on Day 1, instructions have 
been included for a change in the PK collection schedule. 


 
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Section No./Title 
Text Revisions 
Table 9.1.1 footnote L 
Section 9.11.5 
Pharmacokinetics 
Variables 
In the event of interruption of study drug administration for a sentinel patient on 
Day 1 when PK samples are scheduled, the collection of PK samples should be 
delayed until the subsequent day and only performed after successful 
administration of study drug has been completed in a single injection. 
#17k: 
Footnote m in Table 9.1.1 has been updated to correspond to the information in Section 9.11.6.10, Anti-
BMN 111 Immunogenicity Assessments and IgE Testing 
Table 9.1.1 footnote m 
m.  Antibodies:  Total anti-BMN 111 (TAb), TAb cross-reacting with 
endogenous natriuretic peptides, and neutralizing antibody (NAb) samples 
(serum) will be drawn pre-dose at each time point listed on the SOE. TAb cross-
reacting with endogenous natriuretic peptides and NAb testing will be performed 
only on baseline and TAb positive samples from subjects weighing ≥ 7.0 kg and 
waived for subjects < 7.0 kg. 
#17l: 
In Table 9.1.1, footnotes n and o, and Section 9.11.3, Secondary Efficacy Variables, text has been added 
to specify the biomarkers used to assess changes in bone and collagen metabolism 
Table 9.1.1 footnotes n 
and o 
 
 
Table 9.1.1 footnotes n and o 
 
 
Section 9.11.3 
Secondary Efficacy 
Variables 
Section 9.11.3 Secondary Efficacy Variables 
#17m: 
In Table 9.1.1 footnote q, instruction has been included that efforts to obtain a satisfactory MRI image 
can be discontinued after 3 unsuccessful attempts. 
Table 9.1.1 footnote q 
Efforts to obtain a satisfactory image can be discontinued after 3 unsuccessful 
attempts.   
#17n: 
In Table 9.1.1, footnote v now includes instructions for managing a dose interruption. 
 
Table 9.1.1 footnote v 
If interruption of study drug injection occurs, the remainder of the assigned dose 
should be administered immediately (and no later than within 5 minutes) in a 
different location. The same syringe should be used and newly reconstituted 
investigational drug should be used to draw the remainder of the dose. 


 
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Section No./Title 
Text Revisions 
#17o: 
Section 9.1.1, Dose Adjustments, has been corrected to state that a DMC review will occur after the 
third sentinel subject reaches Week 12 post-dose adjustment 
Section 9.1.1 Dose 
Adjustments 
The remainder of the subjects in the age cohort will also be enrolled starting at 
the new adjusted dose. After the third sentinel subject reaches day 30 Week 12 
post dose adjustment 
#17p: 
In Section 9.3.8, Duration of Subject Participation, final follow-up visit for subjects who discontinue 
from the study has been changed from 2 weeks to 4 weeks 
Section 9.3.8 Duration of 
Subject Participation 
If subjects discontinue from study treatment and decline to participate for the 
remainder of the study, they will be asked to return for a final follow-up visit 2 4 
weeks after their last study visit 
#17q: 
In Section 9.4.1, Treatments Administered, text has been added to reiterate that sentinel subjects will be 
treated with BMN 111, versus randomized subjects who will receive either BMN 111 or placebo.  
Additionally, the BMN 111 dose level is subject to potential per-protocol adjustment. 
Section 9.4.1 Treatments 
Administered 
Subjects Sentinel subjects will receive BMN 111 at a daily dose of 15 µg/kg 
(subject to adjustment per protocol). Randomized subjects will be randomized to 
BMN 111 at a daily dose of 15 µg/kg (subject to adjustment per protocol) or 
placebo for the duration of the study. 
#17r: 
Directions for subject observation following BMN 111 administration at study visits has been revised 
in Section 9.4.1.1, Study Drug Administration, for consistency with Section 9.4.4, Directions for 
Administration 
Section 9.4.1.1 Study 
Drug Administration 
During the study, BMN 111 or placebo will be administered as a single 15 µg/kg 
SC injection given daily at approximately the same time each day whenever 
possible.  Determination of appropriate injection sites will be left to the 
discretion of the investigator.  The same injection site should not be used 2 days 
in a row, and sites should be rotated between the 4 injection sites.  Study drug 
should be administered at age-appropriate locations (upper thigh, upper back of 
arm, abdomen or buttocks). Doses may be administered in any of the common 
SC areas (upper arm, thigh, abdomen, buttocks).  Following administration of 
each dose at clinic visits, subjects will should be observed for at least 2 8 hours 
after the injection for on Days 1 to 3,  and 2; 4 hours on Days 3 and 8; and 1 hour 
on subsequent dosing visits. Subjects should be observed for 30 minutes for all 
other days of dose administration (longer if clinically indicated) either in after 
every injection that is not administered at the clinic by study personnel, by a 
home health nurse, or by a parent/caregiver.  


 
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Section No./Title 
Text Revisions 
#17s: 
Text in Section 9.4.1.1, Study Drug Administration now indicates that study drug injections will be 
administered at age-appropriate sites, determined at the discretion of the investigator 
Section 9.4.1.1 Study 
Drug Administration 
During the study, BMN 111 or placebo will be administered as a single 15 µg/kg 
SC injection given daily at approximately the same time each day whenever 
possible.  Determination of appropriate injection sites will be left to the 
discretion of the investigator.   
#17t: 
Text has been revised to indicate that in the hour prior to injection, all subjects should be well 
hydrated and fed.   
Section 9.4.4 Directions 
for Administration 
Section 9.6 Dietary or 
Other Protocol 
Restrictions 
Subjects should have adequate food intake prior to dosing. n the hour prior to 
injection, all All subjects should have been well hydrated and fed in the hour 
prior to administration of BMN 111 or placebo. 
#17u: 
In Section 9.4.5, Method of Assigning Subjects to Treatment Groups, a note has been added that in 
Japan, subjects are randomized separately within each cohort. 
Section 9.4.5 Method of 
Assigning Subjects to 
Treatment Groups 
NOTE: In Japan, subjects are randomized separately within each cohort. 
#17v: 
Section 9.11.4.2, Imaging Assessment Procedures, has been corrected by removing lateral views from 
bilateral lower extremity x-rays, and clarified to state that bilateral lower extremity x-rays, anterior-
posterior (AP) view, are done to assess growth plate morphology. Instruction has been added to 
contact the medical monitor to discuss alternate non-radiological methods for assessment if there are 
IRBs or IECs unwilling to allow x-rays in Cohort 3 subjects (also, Table 9.1.1, footnote t). Additionally, 
the list of DXA acquisitions has been clarified.   
Table 9.1.1 footnote t 
Although X-rays are preferable for consistency across the study population, if 
there are IRBs or IECs unwilling to allow x-rays in Cohort 3 subjects, contact the 
MM to discuss alternate non-radiological methods for assessment. 
Section 9.11.4.2 Imaging 
Assessment Procedures 
• 
Bilateral lower extremity x-rays including both, anterior-posterior (AP) 
and lateral views view, to assess growth plates.  plate morphology. 
• 
Hip imaging via pelvis x-ray to identify hip pathology (if changes from 
baseline trigger further evaluation) 
• 
Lumbar spine x-rays to measure changes from baseline in bone 
morphology and pathology.   


 
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Section No./Title 
Text Revisions 
• 
MRI to evaluate the effect of BMN 111 on skull and brain morphology, 
including foramen magnum, ventricular and brain parenchymal 
dimensions. 
• 
DXA scan ( (BMD and BMC) of whole body [less head], 
includingspine, one third and forearm and tibia, (including ultra-distal, 
mid-distal, and one third radius regions of interest) to assess bone 
mineral density (BMD) and bone mineral content (BMC). 
Although X-rays are preferable for consistency across the study population, if 
there are IRBs or IECs unwilling to allow x-rays in Cohort 3 subjects, contact the 
medical monitor to discuss alternate non-radiological methods for assessment.   
#17w: 
Section 9.11.4.7.1, Bayley-III, has been revised to remove reference to the Social-Emotional and 
Adaptive Behavior Scale components because these scales will not be used in this study.  Additionally, 
the duration of the assessment has been clarified. 
Section 9.11.4.7.1 
Bayley-III 
Scales include Cognitive subscale, Receptive and Expressive subscales, and 
Gross and Fine Motor subscales. The two language scales make up a composite 
Language Scale score and the Gross and Fine Motor subscales yield a composite 
Motor Scale score. In addition, there is a Social-Emotional Scale and Adaptive 
Behavior Scale, which is a questionnaire read and completed by parent or 
caregiver.  
In addition to its use for subjects ranging from 1 to 42 months old, the Bayley-III 
assessment will be administered to those entering the study between 42 and 60 
months old (Figure 9.11.4.7.1) and for the remainder of the duration of this 
study, 
#17x: 
In Section 9.11.4.7.4, Child Behavior Checklist, the duration of the assessment has been clarified. 
Section 9.11.4.7.4 Child 
Behavior Checklist 
The Child Behavior Checklist (CBCL) is for use in children from 1.5-5 years old, 
and will be administered for those entering the study at less than 5 years old and 
for the remainder of the duration of the study.   
#17y: 
In Section 10.1.2, the statement that hospitalization for less than 24 hours will not be considered an 
SAE has been deleted to make the criterion consistent across all BioMarin protocols. Section 10.1.2, 
Serious Adverse Events. 
Section 10.1.2 Serious 
Adverse Events 
Requires or prolongs inpatient hospitalization.  Hospitalization for less than 24 
hours will not be considered to be an SAE. 


 
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Section No./Title 
Text Revisions 
#17z: 
Error in Table 10.2.3.3.1 has been corrected to read “The AE could not be explained by factors or 
causes other than exposure to the IP” 
Table 10.2.3.3.1 
• 
The AE could possibly not be explained by factors or causes other than 
exposure to the IP 
 
 
Table 9.11.6.5.1 Vital Sign Assessment Frequency (tracked changes) 
Vital Sign Assessment Frequency Pre-Dose 
Screening 
After at least 5 min of rest, subject’s BP is vital signs are taken, preferably in sitting or supine 
position. Then the subject will stand Vital sign measurements should be repeated and BP will 
be taken again documented 3 times with at approximately 1 and 3 minutes after standing. least 
5 min intervals between assessments.   
All other visits 
After at least 5 min of rest, subject’s BP is taken 1 time in sitting position 
 
Assessment Frequency Post-Dose 
Dosing Visits 
0-1 hr post-dose 
1 0-2 hr post-
dose 
2-4 hr post dose 
4-8 
hr 
post-
dose 
Days 1Day, 
2 -3 
 
Q15 q 15 min 
((± 5 min)Q30 
min ((± (± 5 
min) 
Q q 30 min (± 5 
min)Q30 min ((± 5 
min) 
q 60 
min 
(± 
10 
min) 
Days 3, 8 
 
q 15 min (± 5 
min) 
q 30 min (± 5 min) 
 
Subsequent 
dosing visits 
q 15 min (± 5 min); 
final assessment prior to end of visit (if 
longer than 1 hr) 
 
 
 
1. All other dosing 
visits: vital Vital 
sign measurements 
are taken once per 
time point, 
preferably in a 
sitting or supine 
position, after at 
least 5 minutes of 
rest.   
2. Heart rate, blood 
pressure, and 
respiratory rate should 
Q 30 min (± 5 min); 
 for 1 hour 
 


 
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be taken and recorded 
at each indicated time 
point.   
3. When blood samples 
and vital sign 
assessments are 
scheduled at the same 
time or within the same 
time window, vital 
signs should be 
measured before blood 
samples are drawn.   
4. If a vital sign 
measurement must be 
taken after a blood 
draw, ensure adequate 
analgesia for the blood 
draw and wait several 
minutes before 
measuring vital signs.   
5. Vital signs may be 
monitored more 
frequently or for longer 
duration post-dose as 
clinically indicated. 
6. If a subject has a 
hypotensive event, or 
signs potentially 
consistent with 
hypotension, or a 
decrease of 20 mm Hg 
systolic BP or more 
from baseline (defined 
by pre-dose vitals 
collected that day), 
vital signs should be 
measured and recorded 
approximately every 15 
minutes (± 5 minutes) 
for the first hour and 
every 30 minutes (± 5 
minutes) thereafter 
until the BP returns to 


 
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baseline (or within the 
normal range for this 
subject as defined by 
PI) and signs (if 
present) resolve.  
7. If the decision is made 
to adjust the dose, vital 
signs will be obtained 
for at least 4 hr 
following the first dose 
at the adjusted dose 
level, similar to the 
Day 3, 8 schedule. 
8. If a dose adjustment 
visit coincides with a 
visit at which a full PK 
is drawn, vital signs 
will be obtained for 8 
hours, similar to the 
Day 1,2 schedule. 
 


 
 
Proprietary and Confidential 
8 February 2019 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical 
Trial to Evaluate the Safety and Efficacy of BMN 111 in Infants and 
Young Children with Achondroplasia, Age 0 to < 60 Months 
Protocol Number: 
111-206 
Active Investigational Product: 
BMN 111 (modified rhCNP)  
IND 
111299 
European Union Drug Regulating 
Authorities Clinical Trials 
(EudraCT) Number: 
2016-003826-18 
Indication: 
Achondroplasia 
Sponsor: 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Development Phase: 
Phase 2 
Sponsor's Responsible Medical 
Monitor: 
, MD 
  
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Study Design: 
Phase 2 randomized, double-blind, placebo-controlled clinical trial of 
BMN 111 in infants and younger children with a diagnosis of ACH 
Treatment Duration 
52 weeks 
Duration of Subject 
Participation: 
60 weeks for Cohorts 1 and 2 (screening, treatment, follow-up). 
Subjects in Cohort 3 who enter the study for a 12-week observational 
period will participate for approximately 70 weeks (screening, 
observational period, treatment, follow-up) 
Dose: 
15 µg/kg BMN 111 or placebo daily, subject to adjustment per protocol 
Study Population: 
Children 0 to < 60 months old with achondroplasia 
Date of Original Protocol: 
06 December 2017 
Date of Amendment 1: 
16 August 2018 
Date of Amendment 2: 
08 February 2019 
Property of BioMarin 
CONFIDENTIAL 
May not be divulged, published, or otherwise disclosed to others without prior written approval from 
BioMarin. 
This study will be conducted according to the principles of Good Clinical Practice as described in the U.S. 
Code of Federal Regulations and the International Conference on Harmonisation Guidelines, including the 
archiving of essential documents. 
BioMarin is a registered trademark of BioMarin Pharmaceutical Inc. 
PI
PI


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8 February 2019 
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY 
Amendment: 2 
Date: 08 February 2019 
RATIONALE AND SUMMARY OF MAJOR CHANGES 
The protocol has been amended to include the following changes: 
1.
The following exploratory objectives have become secondary objectives in
Amendment 2. [§8.0]
•
Evaluate the effect of BMN 111 on growth parameters and body proportions,
including change from baseline in upper:lower segment ratio.
•
Evaluate the effect of BMN 111 on sleep apnea
•
Evaluate the effect of BMN on skull and brain morphology, including foramen
magnum, ventricular and brain parenchymal dimensions
•
Describe the incidence of surgical interventions, including cervical decompression,
adenotonsellectomy, and typanostomy
Rationale: Because of the importance of clinical and morbidity outcomes in 
achondrodroplasia (ACH), all outcome endpoints (with the exception of optional 
assessments) have been moved from exploratory to secondary.  
2.
The secondary imaging assessment procedures, excluding the MRI assessment, have been
moved to the secondary safety variables section. The hip imaging assessment has been
removed, the X-ray assessment has been modified to include long bone growth, and the
DXA assessment will no longer include the forearm. Also, the paragraph discussing the
possibility of non-radiological methods of assessment for subjects in Cohort 3 has been
deleted. [§9.12.6.3]
Rationale: Imaging assessments, excluding MRI, evaluate the safety of BMN-111 by 
identifying bone pathologies, morphologies, BMD, and BMC. The pelvis X-ray assessment 
has been removed to reduce the subjects’ radiation burden, because the femoral head is 
captured on X-rays of the lower extremities. DXA of the forearm has also been removed. 
Thus, concerns regarding excess radiological exposure have been addressed.  
3.
The MRI assessments remain as a subsection in the Secondary Efficacy Variables
section. [9.11.2]
Rationale: MRIs evaluate the effect of BMN 111 on skull and brain morphology, an efficacy 
variable. 


 
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4. The screening baseline hip assessment with pelvis X-ray has been removed from the 
Schedule of Events [Table 9.1.1] 
Rationale: Eliminating the pelvis X-rays at the screening visit will help minimize the 
radiation burden on study subject. 
5. Footnotes have been changed to modify procedures and to add early termination visits 
(ETV) for anthropomorphic measurements, DXA, and X-rays [Table 9.1.1] 
Rationale: The changes in ETV for have been made to align 111-206 with other studies in 
the clinical program. Changes in the X-ray and DXA procedures also help minimize the 
radiation burden on the study subjects. 
6. The Child Behavior Checklist has been moved from §4.12.3.3 Clinical Outcome 
Assessments to be a subsection of §9.12.6 Safety Variables [§9.12.6.6]. A sentence 
specifying that the CBCL should be given prior to other study assessments was added. 
Rationale: The CBCL checklist addresses symptoms related to issues of safety (eg, sleep 
problems, aggressive behavior) rather than efficacy. It is thought that the answers to the 
CLCL, as a Patient Reported Outcome instrument, may be affected by the study procedures. 
7. The following sentence was added to §9.3.3 and §9.3.4 “After completing the observation 
period, subjects must fulfill the general eligibility criteria prior to receiving treatment 
with study drug.”  
Rationale: Cohort 3 subjects have different eligibility criteria during the observational 
period, thus Cohort 3 subjects who complete the observation period must also fulfill the 
general eligibility criteria before receiving treatment. 
8. Mention of sterile diluent for reconstitution of BMN 111 has been deleted. [§9.4.2.1] 
Rationale: Only sterile water for injection is provided for reconstitution of drug product. 
9. The secondary efficacy variables were updated. [§9.12.3]  
Rationale: The secondary efficacy variables were updated to match the changes in secondary 
endpoints. 
10. Additions and corrections have been made to the PK parameters to be estimated by 
non-compartmental analysis. [§9.12.5] 
Rationale: Clarification that PK parameters for both sentinels and study subjects will be 
analyzed, as well as the addition of Cmax and Tmax to the PK parameters.  
11. Updates have been made §13 Data Quality Assurance and §17 Case Report Forms and 
Study Documents. 
Rationale: Language required in the current BioMarin protocol template was added. 


 
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12. The identity of the medical monitor has been updated to George S. Jeha [§10.8]. 
13. Administrative changes have been made throughout the amended protocol for 
consistency, accuracy, and clarity.  
Refer to Section 24 for a summary of revisions to Amendment 1 (dated 13 August 2018). 


 
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2 
SYNOPSIS 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
TITLE OF STUDY:  A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial to 
Evaluate the Safety and Efficacy of BMN 111 in Infants and Young Children with Achondroplasia, 
Age 0 to < 60 Months 
PROTOCOL NUMBER:  111-206 
STUDY SITES:  Approximately 10-15 sites worldwide  
PHASE OF DEVELOPMENT:  Phase 2 
STUDY RATIONALE: 
BMN 111 is a recombinant CNP analogue that has been engineered to resist degradation by NEP, 
allowing for a longer half-life. 
The pharmacological activity of BMN 111 was explored in two mouse models of ACH, a severe, 
Fgfr3Y367C/+ (TD) model (Lorget, 2012), and a milder [Ach] /+ (Ach) model. These included 
studies in 7-day old TD mice given BMN 111 daily by SC administration for up to 20 days and a 
study in 3-week old Ach mice given BMN 111 daily by SC administration for 5 weeks. Partial or 
complete reversion of the ACH phenotype was observed in these mouse models after BMN 111 
administration. In wild-type mice, and normal rats and monkeys, BMN 111 administration resulted 
in growth plate expansion and dose-dependent skeletal growth at hemodynamically tolerated dose 
levels (Wendt, 2015). Additionally, the potential effect of age on BMN 111 PK was evaluated in 
normal rats aged between 7 days and 12-13 weeks.  
Infants and young children with ACH have a high incidence of medical complications and currently 
there is no approved pharmacological therapy for ACH in the US or EU. The most severe 
complication, cervicomedullary compression (CMC), occurs in a subset of subjects with ACH due 
to abnormal endochondral bone growth and narrowing of the foramen magnum (White, 2016). CMC 
has been linked to serious respiratory and neurological complications including hypotonia, apnea, 
ataxia, developmental delay, and respiratory arrest associated with sudden death (Mukherjee, 2014). 
Foramen magnum decompression surgery is currently the only treatment for this condition.   
Sleep apnea has also been extensively described in ACH, and sleep-disordered breathing may affect 
up to 85% of all children with ACH (Ireland, 2012). This is thought to be due to midface 
hypoplasia, relative adenotonsillar hypertrophy, and potential posterior cranial fossa compression 
secondary to abnormal endochondral bone growth. Sleep apnea in ACH not only results in the need 
for surgical intervention, but has also been linked to sudden death in rare cases (Pauli, 1984).   
Similarly, the dysregulation of endochondral bone growth in ACH leads to other medical 
complications which are prevalent in this subject population, such as the following: 


 
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8 February 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
• 
Spinal stenosis, kyphosis, and lordosis (secondary to altered growth plate ossification in the 
vertebrae and narrowing of the interpedicular distances) (Shirley, 2009) 
• 
Developmental delay of gross motor and ambulatory skills (associated with proximal limb 
shortening, macrocephaly, and hypotonia) (Ireland, 2010) 
• 
Delayed functional skills and increased need for caregiver assistance (eg, eating, bladder 
management, bowel management, transfer to chair, climbing stairs) (Ireland, 2011) 
BMN 111 was first tested in humans in Study 111-101, a Phase 1 double-blinded, placebo-
controlled clinical trial of the safety and tolerability of BMN 111 in healthy adult male volunteers 
without ACH. Part 1 examined a series of single subcutaneous doses (5 µg/kg, 10 µg/kg and 15 
µg/kg), and Part 2 included 10 days of either fixed dosing or dose escalation (0.5 µg/kg to 8 µg/kg). 
BMN 111 was generally well tolerated at all doses. As expected, mild, transient, self-limited 
hypotension was reported (refer to current Investigators Brochure for additional information). 
Following SC administration, BMN 111 was rapidly absorbed with maximal plasma concentrations 
achieved in less than 30 minutes. BMN 111 was rapidly cleared from the plasma with a mean t1/2 
ranging from 40 to 55 minutes across dose levels. BMN 111 exposure (Cmax and AUC0-t) generally 
increased greater than proportional to the increase in dose across the 2.5-to-15 µg/kg dose range. 
Exposure following multiple dosing was found to be similar to exposure following single doses, 
indicating no apparent accumulation or time-dependence with once-daily SC administration. 
Study 111-202, the second clinical trial in humans and the first in children with ACH, is an ongoing 
Phase 2, open-label, sequential-cohort, dose-escalation study that assesses daily SC BMN 111 in 
pediatric subjects with ACH aged 5-14 years with doses ranging from 2.5 µg/kg to 30 µg/kg. The 
primary objective of Study 111-202 is to evaluate the safety and tolerability of BMN 111 
administered for 6 months and up to 24 months; the secondary objectives are to determine change 
from baseline in annualized growth velocity (AGV), growth parameters, body proportions, and 
evaluate the pharmacokinetics (PK) of BMN 111 in children with ACH. 


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
Analysis of safety data from the 6 month initial phase of Study 111-202 showed that treatment with 
BMN 111 for 6 months at the doses of 2.5, 7.5, 15, and 30 µg/kg was generally well tolerated (refer 
to current Investigator’s Brochure for specific details). One subject (30 µg/kg) in 111-202 withdrew 
due to an AE. The subject developed non-serious, asymptomatic Grade 1 intermittent Wolff-
Parkinson-White pattern, which was discovered on a routine day 10-study monitoring ECG. The 
most common AEs across all cohorts were injection site reactions, asymptomatic hypotension, 
headache, and nasopharyngitis. Based on previous experience of the ongoing Phase 2 clinical trial, 
including the 24 month data cut at 15 µg/kg, injection site reactions have been identified as risks 
associated with BMN 111 injections. The majority of hypotension events were grade 1 and reported 
in the setting of routine BP measurement. All reported events of hypotension were transient and 
resolved without medical intervention. For a detailed summary of risks, please refer to the current 
version of the Investigator’s Brochure supplied by BioMarin.  
Analysis of efficacy data from the 6 month initial phase of Study 111-202 showed that subjects 
treated with BMN 111 for 6 months at doses ranging from 2.5 15 µg/kg daily had a dose-dependent 
improvement in AGV, with ~50% improvement in AGV seen at the 15 µg/kg dose. The data from 
Cohort 4 (30 µg/kg) show an apparent greater than dose-proportional increase in BMN 111 plasma 
exposure (Cmax and AUC0-t), with a marginal improvement in both absolute AGV and change from 
baseline AGV after 6 months of BMN 111 treatment when compared with Cohort 3 (15 µg/kg).    
Study 111-206 is a Phase 2 randomized, double-blind, placebo-controlled clinical trial of BMN 111 
in infants and younger children with a diagnosis of ACH who are 0 to < 60 months old. This 52-
week study will enable assessment of BMN 111 efficacy and safety, tolerability, pharmacodynamics 
biomarkers, and PK in this population. Additional exploratory endpoints pertaining to medical 
complications of ACH will also be evaluated.   
Efficacy/toxicity studies have been conducted in neonatal and very young animals (7 day 
postpartum mouse and rat) in both a disease (TD mouse) and non-disease (rat) model. Given that 
this is the first study in infants and young children, an age based cohort study design is used to 
assess safety and PK in young children (Cohort 1, ≥ 24 to < 60 months) prior to dosing toddlers 
(Cohort 2, ≥ 6 to < 24 months) and infants (Cohort 3, 0 to < 6 months). PK will be monitored and 
evaluated; Day 1 PK data from the sentinel subjects will inform dose selection modification for the 
sentinel subjects and for the rest of the cohort to target the observed exposure of the 15 µg/kg dose 
group in Study 111-202. Safety, efficacy and PK data from Study 111-202, a Phase 2 study in 
children with ACH, where a dose of 15 µg/kg has been and continues to be studied, are expected to 
be the most relevant, and translatable to this study (111-206). 


 
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8 February 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
OBJECTIVES:  
The primary objectives of the study are to: 
• 
Evaluate the safety and tolerability of BMN 111 in children age 0 to < 60 months with ACH  
• 
Evaluate the effect of BMN 111 on change from baseline in length/height Z-score 
The secondary objectives of the study are to: 
• 
Evaluate the effect of BMN 111 on change from baseline in AGV throughout the 52 weeks 
of the study  
• 
Evaluate the effect of BMN 111 on bone morphology/quality by X-ray and dual X-ray 
absorptiometry (DXA) 
• 
Evaluate the PK of BMN 111 in children age 0 to < 60 months with ACH  
• 
Evaluate hip function 
• 
Evaluate for hip, thigh, or knee pain, or change in gait  
• 
Evaluate the effect of BMN 111 on health-related quality of life (HRQoL), developmental 
status, and functional independence using age-specific QoL and functional independence 
questionnaires (Bayley Scales of Infant and Toddler Development, Third edition 
[Bayley-III], Activity of Daily Living and Functional Independence Measure (Wee-FIM), 
Infant Toddler Quality of Life Questionnaire (ITQOL), Child Behavior Checklist (CBCL) 
• 
Evaluate immunogenicity of BMN 111 and assess impact on safety, PK, and efficacy 
measures  
• 
Evaluate the effect of BMN 111 on bone metabolism and BMN 111 pharmacodynamic 
biomarkers 
• 
Evaluate the effect of BMN 111 on growth parameters and body proportions, including 
change from baseline in upper:lower segment body ratio 
• 
Evaluate the effect of BMN 111 on sleep apnea 
• 
Evaluate the effect of BMN 111 on skull and brain morphology, including foramen 
magnum, ventricular and brain parenchymal dimensions 
• 
Describe the incidence of surgical interventions, including cervical decompression, 
adenotonsillectomy, and tympanostomy 
The exploratory objectives of the study are to: 
• 
Document physical and phenotypic changes with clinical photography (optional) 
• 
Evaluate genomic biomarkers (optional) 


 
Study 111-206A2 
Page 9 
 
Proprietary and Confidential 
8 February 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
STUDY DESIGN AND PLAN:  
This study, 111-206, is a Phase 2 randomized, double-blind, placebo-controlled clinical trial of 
BMN 111 in infants and younger children with a diagnosis of ACH.  
Study 111-901 is an ongoing study to collect serial growth measurements on pediatric subjects with 
ACH who are being considered for subsequent enrollment in future BioMarin studies.  Subjects who 
are age ≥ 6 months to < 60 months old; who have documented ACH confirmed by genetic testing; at 
least a 6-month period of pretreatment growth assessment in Study 111-901 immediately before 
screening; and who meet the study eligibility criteria, will participate. Eligible subjects ranging from 
0 months to < 3 months old may enroll directly into 111-206 and have a minimum of 3 months of 
pretreatment observation prior to commencing treatment with investigational product, or may enroll 
in 111-901 for a minimum of 3 months of pretreatment growth assessment immediately before 
roll-over to 111-206. 
Approximately 70 subjects will be enrolled at approximately 10-15 clinical centers worldwide.   
The primary objectives of this study are to assess the safety and tolerability of daily SC BMN 111 
administered to infants and young children with ACH, and to evaluate the effect of BMN 111 on 
length/height Z-score. Subjects will be enrolled into 3 age cohorts based on age at study screening 
starting with the eldest population.  Within Cohorts 1 and 2, subjects will be stratified by age: 
• 
Cohort 1 – children aged ≥ 24 to < 60 months (n ≥ 30 total: 3 sentinel subjects who receive 
BMN 111, and at least 27 additional subjects randomized 1:1 to treatment or placebo 
control), stratified by age (≥ 24 to < 36 months and ≥ 36 months to < 60 months)  
• 
Cohort 2 – children aged ≥ 6 to < 24 months (n ≥ 20 total: 3 sentinel subjects who receive 
BMN 111, and at least 17 additional subjects randomized 1:1 to treatment or placebo 
control), stratified by age (≥ 6 months to < 15 months and ≥ 15 months to < 24 months)  
• 
Cohort 3 – children aged 0 to < 6 months (n ≥ 20 total: 3 sentinel subjects who will be under 
observation or receive BMN 111, and at least 17 additional subjects randomized 1:1 to 
treatment or placebo control).  Treatment begins at ≥ 3 months to  < 6 months after 
3 months of observation. 
If subjects who enroll in Cohort 3 are not able to begin treatment by  < 6 months of age, they will 
continue in the pretreatment period for another 3 months before enrolling in Cohort 2 to fulfill the 
pretreatment requirement for Cohort 2. 
Sentinel subjects from each cohort will be enrolled, treated with BMN 111, and studied for short-
term safety and PK data. No two sentinel subjects will be dosed on the same day for any cohort. 
After the sentinel data are evaluated additional recruited subjects will be randomized to receive 
BMN 111 or placebo SC daily (1:1 ratio) for 52 weeks.  


 
Study 111-206A2 
Page 10 
 
Proprietary and Confidential 
8 February 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
At the start of the study, 3 sentinel subjects will be enrolled and monitored in Cohort 1. After all 3 
sentinel subjects reach Day 8, the Sponsor will review and evaluate all available safety data and Day 
1 PK data. Based on PK data and criteria set in the protocol, the dose may be adjusted for the 
sentinel subjects and the rest of the cohort, and will be the starting dose for the younger cohort 
sentinel subjects.  Upon review of the clinical and PK data, the remainder of Cohort 1 (≥ 27 
additional subjects) will be enrolled and randomized to treatment with BMN 111 or placebo (1:1 
ratio).  After the sentinel subjects complete 12 weeks of dosing, a data monitoring committee 
(DMC) review will occur to evaluate all available safety and PK data.  Upon approval by the DMC, 
the next younger cohort (Cohort 2) will be opened and the 3 sentinel subjects will be enrolled. 
The same procedure will be followed for Cohort 2. After all 3 sentinel subjects reach Day 8, the 
Sponsor will review and evaluate all available safety data and Day 1 PK data. Based on PK data and 
criteria set in the protocol, the dose may be adjusted for the sentinel subjects and the rest of the 
cohort, and will be the starting dose for the younger cohort sentinel subjects.  Upon review of the 
clinical and PK data, the remainder of Cohort 2 (≥ 17 additional subjects) will be enrolled and 
randomized to treatment with BMN 111 or placebo (1:1 ratio). After the sentinel subjects complete 
12 weeks of dosing, a DMC review will occur to evaluate all available safety and PK data.  Upon 
approval by the DMC, the youngest cohort (Cohort 3) will be opened and the 3 sentinel subjects will 
be enrolled.  
The same procedure will be followed for Cohort 3. After all 3 sentinel subjects reach Day 8, the 
Sponsor will review and evaluate all available safety data and Day 1 PK data. Based on PK data and 
criteria set in the protocol, the dose may be adjusted for the sentinel subjects and the rest of the 
cohort, and will be the starting dose for the younger cohort sentinel subjects.  Upon review of the 
clinical and PK data, the remainder of Cohort 3 (≥ 17 additional subjects) will be enrolled and 
randomized to treatment with BMN 111 or placebo (1:1 ratio).  
Cohort 3 subjects must have a minimum of 3 months of observation prior to commencement of 
treatment.  These subjects will have the option to enroll in either 111 901 or 111-206. 
Additional sentinels may be added to any cohort if needed for additional safety and/or PK 
assessment. 


 
Study 111-206A2 
Page 11 
 
Proprietary and Confidential 
8 February 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
As subjects age on study, they will be administered the dose determined to be appropriate for their 
current age.  For example, if a subject enrolls into Cohort 2 at age 20 months, they will receive the 
recommended dose for subjects aged ≥ 6 to < 24 months until they turn 24 months in age.  When 
they turn 24 months in age, they will begin to receive the recommended dose for subjects 
aged  ≥ 24 to  < 60 months.  Duration of the study is 52 weeks of treatment with a safety follow up at 
Week 56. Following completion of the study, subjects in all treatment groups may be eligible to 
receive BMN 111 in an open-label extension study, to assess safety and efficacy of BMN 111 over 
the longer term; and to study the long-term outcomes on sustained growth, proportionality, bone 
maturation and medical comorbidities.  
For subjects enrolling into the extension study, safety follow up visit at Week 56 will be waived.  
Data Monitoring Committee (DMC) 
In addition to safety and PK monitoring by BioMarin personnel, an independent DMC will act as an 
advisory body to BioMarin and will monitor the safety and PK of subjects in the study. After the 
sentinel subjects complete 12 weeks of dosing, a DMC review will occur to evaluate all available 
safety and PK data.  Upon approval by the DMC, the next younger cohort will be opened and the 
3 sentinel subjects will be enrolled. 
The DMC will make recommendations for stopping or continuing the study on an individual subject 
level and/or on a cohort level per the pre-specified stopping criteria. Based on criteria outlined in the 
protocol, the DMC may also make endorsements for dose adjustments if needed.  
Please see DMC Charter for further details. 
Individual Subject Stopping Criteria  
For individual subjects treated with BMN 111, DMC will be informed if any of the following 
individual subject stopping criteria should occur. Temporary dosing suspension, permanent 
discontinuation of dosing, or dose reduction for the individual subject will be considered. 
• 
Any treatment-emergent adverse event (AE) assessed as at least Grade 4 by the Investigator 
and/or Sponsor Medical Monitor  
• 
Any treatment-emergent AE of at least Grade 3 assessed as related to study drug by the 
Investigator and/or Sponsor Medical Monitor  
• 
Any two treatment-emergent Grade 2 symptomatic hypotension events within 7 days 
(non-urgent medical intervention indicated) or any Grade 3 hypotensive event (urgent 
medical intervention or hospitalization indicated) assessed by the Investigator and/or 
Sponsor’s Medical Monitor  


 
Study 111-206A2 
Page 12 
 
Proprietary and Confidential 
8 February 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
• 
Clinically significant finding or arrhythmia on ECG that indicates abnormal cardiac 
function or conduction or prolongation of QTc-F >500 msec 
• 
Clinically significant new or worsening signs of cervicomedullary compression as 
determined by the Investigator and in consultation with Sponsor medical monitor and 
neurosurgical specialist (if needed) 
• 
Adverse findings on clinical hip exam or hip imaging assessments that are determined to be 
clinically significant as determined by the Investigator and in consultation with Sponsor 
Medical Monitor and orthopedic specialist (if needed)  
If the subject meets any stopping criterion, after Investigator consultation with the BioMarin 
Medical Monitor and DMC, the subject may be re-challenged at the same dose. If the subject meets 
stopping criteria on re-challenge or if re-challenge is not clinically indicated, other options that may 
be considered include:  
• 
Re-challenge at lower dose with consideration given to upward titration to tolerated dose  
• 
Permanent treatment discontinuation (with an option of ongoing assessment in the study)  
Cohort Stopping Criteria  
For each cohort, a DMC review will be conducted if any of the following cohort stopping criteria 
occur in subjects treated with BMN 111.  Temporary dosing suspension, permanent discontinuation 
of dosing, or dose reduction for the cohort(s) will be considered and the impact on all other age 
cohorts will be assessed.  
• 
Any treatment-emergent AE assessed as at least Grade 4 by the Investigator and/or Sponsor 
Medical Monitor  
• 
Any two subjects have a treatment-emergent AE of at least Grade 3 assessed as related to 
study drug by the Investigator and/or Sponsor Medical Monitor  
• 
Any two subjects have two treatment-emergent Grade 2 symptomatic hypotension events 
within 7 days (non-urgent medical intervention indicated) or any two subjects cohort have a 
Grade 3 hypotensive event (urgent medical intervention or hospitalization indicated) 
assessed by the Investigator and/or Sponsor’s Medical Monitor  
• 
Any two subjects have a clinically significant finding or arrhythmia on ECG that indicates 
abnormal cardiac function or conduction or prolongation of QTc-F >500 msec 


 
Study 111-206A2 
Page 13 
 
Proprietary and Confidential 
8 February 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
• 
Any two subjects have adverse findings on clinical hip exam or hip imaging assessments 
that are determined to be clinically significant as decided by principal investigator and in 
consultation with Sponsor medical monitor and orthopedic specialist (if needed)  
Dose Adjustments 
Analysis of available PK data from studies 111-101 and 111-202 indicated that differences in 
subject body weight did not directly translate to differences in total body clearance of BMN 111.  
The same weight-based dose in the pediatric population of Study 111-202 (5-12 years old) yielded 
lower exposure (Cmax and AUC) than that characterized in the adult population of Study 111-101.  
Therefore, the same weight-based dose in the young pediatric population in this study may yield 
exposure less than the target exposure range characterized to be safe and effective in Study 111-202 
at the 15 µg/kg dose. Since this is the first experience with BMN 111 in this young pediatric 
population, it is also possible the exposure at 15 µg/kg could be greater than the target exposure 
range, and dose adjustment may be warranted. Thus, an option for adjustment of the weight-based 
dose is provided to ensure that the appropriate target exposure for safety and efficacy is reached for 
the young subjects in this study.   
The need for dose adjustment will be evaluated as follows: three sentinel subjects in Cohort 1 will 
receive an initial dose of 15 µg/kg. After all three sentinel subjects reach Day 8, a review will occur 
to evaluate all available safety and PK data (at minimum). If the criteria for dose adjustment are 
met, the three sentinel subjects will be started on the new adjusted dose at their next scheduled visit, 
and vital signs will be obtained for at least 4 hours post-dose. 
The remainder of the subjects in the age cohort will also be enrolled starting at the new adjusted 
dose. After the third sentinel subject reaches Week 12 post-dose adjustment, a DMC review will 
occur to evaluate all safety and PK data and, upon endorsement, the three sentinel subjects from the 
next younger cohort will be enrolled starting at the new adjusted dose.  The three sentinel subjects 
for the second and third cohorts will be evaluated similarly to the sentinel subjects in the first cohort 
for potential dose adjustment. 
As subjects age on study, they will be administered the dose determined to be appropriate for their 
current age.  For example, if a subject enrolls into Cohort 2 at age 20 months, they will receive the 
recommended dose for subjects aged ≥ 6 to < 24 months until they turn 24 months in age.  When 
they turn 24 months in age, they will begin to receive the recommended dose for subjects aged ≥ 24 
to < 60 months. 


 
Study 111-206A2 
Page 14 
 
Proprietary and Confidential 
8 February 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
Safety and Efficacy Monitoring 
Each treated subject will have expanded outpatient safety monitoring for a minimum of 3 days of 
dosing, during which they will be closely observed and non-invasive hemodynamic monitoring will 
be conducted for at least 4-8 hours post-dosing. Because younger children may not be able to 
verbalize complaints of dizziness or lightheadedness that are potentially associated with 
hypotension, study personnel and caregivers will be trained to recognize the signs of hypotension in 
this population, which may include tachycardia, pallor, diaphoresis, lethargy, delayed capillary 
refill, and poor feeding. Appropriate rigorous training will be required for parents and caregivers 
prior to daily injections at home. Training includes the storage, reconstitution, and administration of 
BMN 111, as well as documentation/reporting of AEs and vigilance for signs of hypotension. 
It is generally expected that after subjects are tolerating the drug well and specified criteria have 
been met, caregivers will begin administering study drug. Home health care is not required at any 
point but may be provided if the caregiver is unable or unavailable to administer the study drug. A 
Home Healthcare nurse will train the caregiver(s) if training has not been completed by the Day 3 
visit. A phone call by the study staff member to the caregiver will be required weekly for 6 months 
and then every 2 weeks for the remainder of the study. During these contacts, study staff will ask the 
caregiver about dose administration and seek information on AEs and SAEs by specific questioning. 
If the caregiver cannot be contacted by phone after two attempts, contact can be made via email.   
Safety will be evaluated by the incidence of AEs, serious AEs (SAEs), X-rays will be performed of 
the entire lower extremities and spine to evaluate for changes in bone morphology and growth, 
laboratory test results (urinalysis, chemistry, and hematology), vital signs, physical examination, 
ECG and echocardiogram, hip clinical assessment, and anti-BMN 111 immunogenicity assessments.  
Clinical laboratory tests, PK, immunogenicity and blood biomarker assessments will be limited to 
the minimum necessary for evaluation of safety and efficacy in order to minimize blood volume in 
the pediatric population. 
Efficacy will be assessed by change from baseline in AGV and length/height Z-score. Secondary 
assessments will include change from baseline in growth parameters and body proportions by 
anthropometry. An MRI will be performed to assess the effect of BMN 111 on skull and brain 
morphology, including foramen magnum, ventricular, and brain parenchymal dimensions.  A board-
certified, fellowship-trained (or equivalent) pediatric anesthesiologist will administer anesthesia 
during MRI measurements in the event that the subject is unable to remain still for the duration of 
the scan. Sleep studies will be conducted to evaluate sleep apnea. Additional assessments will be 
conducted to evaluate changes from baseline in bone metabolism and BMN 111 pharmacodynamic 
biomarkers, and developmental/functional status.   


 
Study 111-206A2 
Page 15 
 
Proprietary and Confidential 
8 February 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
NUMBER OF SUBJECTS PLANNED: 
Approximately 70 subjects, including at least 30 subjects in Cohort 1, at least 20 subjects in Cohort 
2, and at least 20 subjects in Cohort 3. 
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:  
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Diagnosis of ACH, confirmed by genetic testing.  If subjects had previous genetic testing, 
subjects must have a lab report from a certified laboratory with the study specific mutation 
documented. 
2. Age 0 to < 60 months, at study entry (Day 1) 
3. Cohort 1 and 2 subjects must have at least a 6-month period of pretreatment growth 
assessment in Study 111-901 immediately before screening and have one documented 
measurement of height/body length a minimum of 6 months prior to the screening visit for 
111-206.  Cohort 3 subjects must have a minimum of 3 months of observation prior to 
treatment.  This observational period can be obtained either (1) via prior enrollment in 
Study 111-901 or (2) via enrollment in this Study 111-206 for a minimum of 3 months of 
non-treatment observation prior to commencement of treatment. 
4. Parent(s) or guardian(s) (and the subjects themselves, if required by local regulations or 
ethics committee) are willing and able to provide written, signed informed consent after the 
nature of the study has been explained and prior to performance of any research-related 
procedure 
5. Willing and able to perform all study procedures as physically possible 
6. Parent(s) or caregiver(s) are willing to administer daily injections to the subjects and 
complete the required training 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
1. Have hypochondroplasia or short-stature condition other than achondroplasia (e.g., 
trisomy 21, pseudoachondroplasia, etc.) 
2. Subject weighs < 5.0 kg (Cohorts 1 and 2) or <  4.0 kg (Cohort 3; treatment phase) 
3. Have any of the following: 
• 
Hypothyroidism or hyperthyroidism 
• 
Insulin-requiring diabetes mellitus 
• 
Autoimmune inflammatory disease (including celiac disease, systemic lupus 
erythematosus, juvenile dermatomyositis, scleroderma, etc.) 
• 
Inflammatory bowel disease 
• 
Autonomic neuropathy 
4. Have a history of any of the following: 


 
Study 111-206A2 
Page 16 
 
Proprietary and Confidential 
8 February 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
• 
Renal insufficiency defined as serum creatinine > 2 mg/dL 
• 
Chronic anemia or Hgb  < 10.0 g/dL (based on screening clinical laboratory testing) 
• 
Baseline systolic blood pressure (BP) below age and gender specified normal range 
or recurrent symptomatic hypotension (defined as episodes of low BP generally 
accompanied by symptoms e.g., dizziness, fainting) or recurrent symptomatic 
orthostatic hypotension 
• 
Cardiac or vascular disease, including the following: 
o Cardiac dysfunction (abnormal echocardiogram determined to be 
clinically significant by PI and medical monitor) at Screening Visit  
o Hypertrophic cardiomyopathy 
o Pulmonary hypertension 
o Congenital heart disease with ongoing cardiac dysfunction  
o Cerebrovascular disease 
o Aortic insufficiency or other clinically significant valvular dysfunction 
o Clinically significant atrial or ventricular arrhythmias 
5. Have a clinically significant finding or arrhythmia that indicates abnormal cardiac function 
or conduction or QTc-F  > 450 msec on screening ECG 
6. Have evidence of cervicomedullary compression (CMC) likely to require surgical 
intervention within 60 days of Screening as determined by the Investigator and informed by 
the following assessments: 
• 
Physical exam (eg, neurologic findings of clonus, opisthotonus, exaggerated 
reflexes, dilated facial veins) 
• 
Polysomnography (eg, severe central sleep apnea) 
• 
MRI indicating presence of severe CMC or spinal cord damage 
7. Have an unstable medical condition likely to require surgical intervention in the next 
6 months, or planned spine or long-bone surgery (i.e., surgery involving significant 
disruption of bone cortex) during the study period 
8. Have documented uncorrected Vitamin D deficiency: 25(OH)D   ≤ 15 ng/mL (37.5 nmol/L) 
9. Require any other investigational product prior to completion of the study period 
10. Have received another investigational product or investigational medical device within 
30 days prior to the Screening visit 
11. Have used any other investigational product or investigational medical device for the 
treatment of achondroplasia or short stature at any time  
12. Require current chronic therapy with antihypertensive medication or any medication that, in 
the investigator’s judgment, may compromise the safety or ability of the subject to 
participate in this clinical study (Table 9.3.5.1) 


 
Study 111-206A2 
Page 17 
 
Proprietary and Confidential 
8 February 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
13. Have been treated with growth hormone, insulin-like growth factor 1 (IGF-1), or anabolic 
steroids in the 6 months prior to screening, or long-term treatment ( > 3 months) at any time 
14. Have had regular long-term treatment (> 1 month) with oral corticosteroids (low-dose 
ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable) in the 12 months 
prior to screening 
15. Have ever had CMC surgery (Cohorts 2 and 3 only), spine or long-bone surgery (ie, surgery 
involving disruption of bone cortex) or have ever had bone-related surgery with chronic 
complications 
NOTE: Subjects with prior cervicomedullary decompression may be allowed into 
Cohort 1 only after discussion and agreement with Medical Monitor. 
16. Have ever had limb-lengthening surgery or plan to have limb-lengthening surgery during 
the study period 
17. Have had a fracture of the long bones or spine within 6 months prior to screening 
18. Have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or total bilirubin 
greater than upper limit of normal at screening (except for subjects with a known history of 
Gilberts or newborns entering screening in Cohort 3) 
19. Have evidence of severe untreated sleep apnea; or have newly initiated sleep apnea 
treatment (eg, continuous positive airway pressure [CPAP] or sleep apnea-mitigating 
surgery) in the 2 months prior to screening  
20. Have current malignancy, history of malignancy, or currently under work-up for suspected 
malignancy 
21. Have known hypersensitivity to BMN 111 or its excipients 
22. Have a history of hip surgery or severe hip dysplasia 
23. Have a history of clinically significant hip injury in the 30 days prior to screening  
24. Have a history of slipped capital femoral epiphysis or avascular necrosis of the femoral 
head  
25. Have abnormal findings on baseline clinical hip exam or imaging assessments that are 
determined to be clinically significant as determined by the Investigator 
26. Have a condition or circumstance that, in the view of the Investigator, places the subject at 
high risk for poor treatment compliance or for not completing the study 
27. Have any concurrent disease or condition that, in the view of the Investigator, would 
interfere with study participation or safety evaluations, for any reason 
Inclusion Criteria for Cohort 3 Observation Period 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Parent(s) or guardian(s) willing and able to provide signed informed consent after the nature 
of the study has been explained and prior to performance of any research-related procedure. 


 
Study 111-206A2 
Page 18 
 
Proprietary and Confidential 
8 February 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
Also, willing and able to provide written assent (if applicable) after the nature of the study 
has been explained and prior to performance of any research-related procedure. 
2. Birth to ≤ 3 months of age at study entry.  
3. Have ACH, documented by genetic testing 
4. Are willing and able to perform all study procedures as physically possible 
After completing observation period subjects must fulfill the general eligibility criteria prior to 
receiving treatment with study drug. 
Exclusion Criteria for Cohort 3 Observation Period 
Individuals who meet any of the following exclusion criteria are not eligible to participate in the 
study: 
1. Have hypochondroplasia or short stature condition other than ACH (e.g., trisomy 21, 
pseudoachondroplasia) 
2. Have any of the following disorders: 
• 
Hypothyroidism 
• 
Insulin-requiring diabetes mellitus 
• 
Autoimmune inflammatory disease (including celiac disease, lupus (SLE), juvenile 
dermatomyositis, scleroderma, and others) 
• 
Inflammatory bowel disease 
• 
Autonomic neuropathy 
3. Have an unstable clinical condition likely to lead to intervention during the course of the 
study, including progressive cervical medullary compression  
4. Have a history of any of the following: 
• 
Renal insufficiency  
• 
Anemia  
5. Have a history of cardiac or vascular disease, including the following: 
• 
Cardiac dysfunction  
• 
Hypertrophic cardiomyopathy 
• 
Congenital heart disease 
• 
Cerebrovascular disease, aortic insufficiency 
• 
Clinically significant atrial or ventricular arrhythmias 
6. Current treatment with antihypertensive medications, ACE inhibitors, angiotensin II 
receptor blockers, diuretics, beta-blockers, calcium-channel blockers, cardiac glycosides, 
systemic anticholinergic agents, any medication that may impair or enhance compensatory 
tachycardia, drugs known to alter renal function that is expected to continue for the duration 
of the study 


 
Study 111-206A2 
Page 19 
 
Proprietary and Confidential 
8 February 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
7. Have had regular long-term treatment (> 1 month) with oral corticosteroids (low-dose 
ongoing inhaled steroid for asthma is acceptable) in the previous 3 months 
8. Concomitant medication that prolongs the QT/QTc interval within 14 days or 5 half-lives, 
whichever is longer, before the Screening visit 
9. Have used any other investigational product or investigational medical device for the 
treatment of ACH or short stature 
10. Planned or expected bone-related surgery (ie. surgery involving disruption of bone cortex), 
during the study period.  
11.  Planned or expected to have limb-lengthening surgery during the study period.   
12. Have any condition that, in the view of the Investigator, places the subject at high risk of 
poor compliance with the visit schedule or of not completing the study. 
13. Concurrent disease or condition that, in the view of the Investigator, would interfere with 
study participation 
After completing observation period subjects must fulfill the general eligibility criteria prior 
to receiving treatment with study drug. 
INVESTIGATIONAL PRODUCT, DOSE, ROUTE, and REGIMEN: 
The clinical drug product will be supplied in sterile, single-dose, Type I glass vials with coated 
stopper and flip-off aluminum cap. BMN 111 drug product is supplied as a 0.8-mg or 2-mg 
lyophilized, preservative-free, white-to-yellow powder for reconstitution with sterile water for 
injection (WFI). The reconstituted solution is colorless to yellow and contains 0.8 mg/mL to 
2 mg/mL of BMN 111, as well as citric acid, sodium citrate, trehalose, mannitol, methionine, 
polysorbate 80, and sterile WFI. The target pH of the reconstituted solution is 5.5. Sterile WFI will 
be commercially sourced. All reconstitution and dose preparation steps will be performed as 
indicated in the BMN 111 Injection Guide and Injection video.  
BMN 111 will be administered as a single SC injection given daily at approximately the same time 
each day whenever possible. Following administration of each dose at clinic visits, subjects should 
be observed for 8 hours after the injection on Days 1 and 2; 4 hours on Days 3 and 8; and 1 hour on 
subsequent dosing visits. Subjects should be observed for 30 minutes after every injection that is not 
administered at the clinic. 
REFERENCE THERAPY, DOSE, ROUTE, and REGIMEN: 
BMN 111-placebo lyophilized product will be supplied in sterile, single-dose, Type I glass vials 
with coated stopper and flip-off aluminum cap. The placebo is designed to be comparable in 
appearance to the drug product and contains all of the components of the drug product except the 
drug substance.  
All reconstitution and dose preparation steps should be performed as indicated in the Study Drug 
Injection Guide and Injection instruction media. 


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
Placebo will be administered as a single SC injection given daily at approximately the same time 
each day whenever possible. Following administration of each dose at clinic visits, subjects should 
be observed for 8 hours after the injection on Days 1 and 2; 4 hours on Days 3 and 8; and 1 hour on 
subsequent dosing visits. Subjects should be observed for 30 minutes after every injection that is not 
administered at the clinic. 
DURATION OF TREATMENT: 52 weeks 
CRITERIA FOR EVALUATION: 
Safety: The following safety outcome measurements will be assessed: 
• 
Incidence of AEs and SAEs 
• 
Imaging assessments (X-rays of the spine and entire lower extremities, DXA of total body 
less head and spine) 
• 
CBCL  
• 
Vital signs (heart rate, blood pressure, respiratory rate, and temperature) 
• 
Physical examination (including neurological assessment) 
• 
Hip clinical assessment 
• 
Laboratory test results (urinalysis, chemistry, hematology) 
• 
Electrocardiogram (ECG) 
• 
Echocardiogram  
• 
Anti-BMN 111 immunogenicity assessments 
• 
Cortisol levels 
• 
Prolactin levels 
Primary Efficacy: The following efficacy outcome measurements will be assessed: 
• 
Safety and tolerability of BMN 111 in children age 0 to < 60 months with ACH 
• 
Change from baseline in length/height Z-score 
Secondary Efficacy: 
The following measurements will be assessed: 
• 
Change from baseline in AGV 
• 
Change from baseline in upper:lower body segment ratio 
• 
MRI to define skull and brain morphology (including dimensions of foramen magnum, 
ventricular and brain parenchymal dimensions) 
• 
Sleep study 
• 
Changes in bone and collagen metabolism and BMN 111 pharmacodynamic biomarkers 
Clinical outcome assessments: 
• 
Bayley-III  
• 
Wee-FIM  


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
• 
ITQOL 
Pharmacokinetics: PK sampling will be carried out over the entire study period in sentinel subjects 
and subjects randomized to BMN 111 or placebo. Whenever possible, the following PK parameters 
for sentinel subjects and subjects randomized to BMN 111 will be estimated by non-compartmental 
analysis: 
• 
Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞)  
• 
Area under the plasma concentration-time curve from time 0 to the time of last measurable 
concentration (AUC0-t) 
• 
Maximum observed plasma concentration (Cmax)  
• 
Time to reach Cmax (Tmax)  
• 
Elimination half-life (t1/2)  
• 
Apparent clearance (CL/F)  
• 
Apparent volume of distribution (Vz/F)  
Exploratory: The following exploratory measurements will be assessed: 
• 
Clinical photography (optional) 
• 
Optional evaluation of genomic biomarkers 
STATISTICAL METHODS:  
Sample Size Determination: 
Approximately 70 subjects age 0 to < 60 months at study entry will participate in this study. No 
formal sample size calculations were performed. The number of subjects is considered appropriate 
to evaluate the safety and efficacy of BMN 111 in the target population.    
Safety Analysis: 
All AEs will be coded using the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA) to assign system organ class and preferred term classification to event and 
disease, based on the original terms entered on the eCRF. The incidence of AEs will be summarized 
by system organ class, preferred term, relationship to study treatment as assessed by the 
investigator, seriousness, and severity. All AEs, including SAEs and AEs that lead to permanent 
discontinuation from the study and from the study treatment, will be listed. 
All other safety measures including laboratory tests, vital signs, ECG, echocardiogram, hip clinical 
assessment, and concomitant medication data will also be summarized descriptively. Data 
summaries will be presented by treatment group (when applicable) for each cohort and overall. All 
safety results will be listed.  


 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 111 
 
NAME OF ACTIVE INGREDIENT: 
Modified rhCNP 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
Efficacy Analysis: 
Efficacy variables, including AGV (based on length/height) and length/height Z-score according to 
normal reference standards (not ACH), along with their change from baseline will be summarized 
by treatment group and cohort. Comparisons between treatment groups by cohort on these variables 
will be carried out where appropriate. Statistical comparisons will be considered descriptive. 95% 
CIs will be provided along with p values for treatment group comparisons.  
Sentinel subjects will be summarized apart for both efficacy and safety. 
Pharmacokinetic Analysis:  
PK parameters generated over the course of the study will be evaluated and summarized with 
descriptive statistical measures (mean, standard deviation, coefficient of variation [CV%], 
minimum, median and maximum). Correlative analyses of some of the PK parameters with efficacy, 
safety and immunogenicity measures may be conducted. 
HRQoL and Functional Independence: 
For the Health-Related Quality of Life (HRQoL) and functional independence assessments, 
individual items, domain, and summary scores generated over the course of the study will be 
evaluated with descriptive statistical measures (mean, standard deviation, minimum, median, and 
maximum) as well as displayed visually. 


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3 TABLE OF CONTENTS 
TITLE PAGE.….……………………………………………………………………………...1 
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY ............................................2 
2 SYNOPSIS ...........................................................................................................................5 
3 TABLE OF CONTENTS ...................................................................................................23 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................30 
5 ETHICS..............................................................................................................................33 
5.1 Institutional Review Board or Independent Ethics Committee ................................33 
5.2 Ethical Conduct of Study ..........................................................................................34 
5.3 Subject Information and Informed Consent ..............................................................34 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................36 
7 INTRODUCTION .............................................................................................................37 
7.1 Nonclinical Studies ...................................................................................................38 
7.2 Previous Clinical Studies ..........................................................................................39 
7.2.1 
Study 111-101 .............................................................................................39 
7.3 Ongoing Clinical Studies ..........................................................................................40 
7.3.1 
Study 111-901 .............................................................................................40 
7.3.2 
Study 111-202 .............................................................................................40 
7.3.3 
Study 111-205 .............................................................................................41 
7.3.4 
Study 111-301 .............................................................................................41 
7.3.5 
Study 111-302 .............................................................................................41 
7.4 Study Rationale .........................................................................................................42 
7.5 Summary of Overall Risks and Benefits ...................................................................43 
7.5.1 
Summary of Risks from Nonclinical Studies ..............................................43 
7.5.2 
Summary of Risks from Clinical Studies ....................................................44 
7.5.2.1 
Study 111-101 ..............................................................................44 
7.5.2.2 
Ongoing Studies ...........................................................................44 
7.5.3 
Summary of Potential Benefits from Clinical Studies ................................44 
8 STUDY OBJECTIVES ......................................................................................................45 


 
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9 INVESTIGATIONAL PLAN ............................................................................................46 
9.1 Overall Study Design and Plan .................................................................................46 
9.1.1 
Dose Adjustments ........................................................................................58 
9.1.2 
Stopping Criteria .........................................................................................59 
9.2 Discussion of Study Design, Including Choice of Control Group ............................61 
9.3 Selection of Study Population ...................................................................................61 
9.3.1 
Inclusion Criteria .........................................................................................61 
9.3.2 
Exclusion Criteria ........................................................................................62 
9.3.3 
Inclusion Criteria for Cohort 3 Observation Period ....................................64 
9.3.4 
Exclusion Criteria for Cohort 3 Observation Period ...................................64 
9.3.5 
Current Chronic Therapy with Restricted Medications ..............................66 
9.3.6 
Removal of Subjects from Treatment or Assessment .................................66 
9.3.7 
Subject Identification ..................................................................................68 
9.3.8 
Duration of Subject Participation ................................................................68 
9.4 Treatments .................................................................................................................69 
9.4.1 
Treatments Administered ............................................................................69 
9.4.1.1 
Study Drug Administration ..........................................................69 
9.4.2 
Identity of BMN 111 ...................................................................................69 
9.4.2.1 
Product Characteristics and Labeling ..........................................70 
9.4.3 
Storage .........................................................................................................70 
9.4.4 
Directions for Administration .....................................................................71 
9.4.5 
Method of Assigning Subjects to Treatment Groups ..................................72 
9.4.6 
Selection of Dose and Dosing Schedule Used in the Study ........................72 
9.4.6.1 
Selection of Timing of Dose for Each Subject ............................73 
9.4.7 
Blinding .......................................................................................................73 
9.4.8 
Prior and Concomitant Medications ............................................................73 
9.5 Treatment Compliance ..............................................................................................73 
9.6 Investigational Product Accountability (BMN 111 or Placebo) ...............................74 
9.6.1 
Return and Disposition of Clinical Supplies ...............................................74 
9.7 Dietary or Other Protocol Restrictions ......................................................................74 


 
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9.8 Demographic Data and Medical History ..................................................................75 
9.9 Biological Parental Standing Height .........................................................................75 
9.10 Physical Examination Findings .................................................................................75 
9.11 Echocardiogram ........................................................................................................75 
9.12 Efficacy and Safety Variables ...................................................................................75 
9.12.1 Efficacy and Safety Measurements Assessed .............................................75 
9.12.2 Primary Efficacy Variables .........................................................................76 
9.12.3 Secondary Efficacy Variables .....................................................................76 
9.12.3.1 
Body Proportion Ratios of the Extremities ..................................76 
9.12.3.2 
MRI Assessments.........................................................................77 
9.12.3.3 
Sleep Study ..................................................................................77 
9.12.3.4 
Clinical Outcome Assessments ....................................................77 
9.12.4 Exploratory Efficacy Variables ...................................................................79 
9.12.4.1 
Clinical Photography ...................................................................79 
9.12.4.2 
Exploratory Biomarker Research Sample Analyses ....................79 
9.12.4.3 
Genomic Biomarker Analysis ......................................................79 
9.12.5 Pharmacokinetics Variables ........................................................................80 
9.12.6 Safety Variables ..........................................................................................80 
9.12.6.1 
Adverse Events ............................................................................81 
9.12.6.2 
Procedures During the Study .......................................................81 
9.12.6.3 
Imaging Assessment Procedures (per Schedule of Events) .........81 
9.12.6.4 
Clinical Laboratory Assessments .................................................81 
9.12.6.5 
Other Laboratory Assessments ....................................................83 
9.12.6.6 
Child Behavior Checklist .............................................................83 
9.12.6.7 
Vital Signs, Physical Examinations and Other 
Observations Related to Safety ....................................................84 
9.12.6.8 
Mitigating the Risk of Potential Hypotension .............................85 
9.12.6.9 
Electrocardiography .....................................................................86 
9.12.6.10 Hip Clinical Assessment ..............................................................86 
9.12.6.11 Pediatric Blood Volume ...............................................................86 
9.12.6.12 Anti-BMN 111 Immunogenicity Assessments ............................87 


 
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9.12.6.13 HPA Axis Assessments................................................................87 
9.12.6.14 IgE Safety Assessments ...............................................................87 
9.12.6.15 Unscheduled Safety Visits ...........................................................88 
10 REPORTING ADVERSE EVENTS .................................................................................89 
10.1 Safety Parameters and Definitions ............................................................................89 
10.1.1 Adverse Events ............................................................................................89 
10.1.2 Serious Adverse Events ...............................................................................89 
10.1.3 Events of Special Interest (EOSI) ...............................................................90 
10.2 Methods and Timing for Capturing and Assessing Safety Parameters .....................90 
10.2.1 Adverse Event Reporting Period .................................................................90 
10.2.2 Eliciting Adverse Events .............................................................................90 
10.2.3 Assessment of Seriousness, Severity, and Causality ...................................90 
10.2.3.1 
Seriousness ...................................................................................91 
10.2.3.2 
Severity ........................................................................................91 
10.2.3.3 
Causality ......................................................................................92 
10.3 Procedures for Recording Adverse Events ...............................................................93 
10.3.1 Recording Adverse Events on a eCRF ........................................................93 
10.3.1.1 
Diagnosis versus Signs and Symptoms........................................93 
10.3.1.2 
Adverse Events Occurring Secondary to Other Events ...............93 
10.3.1.3 
Persistent or Recurrent Adverse Events .......................................93 
10.3.1.4 
Hypotension .................................................................................94 
10.3.1.5 
Injection Site Reactions ...............................................................94 
10.3.1.6 
Abnormal Laboratory Values ......................................................94 
10.3.1.7 
Pre-existing Conditions ................................................................95 
10.3.1.8 
General Physical Examination Findings ......................................95 
10.3.1.9 
Hospitalization, Prolonged Hospitalization, or Surgery ..............95 
10.3.1.10 Deaths ..........................................................................................96 
10.4 Reporting Requirements ...........................................................................................96 
10.4.1 Expedited Reporting Requirements .............................................................96 
10.4.2 IRB Reporting Requirements ......................................................................97 


 
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10.5 Follow-up of Subjects after Adverse Events .............................................................97 
10.6 Post-Study Adverse Events .......................................................................................97 
10.7 Urgent Safety Measures ............................................................................................97 
10.8 BioMarin Pharmacovigilance Contact Information ..................................................99 
11 APPROPRIATENESS OF MEASUREMENTS .............................................................100 
12 STUDY PROCEDURES .................................................................................................101 
12.1 Treatment Visit(s) ...................................................................................................101 
12.1.1 Screening/Baseline Day -30 to Day -1 ......................................................101 
12.1.2 Day 1 and Week 13 (±7d) .........................................................................102 
12.1.3 Days 2 and 3 ..............................................................................................102 
12.1.4 Day 8 (±1d) and Week 20 (±7d) ................................................................103 
12.1.5 Week 3 (±7d) .............................................................................................103 
12.1.6 Week 6 (±7d) .............................................................................................104 
12.1.7 Week 26 (±7d) ...........................................................................................104 
12.1.8 Week 39 (±7d) ...........................................................................................105 
12.1.9 Week 52 (±7d) ...........................................................................................106 
12.1.10 Week 56 Safety Follow-up ( + 7d) ............................................................107 
12.1.11 Early Termination Visit .............................................................................107 
12.2 Observational Period for Cohort 3 (Infants between birth and  < 3 months 
old [0 days to   < 13 weeks]) ...................................................................................108 
12.2.1 Screening Visit ..........................................................................................108 
12.2.2 Day 1 (Month 0) ........................................................................................109 
12.2.3 3 Months (± 10 days) .................................................................................109 
13 DATA QUALITY ASSURANCE ...................................................................................110 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ................111 
14.1 Statistical and Analytical Plans ...............................................................................111 
14.1.1 Interim Analyses ........................................................................................111 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data ........111 
14.2 Safety Analysis .......................................................................................................111 
14.3 Efficacy Analysis ....................................................................................................112 
14.4 Pharmacokinetic Analyses ......................................................................................113 


 
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14.5 Immunogenicity Analysis .......................................................................................113 
14.6 Determination of Sample Size ................................................................................113 
14.7 Analysis Populations ...............................................................................................113 
14.7.1 Efficacy Population ...................................................................................113 
14.7.2 Safety Population ......................................................................................113 
15 DATA MONITORING COMMITTEE ...........................................................................114 
16 COSTS, COMPENSATION, AND SUBJECT INJURY ................................................115 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS ............................................116 
18 STUDY MONITORING AND AUDITING ...................................................................118 
19 RETENTION OF RECORDS..........................................................................................119 
20 USE OF INFORMATION AND PUBLICATION ..........................................................120 
21 REFERENCES ................................................................................................................121 
22 INVESTIGATOR RESPONSIBILITIES ........................................................................123 
22.1 Conduct of Study and Protection of Human Subjects .............................................123 
23 SIGNATURE PAGE .......................................................................................................124 
24 PROTOCOL AMENDMENT TEXT REVISIONS ........................................................125 
 


 
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LIST OF TABLES 
Table 9.1.1:  Schedule of Events .............................................................................................50 
Table 9.1.2:  Schedule of Events Observational Period for Cohort 3 (infants between 
birth and < 3 months old) ..............................................................................56 
Table 9.3.5.1:  Current Chronic Therapy with Restricted Medications ...................................66 
Table 9.12.6.4.1: Clinical Laboratory Tests ............................................................................82 
Table 9.12.6.5.1:  Biomarkers and Anti-BMN 111 Antibodies ...............................................83 
Table 9.12.6.5.1:  Vital Sign Assessment Frequency ..............................................................85 
Table 10.2.3.2.1:  Adverse Event Grading (Severity) Scale ....................................................91 
Table 10.2.3.3.1:  Causality Attribution Guidance ..................................................................92 
LIST OF FIGURES 
Figure 9.1.1:  Study Design .....................................................................................................49 
Figure 9.12.3.4.1:  Clinical Outcomes Assessment Tools .......................................................78 
 


 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
°C 
degree Celsius 
ACE 
angiotensin-converting enzyme 
Ach 
Fgfr3G380R achondroplasia mouse model 
ACH  
achondroplasia 
ADR 
adverse drug reaction 
AE 
adverse event 
AGV 
annualized growth velocity 
ALT 
alanine aminotransaminase 
ANP 
atrial natriuretic peptide 
AP 
anterior-posterior 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve  
BMC 
bone mineral content 
BMD  
bone mineral density 
BNP 
B-type Natriuretic Peptide 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
cGMP 
cyclic guanosine monophosphate 
Cmax 
maximum observed plasma concentration 
CBCL 
Child Behavior Checklist 
CMC 
cervicomedullary compression 
CNP  
C-type natriuretic peptide 
CNP53 
C-type natriuretic peptide (53 amino acids in length) 
CPAP 
continuous positive airway pressure 
CRA 
clinical research associate 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX-II 
C-terminal telopeptide of cross-linked collagen type II 
CV 
cardiovascular 
CV% 
coefficient of variation 
DCF 
data clarification form 
DMC 
data monitoring committee 
DXA 
dual X-ray absorptiometry 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eCRF 
electronic case report form 
EOSI 
events of special interest 
ERK 
extracellular signal-regulated kinase 
EU 
European Union 
FDA 
Food and Drug Administration 
FGF 
fibroblast growth factor 


 
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G380R 
substitution in the transmembrane domain of the FGFR3 receptor at position 380 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HRQoL 
health-related quality of life 
IB 
investigator brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICH E6 [R2] 
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
IEC 
Independent ethics committee 
IgE 
immunoglobulin E 
IND 
Investigational New Drug (application) 
IP 
investigational product 
IRB 
institutional review board 
ITQOL 
Infant Toddler Quality of Life questionnaire 
IXRS 
Interactive Voice/Web Response System 
MAPK 
mitogen-activated protein kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
msec 
millisecond 
NAb 
neutralizing antibodies 
NEP 
neutral endopeptidase 
NP 
natriuretic peptide 
NPR-B 
natriuretic peptide receptor type B 
PI 
Principal Investigator 
PK 
pharmacokinetics 
QT 
a measure of the time between the start of the Q wave and the end of the T wave  
QTc-F 
Fridericia’s corrected QT interval 
REB 
research ethics board 
rhCNP  
recombinant C-type natriuretic peptide 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SOI 
Statement of Investigator Form 
t1/2 
elimination half-life 
TAb 
total antibody 
TAF 
human transcription factor 
Tmax 
time to reach Cmax 
ULN 
upper limit of normal 
US 
United States 


 
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Wee-FIM 
Functional independence measure for children 
WFI 
water for injection 
µg/kg 
microgram/kilogram 
Definition of Terms:  
Investigational Product (IP): 
“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use” 
(from International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline: 
Guideline for Good Clinical Practice E6 [ICH E6] (R2)]).  
The terms “IP” and “study drug” may be used interchangeably in the protocol. 
 


 
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5 
ETHICS 
BioMarin Pharmaceutical Inc. (hereafter referred to as BioMarin or the Sponsor) conducts its 
studies according to the highest ethical and scientific standards. The following sections 
articulate standards to which Investigators will be held accountable, as well as matters of 
compliance to document adherence to such standards. 
5.1 
Institutional Review Board or Independent Ethics Committee 
Investigators are expected to interact with independent Ethics Committees (IECs) promptly, 
as required, during the course of the study. This includes, but is not limited to, providing 
appropriate documentation to support study initiation and maintaining appropriate flow of 
safety and other information during the course of the study and for study close-out activities. 
BioMarin (or designee) will assist Investigators with access to timely and accurate 
information and with assurance of prompt resolution of any queries. 
Prior to initiating the study, the Investigator will obtain written confirmation that the 
institutional review board (IRB) or independent ethics committee (IEC), or Research Ethics 
Board (REB) is properly constituted and compliant with International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) and Good Clinical Practice (GCP) requirements, applicable laws, and local 
regulations. A copy of the confirmation from the IRB/IEC/REB will be provided to BioMarin 
Pharmaceutical Inc. (BioMarin) or its designee.  
The Investigator will provide the IRB/IEC/REB with all appropriate material, including the 
protocol, Investigator’s Brochure (IB), the Informed Consent Form (ICF) including 
compensation procedures, and any other written information provided to the subjects, 
including all ICFs translated for subjects who do not speak the local language at the clinical 
site. The study will not be initiated and Investigational Product (IP) supplies will not be 
shipped to the site until appropriate documents from the IRB/IEC/REB confirming 
unconditional approval of the protocol, the ICF and all subject recruitment materials are 
obtained in writing by the Investigator and copies are received at BioMarin or its designee. 
The approval document should refer to the study by protocol title and BioMarin protocol 
number (if possible), identify the documents reviewed, and include the date of the review and 
approval. BioMarin will ensure that the appropriate reports on the progress of the study are 
made to the IRB/IEC/REB and BioMarin by the Investigator in accordance with applicable 
guidance documents and governmental regulations. 


 
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5.2 
Ethical Conduct of Study 
It is expected that Investigators understand and comply with the protocol. This includes, but 
is not limited to: establishing and meeting enrollment commitments, including providing 
eligible subjects for study enrollment; adhering to adverse event reporting, diagnostic, or 
other procedures as specified in the protocol; and assuring appropriate compliance with study 
treatment administration and accountability. 
This study will be conducted in accordance with the following: 
• European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC, for studies conducted within any European country 
• US Code of Federal Regulations (CFR) sections that address clinical research studies, 
and/or other national and local regulations, as applicable 
• ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
(ICH E6) or E6(R2) (ICH E6R2) if adopted 
• The ethical principles established by the Declaration of Helsinki 
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB/IEC/REB and will be conducted by scientifically and medically qualified persons. 
The benefits of the study are in proportion to the risks. The rights and welfare of the subjects 
will be respected and the investigators conducting the study do not find the hazards to 
outweigh the potential benefits. Each subject, or his/her legally authorized representative will 
provide written, informed consent before any study-related tests or evaluations are 
performed. 
5.3 
Subject Information and Informed Consent 
A properly written and executed informed consent form (ICF), in compliance with the 
Declaration of Helsinki, ICH E6 (Section 4.8), United States Code of Federal Regulations 
(CFR) 21 CFR §50, European Clinical Trial Directive 2001/20/EC and Good Clinical 
Practice Directive 2005/28/EC, and other applicable local regulations, will be obtained for 
each subject prior to entering the subject into the study. The Investigator will prepare the ICF 
and provide the documents to BioMarin for approval prior to submission to the IRB/EC/REB 
approval. BioMarin and the IRB/IEC/REB must approve the documents before they are 
implemented. A copy of the approved ICF (minor assent form and parental ICF for studies 
involving minors), and if applicable, a copy of the approved subject information sheet and all 
ICFs translated to a language other than the native language of the clinical site must also be 
received by BioMarin or designee prior to any study-specific procedures being performed. 


 
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Subjects under the age of majority will provide written assent (if required), and his/her 
legally authorized representative (parent or legal guardian) will provide written informed 
consent for such subjects. The Investigator will provide copies of the signed ICF to each 
subject (or the legally authorized representative of the subject) and will maintain the original 
in the record file of the subject. 
 


 
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6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE  
During administration of informed consent, expectations regarding participation in the study 
should be made clear to subjects. Subjects who are not willing and/or are not able to comply 
with all aspects of the study should not be encouraged to participate. 
Prior to beginning the study, the Investigator at each site must provide to BioMarin or 
designee a fully executed and signed Statement of Investigator (SOI) form.  A US Food and 
Drug Administration (FDA) Form FDA 1572 serves as an acceptable SOI form.  If Form 
FDA 1572 may not be used in a particular region, the Investigator must provide a fully 
executed SOI on the form provided by the Sponsor.  All Investigators and Sub-Investigators 
must be listed on Form FDA 1672 or its equivalent SOI.  Financial Disclosure Forms must 
also be completed for all Investigators and Sub-Investigators listed on the Form FDA 1572 or 
SOI who will be directly involved in the treatment or evaluation of subjects in this study. 
The study will be administered by and monitored by employees or representatives of 
BioMarin. Clinical research associates (CRAs) or trained designees will monitor each site on 
a periodic basis and perform verification of source documentation for each subject as well as 
other required review processes. BioMarin’s Pharmacovigilance Department (or designee) 
will be responsible for the timely reporting of serious adverse events (SAEs) to appropriate 
regulatory authorities as required. 
In multicenter studies, a Coordinating Investigator will be identified who will be responsible 
for study overview. The Coordinating Investigator will read the clinical study report (CSR) 
and confirm that it accurately describes the conduct and results of the study, to the best of his 
or her knowledge. The Coordinating Investigator will be chosen on the basis of active 
participation in the study, ability to interpret data, and willingness to review and sign the 
report in a specified timeframe. The identity of the Coordinating Investigator and a list of all 
Investigators participating in the study will be provided in the CSR. 


 
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7 
INTRODUCTION 
BMN 111 is a proposed pharmacologic therapeutic option for achondroplasia (ACH), the 
most common form of dwarfism. 
ACH is a rare disease with a prevalence of 1/25000 in the US (Wynn, 2007) The average 
adult heights for men and women with ACH are 131 cm and 124 cm, respectively 
(NIH, Genetics Home Reference, 2012).  Characteristic features include long and narrow 
trunk, a large head with frontal bossing, hypoplasia of the mid-face, bowed legs and stenosis 
of the foramen and spinal canals that can be life-threatening. Foramen magnum stenosis can 
lead to cervicomedullary compression in infants with complications including hydrocephalus, 
hypotonia, respiratory insufficiency, apnea, cyanotic episodes, feeding problems, 
quadriparesis, and sudden death.  
There is no approved pharmacological therapy for achondroplasia in the United States (US) 
or European Union (EU). Current treatments for achondroplasia are focused on neurosurgical 
interventions for foramen magnum stenosis or lumbar stenosis, thoracolumbar braces to help 
ameliorate the kyphosis, or limb lengthening requiring multiple operations over 2 to 3 years 
(Shirley, 2009), (Horton, 2007).  
ACH is caused by a gain-of-function mutation in fibroblast growth factor (FGF)R3, a 
negative regulator of chondrocyte proliferation and differentiation.  The most common 
mutation (98%) in ACH patients is a G380R substitution in the transmembrane domain of 
FGFR3 (at position 380).  The majority of new cases (80%) originate from parents with 
normal stature.   
The extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) 
pathway mediates part of FGFR3 inhibition of chondrocyte proliferation and differentiation 
(Foldynova-Trantirkova, 2012).  The ERK MAPK pathway is modulated by CNP, a positive 
regulator of chondrocyte proliferation and differentiation.  Binding of CNP to the Natriuretic 
Peptide-Receptor B (NPR-B) antagonizes FGFR3 downstream signaling by inhibiting the 
MAPK (ERK1/2) pathway at the level of RAF-1 (Krejci, 2005); (Yasoda, 2004); 
(Yasoda, 2009); (Pejchalova, 2007).  This crosstalk was demonstrated in a mouse model of 
FGFR3-related chondrodysplasia (Yasoda, 2004); (Yasoda, 2009).  The dwarfism phenotype 
of mice harboring the FGFR3G380R mutation was rescued by expression of CNP in cartilage 
or by the continuous administration of CNP (infusion). 
CNP is a member of the natriuretic peptide (NP) family that includes Atrial Natriuretic 
Peptide (ANP) and B-type Natriuretic Peptide (BNP). These peptides are structurally related 
but are distinct paracrine/autocrine (CNP) or endocrine (ANP and BNP) factors that regulate 


 
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the cardiovascular (CV), skeletal, nervous, reproductive and other systems. Synthetic analogs 
of ANP (anaritide and carperitide) and BNP (nesiritide) have been investigated as potential 
therapies for the treatment of decompensated heart failure and cardiovascular-related 
diseases. 
BMN 111 is a 39-amino acid CNP analogue harboring the 37 amino acids of the human 
CNP53 C-terminal sequence and modified by the addition of two amino acids (Pro-Gly) on 
the N-terminus.  It is a recombinant human peptide fused to human transcription factor 
(TAF) and expressed as an inclusion body in E. coli.  BMN 111 is liberated and solubilized 
from the TAF-fusion protein by formic acid cleavage, and purified by column 
chromatography (Long, 2012).  BMN 111 was designed to 1) mimic CNP activities in terms 
of receptor binding and pharmacological activity and 2) be resistant to neutral endopeptidase 
(NEP) digestion in order to have an extended half-life in comparison to CNP that is 
presumed to increase exposure to the target growth plate (Wendt, 2015).  
A comprehensive review of BMN 111 is contained in the current version of the Investigator’s 
Brochure supplied by BioMarin.  Investigators are required to review the Investigator’s 
Brochure prior to initiating this study. 
7.1 
Nonclinical Studies 
The pharmacological activity of BMN 111 was explored in two mouse models of ACH, a 
severe, Fgfr3Y367C/+ model (Lorget, 2012), and a mild [Ach] /+ model.  Partial or complete 
reversion of the ACH phenotype was observed in these mouse models after BMN 111 
administration.  Additionally, in wild-type mice, and normal rats and monkeys, BMN 111 
administration resulted in growth plate expansion and dose-dependent skeletal growth at 
hemodynamically tolerated dose levels (Wendt, 2015).  
BMN 111-related adverse findings in nonclinical species (mice, rats, cynomolgus monkeys) 
were limited to the known mechanism of action of CNP on the growth plate and vasculature.  
Reversible subcutaneous injection site reactions were reported, including injection site 
discoloration and microscopic findings of perivascular mononuclear cell infiltrates that were 
seen with slightly higher incidence and severity in BMN 111-treated rats and monkeys 
compared to the vehicle control.  Adverse skeletal changes associated with exaggerated 
growth were seen in normal nonclinical species with open growth plates, and were dose-, 
exposure- and time-dependent. Decreases in blood pressure and compensatory increases in 
heart rate were detected in monkeys across multiple studies, with overt CV-related clinical 
signs observed in some animals at doses ≥ 236 µg/kg. These overt clinical signs consisted of 
transient, short and repeated bouts of sternal or lateral recumbency and/or reduced motor 


 
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activity, typically within 1-hour post-dose administration.  Additional detailed information 
about nonclinical studies of BMN 111 is provided in the current version of the Investigator’s 
Brochure supplied by BioMarin.   
7.2 
Previous Clinical Studies 
7.2.1 Study 111-101 
Study 111-101, “A Phase 1, Two Part, Double Blind, Placebo-Controlled Study to Evaluate 
the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Doses of BMN 111 
Administered to Healthy Adult Volunteers,” was a first-in-human study conducted in 2 parts 
to allow for assessment of the safety, tolerability, and PK of BMN 111 administered as a 
single dose and as a multiple dose to healthy adult male volunteers. 
Doses ranging from 5.0 µg/kg to 15.0 µg/kg were administered as a single subcutaneous (SC) 
dose; doses ranging from 0.5 µg/kg to 8.0 µg/kg were administered daily in the multiple 
ascending dose segment of the study. As expected, mild, transient, self-limited hypotension 
occurred. The majority of these cases were asymptomatic and observed upon assumption of 
an upright posture following recumbence. Hypotension events were reported in the BMN 111 
treatment groups with higher frequency compared with placebo. All events were judged to be 
mild in severity and resolved spontaneously without an intervention. These events occurred 
across dose ranges.  Due to the limited number of events at each dose, it is unclear if 
symptomatic hypotension is dose related.  No dose limiting toxicities were identified outside 
of these cardiovascular events. The only adverse events (AEs) occurring in more than one 
subject receiving BMN 111 were orthostatic hypotension, contact dermatitis, and back pain, 
and injection site reactions. Most AEs in the study were of mild severity, and no serious 
adverse events (SAEs) were reported. There were no AEs that led to premature 
discontinuation of study drug.   
The PK parameters for BMN 111 were obtained from Part 1 of the study and from the first 
dose on Day 1 of the multiple dose study in Part 2. The results demonstrate that BMN 111 
was rapidly absorbed in human, reaching a mean time to peak concentration (Tmax) between 
15-26 minutes. After reaching maximal plasma concentrations, BMN 111 levels rapidly 
declined, with a t1/2 of 40-55 minutes. Mean plasma concentration-time profiles indicate that 
exposure increased with dose from 2.5 to 15 µg/kg. The corresponding increases in plasma 
Cmax and area under the curve (AUC) exposure parameters were greater than dose 
proportional. The increase in Cmax with dose was linear over the dose range evaluated.  In 
Part 2, with multiple dosing at 5 µg/kg for 10 days, the plasma concentration-time curves 
obtained on each of the three sampling days were nearly superimposable. Comparison of PK 


 
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exposure parameters for AUC and Cmax indicate that Cmax is unchanged and AUC is 
increased slightly by +33% over Day 1. Overall, the results indicate that changes in 
BMN 111 exposure are minimal with repeat dosing out to 10 days. 
7.3 
Ongoing Clinical Studies 
7.3.1 Study 111-901 
Study 111-901 is a multicenter, multinational study to collect serial growth measurements on 
pediatric subjects with ACH who are being considered for subsequent enrollment in future 
studies sponsored by BioMarin. To obtain accurate baseline measurements, at least 6 months 
of growth data are collected for Cohorts 1 and 2; and at least 3 months of data for Cohort 3.  
Data gathered from this study are used to characterize baseline growth data in children or 
infants (defined as children < 2 years of age) who may subsequently be enrolled in future 
studies sponsored by BioMarin, and may also be used to establish historical control cohort 
for use in other BioMarin-sponsored studies, when appropriate. For that reason, data related 
to ACH symptoms, tests, and interventions are collected. 
7.3.2 Study 111-202 
Study 111-202 is an ongoing Phase 2, open-label, sequential cohort, dose escalation study 
that assesses daily SC administration of BMN 111 in pediatric subjects with ACH. 
The primary objective of Study 111-202 is to evaluate the safety and tolerability of BMN 111 
administered for 6 months and up to 24 months; the secondary objectives are to determine 
change from baseline in annualized growth velocity (AGV), growth parameters, body 
proportions, and evaluate the dose-exposure and PK profiles of BMN 111 in children with 
ACH.  
Analysis of safety data from the 6-month initial phase of Study 111-202 showed that 
treatment with BMN 111 for 6 months at dose cohorts of 2.5, 7.5, 15, and 30 µg/kg 
(Cohorts 1 to 4, respectively) was generally well tolerated. The most common AEs were mild 
injection site reactions, asymptomatic hypotension, headache, and nasopharyngitis. For a 
detailed summary of risks, please refer to the current version of the Investigator’s Brochure 
supplied by BioMarin.  
Analysis of efficacy data from the 6-month initial phase of Study 111-202 demonstrated that 
the mean (standard deviation) change from baseline AGV when BMN 111 is administered at 
2.5, 7.5, 15, and 30 µg/kg subcutaneously daily for 6 months is -0.37 (1.592), 1.28 (1.439), 
2.01 (1.999), and 2.08 (2.137) cm/year, respectively.  Thus, a positive dose-dependent 


 
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response was observed in change from baseline AGV at doses ranging from 2.5-15 µg/kg 
daily.   
For longer term follow up data from the 202 study, please refer to the current Investigator 
Brochure supplied by BioMarin. 
7.3.3 Study 111-205 
Study 111-205 is an ongoing open-label, Phase 2 extension study to assess long-term safety, 
tolerability, and efficacy of BMN 111 in children with ACH. Subjects continue receiving the 
same stable dose of BMN 111 received upon completion of the 111-202 study (up to 
30 µg/kg daily). This 5-year study allows for long-term assessment of the effect of daily 
BMN 111 administration on safety, tolerability, growth velocity, height, and body 
proportions in subject completing 2 years of BMN 111 treatment in Study 111-202 (7 years 
total BMN 111 treatment duration). Additional exploratory endpoints are being examined to 
determine long-term effects of BMN 111 on bone physiology and the medical complications 
of ACH. 
7.3.4 Study 111-301 
Study 111-301 is an ongoing Phase 3, double-blind, placebo-controlled multicenter study to 
further characterize and confirm efficacy and safety of BMN 111 at 15 µg/kg in a 58-week 
study (up to 4 weeks of screening, 52 weeks of treatment, plus an additional 2 weeks of 
safety follow up). The study assesses the effect of daily BMN 111 administration on change 
from baseline in AGV, height, and body proportions in subjects treated with BMN 111 
compared with control subjects in the placebo group; and further characterizes safety and 
tolerability of BMN 111 in children with ACH. Additional exploratory endpoints are being 
examined to determine the effect of BMN 111 on bone physiology and to assess quality of 
life and daily function of study subjects. 
7.3.5 Study 111-302 
Study 111-302 is an open-label Phase 3 extension study to further evaluate the efficacy and 
safety of BMN 111 either until subjects reach near-final adult height (defined as evidence of 
growth plate closure and < 1.5 cm/yr annualized growth velocity), or for 5 years if near-final 
adult height (NFAH) occurs prior to the end of the 5-year period.  All subjects will receive 
BMN 111 15 µg/kg. This study will allow for long-term assessment of the effect of daily 
BMN 111 administration on safety, tolerability, growth velocity, height, and body 
proportions in subjects who have completed 1 year of placebo or BMN 111 treatment in 
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7.4 
Study Rationale 
BMN 111 is a recombinant CNP analogue that has been engineered to resist degradation by 
NEP, allowing for a longer half-life. 
The pharmacological activity of BMN 111 was explored in two mouse models of ACH, a 
severe, Fgfr3Y367C/+ (TD) model (Lorget, 2012), and a milder [Ach] /+ (Ach) model. These 
included studies in 7-day old TD mice given BMN 111 daily by SC administration for up to 
20 days and a study in 3 week old Ach mice given BMN 111 daily by SC administration for 
5 weeks. Partial or complete reversion of the ACH phenotype was observed in these mouse 
models after BMN 111 administration. In wild-type mice, and normal rats and monkeys, 
BMN 111 administration resulted in growth plate expansion and dose-dependent skeletal 
growth at hemodynamically tolerated dose levels (Wendt, 2015). Additionally, the potential 
effect of age on BMN 111 PK was evaluated in normal rats aged between 7 days and 
12-13 weeks. 
Infants and young children with ACH have a high incidence of medical complications and 
currently there is no approved pharmacological therapy for ACH in the US or EU. The most 
severe complication, cervicomedullary compression (CMC), occurs in a subset of subjects 
with ACH due to abnormal endochondral bone growth and narrowing of the foramen 
magnum (White, 2016). CMC has been linked to serious respiratory and neurological 
complications including hypotonia, apnea, ataxia, developmental delay, and respiratory arrest 
associated with sudden death (Mukherjee, 2014). Foramen magnum decompression surgery 
is currently the only treatment for this condition.   
Sleep apnea has also been extensively described in ACH, and sleep-disordered breathing may 
affect up to 85% of all children with ACH (Ireland, 2012). This is thought to be due to 
midface hypoplasia, relative adenotonsillar hypertrophy, and potential posterior cranial fossa 
compression secondary to abnormal endochondral bone growth. Sleep apnea in ACH not 
only results in the need for surgical intervention, but has also been linked to sudden death in 
rare cases (Pauli, 1984).   
Similarly, the dysregulation of endochondral bone growth in ACH leads to other medical 
complications which are prevalent in this subject population, such as the following: 
• Spinal stenosis, kyphosis, and lordosis (secondary to altered growth plate ossification 
in the vertebrae and narrowing of the interpedicular distances) (Shirley, 2009) 
• Developmental delay of gross motor and ambulatory skills (associated with proximal 
limb shortening, macrocephaly, and hypotonia) (Ireland, 2010) 


 
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• Delayed functional skills and increased need for caregiver assistance (eg, eating, 
bladder management, bowel management, transfer to chair, climbing stairs) 
(Ireland, 2011) 
Thus, BMN 111 may provide greater benefit when children begin treatment at a younger age, 
as earlier initiation of treatment allows a longer time window to improve growth and 
potential to improve medical complications of achondroplasia. This study (111-206) is being 
conducted to assess safety and the potential benefit of BMN 111 in infants and young 
children.   
BioMarin has engineered a CNP analog (BMN 111) that has a longer half-life than 
endogenous CNP, thereby allowing daily SC administration. Similar to CNP, BMN 111 
activates NPR-B signaling with subsequent inhibition of FGFR3 downstream signaling, 
leading to the promotion of chondrocyte proliferation and differentiation and subsequent 
increased endochondral bone formation. BMN 111 administration has been shown to 
promote endochondral bone formation at hemodynamically tolerated dose levels in both 
normal animals and mouse models of ACH reported (refer to current Investigator’s Brochure 
for additional information). 
Human studies to date have also demonstrated that BMN 111 is generally well tolerated at 
doses that result in improvements in growth velocity approaching that of children of average 
stature (Section 7.3). 
Study 111-206 is a Phase 2 randomized, double-blind, placebo-controlled clinical trial of 
BMN 111 in infants and younger children with a diagnosis of ACH who are age 0 to 
< 60 months. This 52-week study will enable assessment of BMN 111 safety, tolerability, 
pharmacodynamics biomarkers, and PK in this population, and also allow for examination of 
potential impact on efficacy endpoints. Additional exploratory endpoints pertaining to 
medical complications of ACH will also be evaluated.  
7.5 
Summary of Overall Risks and Benefits 
7.5.1 Summary of Risks from Nonclinical Studies 
Individuals in this study will be exposed to a recombinant analogue of human C-type 
natriuretic peptide (CNP). Based on the results of experimentation in animals, the most 
relevant potential toxicities relate to the expected pharmacological effects of exogenous CNP 
administration, including hemodynamic changes, skeletal overgrowth, and injection site 
reactions. Transient and sporadic decreases in blood pressure and compensating increases in 
heart rate occurred within the first hour post-dose in cynomolgus monkeys; the effects were 
mainly asymptomatic with a subset of animals given doses ≥ 236 µg/kg observed with 


 
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symptomatic effects consisting of transient, short and repeated bouts of sternal or lateral 
recumbency and/or reduced motor activity. These hemodynamic effects can be monitored, 
but have the potential to be an acute dose-limiting factor in patients. Exaggerated 
appendicular bone responses to the drug included abnormally shaped femoral head, 
acetabular growth center/plate dysplasia and concomitant articular cartilage degeneration 
with clinical manifestations of restricted use of hips. Adverse skeletal changes associated 
with exaggerated growth were dose-, exposure- and time-dependent. Additional detailed 
information about risks identified in nonclinical studies of BMN 111 is provided in the 
current version of the Investigator’s Brochure supplied by BioMarin.   
7.5.2 Summary of Risks from Clinical Studies 
7.5.2.1 
Study 111-101 
Based on review of the first-in-human Phase 1 study of BMN 111 in healthy adult volunteers, 
Study 111-101, BMN 111 administered SC daily was well tolerated with doses ranging from 
0.5 µg/kg to 15 µg/kg. All AEs were of mild severity, and no SAEs were reported. The most 
common AE was mild, transient, self-limited orthostatic hypotension, of which the majority 
of cases were asymptomatic and observed only upon assumption of an upright posture 
following recumbence. No dose-limiting toxicities were identified outside of these CV 
events. 
7.5.2.2 
Ongoing Studies 
Based on analysis of safety data from ongoing phase 2 and 3 studies, treatment with 
BMN 111 was generally well tolerated. Injection site reactions were the most common 
adverse events reported and are considered to be an identified risk. All injection site reactions 
events have been reported as non-serious, Grade 1 in severity, and transient. Hypotension and 
hypersensitivity reactions including development of BMN 111 antibodies are potential risks 
associated with BMN 111 injections. For a detailed summary of risks, please refer to the 
current version of the Investigator’s Brochure supplied by BioMarin. 
7.5.3 Summary of Potential Benefits from Clinical Studies 
For children with ACH who will receive BMN 111 as part of Study 111-206, potential 
benefits may include improvement of AGV rates such that their increase in growth velocity 
may approach that of children of average stature. Additional potential benefits may include 
improvement of the disproportionate growth as well as improvement in quality of life, 
activities of daily living, and medical complications of ACH.  For example, improvement in 
height could have an impact on daily activity performance. 


 
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8 
STUDY OBJECTIVES 
The primary objectives of the study are to: 
• Evaluate the safety and tolerability of BMN 111 in children age 0 to < 60 months 
with ACH  
• Evaluate the effect of BMN 111 on change from baseline in length/height Z-score  
The secondary objectives of the study are to: 
• Evaluate the effect of BMN 111 on change from baseline in AGV throughout the 
52 weeks of the study 
• Evaluate the effect of BMN 111 on bone morphology/quality by X-ray and dual 
X-ray absorptiometry (DXA) 
• Evaluate the PK of BMN 111 in children age 0 to < 60 months with ACH  
• Evaluate hip function 
• Evaluate for hip, thigh, or knee pain, or change in gait  
• Evaluate the effect of BMN 111 on HRQoL, developmental status, and /functional 
independence using age-specific QoL and functional independence 
questionnaires/QOL status (Bayley Scales of Infant and Toddler Development, Third 
edition [Bayley-III], Activity of Daily Living and Functional Independence Measure 
(Wee-FIM), Infant Toddler Quality of Life Questionnaire (ITQOL), Child Behavior 
Checklist (CBCL) 
• Evaluate immunogenicity of BMN 111 and assess impact on safety, PK, and efficacy 
measures  
• Evaluate the effect of BMN 111 on bone metabolism and BMN 111 
pharmacodynamic biomarkers 
• Evaluate the effect of BMN 111 on growth parameters and body proportions, 
including change from baseline in upper:lower body segment ratio 
• Evaluate the effect of BMN 111 on sleep apnea 
• Evaluate the effect of BMN 111 on skull and brain morphology, including foramen 
magnum, ventricular and brain parenchymal dimensions 
• Describe the incidence of surgical interventions, including cervical decompression, 
adenotonsillectomy, and tympanostomy 
The exploratory objectives of the study are to: 
• Document physical and phenotypic changes with clinical photography (optional) 
• Evaluate genomic biomarkers (optional)  


 
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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a Phase 2 randomized, double-blind, placebo-controlled clinical trial of BMN 111 in 
infants and younger children with a diagnosis of ACH.  
Subjects age ≥ 6 months to < 60 months old who have documented ACH confirmed by 
genetic testing; at least a 6-month period of pretreatment growth assessment in Study 
111-901 immediately before study entry; and who meet the study eligibility criteria, will 
participate. Eligible subjects ranging from 0 months to < 3 months old may enroll directly 
into 111-206 and have a minimum of 3 months of pretreatment observation prior to 
commencing treatment with investigational product, or may enroll in 111-901 for a minimum 
of 3 months of pretreatment growth assessment immediately before roll-over to 111-206. 
Approximately 70 subjects will be enrolled at approximately 10-15 clinical centers 
worldwide.   
The primary objectives of this study are to assess the safety and tolerability of daily SC 
BMN 111 administered to infants and young children with ACH, and evaluate the effect of 
BMN 111 on Z-scores. Subjects will be enrolled into 3 age cohorts based on age at study 
screening starting with the eldest population. Within Cohorts 1 and 2, subjects will be 
stratified by age: 
• Cohort 1 – children aged ≥ 24 to < 60 months (n ≥ 30 total: 3 sentinel subjects who 
receive BMN 111, and at least 27 additional subjects randomized 1:1 to treatment or 
placebo control), stratified by age (≥ 24 to < 36 months and ≥ 36 months to 
< 60 months)  
• Cohort 2 – children aged  ≥  6 to   < 24 months (n ≥ 20 total: 3 sentinel subjects who 
receive BMN 111, and at least 17 additional subjects randomized 1:1 to treatment or 
placebo control), stratified by age (≥ 6 months to < 15 months and ≥ 15 months to 
< 24 months)  
• Cohort 3 – children aged 0 to < 6 months (n ≥ 20 total: 3 sentinel subjects who 
receive BMN 111, and at least 17 additional subjects randomized 1:1 to treatment or 
placebo control).  Treatment begins at ≥ 3 months to < 6 months after 3 months of 
observation. 
If subjects who enroll in Cohort 3 are not able to begin treatment by < 6 months of age, they 
will continue in the pretreatment period for another 3 months before enrolling in Cohort 2 to 
fulfill the pretreatment requirement for Cohort 2.  


 
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Sentinel subjects from each cohort will be enrolled, treated with BMN 111, and studied for 
short-term safety and PK data. No two sentinel subjects will be dosed on the same day for 
any cohort. After the sentinel data are evaluated, additional recruited subjects will be 
randomized to receive BMN 111 or placebo SC daily (1:1 ratio) for 52 weeks. At the start of 
the study, 3 sentinel subjects will be enrolled and monitored in Cohort 1. After all 3 sentinel 
subjects reach Day 8, the Sponsor will review and evaluate all available safety data and 
Day 1 PK data. Based on PK data and criteria set in the protocol, the dose may be adjusted 
for the sentinel subjects and the rest of the cohort, and will be the starting dose for the 
younger cohort sentinel subjects.  Upon review of the clinical and PK data, the remainder of 
Cohort 1 (≥ 27 additional subjects) will be enrolled and randomized to treatment with BMN 
111 or placebo (1:1 ratio).  After the sentinel subjects complete 12 weeks of dosing, a data 
monitoring committee (DMC) review will occur to evaluate all available safety and PK data.  
Upon approval by the DMC, the next younger cohort (Cohort 2) will be opened and the 3 
sentinel subjects will be enrolled. 
The same procedure will be followed for Cohort 2. After all 3 sentinel subjects reach Day 8, 
the Sponsor will review and evaluate all available safety data and Day 1 PK data. Based on 
PK data and criteria set in the protocol, the dose may be adjusted for the sentinel subjects and 
the rest of the cohort, and will be the starting dose for the younger cohort sentinel subjects.  
Upon review of the clinical and PK data, the remainder of Cohort 2 (≥ 17 additional subjects) 
will be enrolled and randomized to treatment with BMN 111 or placebo (1:1 ratio). After the 
sentinel subjects complete 12 weeks of dosing, a DMC review will occur to evaluate all 
available safety and PK data.  Upon approval by the DMC, the youngest cohort (Cohort 3) 
will be opened and the 3 sentinel subjects will be enrolled.  
The same procedure will be followed for Cohort 3. After all 3 sentinel subjects reach Day 8, 
the Sponsor will review and evaluate all available safety data and Day 1 PK data. Based on 
PK data and criteria set in the protocol, the dose may be adjusted for the sentinel subjects and 
the rest of the cohort, and will be the starting dose for the younger cohort sentinel subjects.  
Upon review of the clinical and PK data, the remainder of Cohort 3 (≥ 17 additional subjects) 
will be enrolled and randomized to treatment with BMN 111 or placebo (1:1 ratio).  
Cohort 3 subjects must have a minimum of 3 months of observation prior to commencement 
of treatment.  These subjects will have the option to enroll in either 111-901 or 111-206. 
Additional sentinels may be added to any cohort if needed for additional safety and/or PK 
assessment.  


 
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As subjects age on study, they will be administered the dose determined to be appropriate for 
their current age.  For example, if a subject enrolls into Cohort 2 at age 20 months, they will 
receive the recommended dose for subjects aged ≥ 6 to < 24 months until they turn 24 months 
in age.  When they turn 24 months in age, they will begin to receive the recommended dose 
for subjects aged ≥ 24 to < 60 months. 
Each treated subject will have expanded outpatient safety monitoring for a minimum of 
3 days of dosing, during which they will be closely observed and non-invasive hemodynamic 
monitoring will be conducted for at least 4-8 hours post-dosing. Because younger children 
may not be able to verbalize complaints of dizziness or lightheadedness that are potentially 
associated with hypotension, study personnel and caregivers will be trained to recognize the 
signs of hypotension in this population, which may include tachycardia, pallor, diaphoresis, 
lethargy, delayed capillary refill, and poor feeding. Appropriate rigorous training will be 
required for parents and caregivers prior to daily injections at home. Training includes the 
storage, reconstitution, and administration of BMN 111, as well as documentation/reporting 
of AEs and vigilance for signs of hypotension. 
It is generally expected that after subjects are tolerating the drug well and specified criteria 
have been met, caregivers will begin administering study drug. Home health care is not 
required at any point but may be provided if the caregiver is unable or unavailable to 
administer the study drug. A Home Healthcare nurse will train the caregiver(s) if training has 
not been completed by the Day 3 visit. A phone call by the study staff member to the 
caregiver will be required weekly for 6 months and then every 2 weeks for the remainder of 
the study. During these contacts, study staff will ask the caregiver about dose administration 
and seek information on AEs and SAEs by specific questioning. If the caregiver cannot be 
contacted by phone after two attempts, contact can be made via email.   
Duration of the study is 52 weeks of treatment with a safety follow up at Week 56. Following 
completion of the study, subjects in all treatments groups may be eligible to receive 
BMN 111 in an open-label extension study, to assess safety and efficacy of BMN 111 over 
the longer term.  For subjects enrolling into the extension study, safety follow up visit at 
Week 56 will be waived. 
A summary of events and assessments are provided by visit in Table 9.1.1 and Table 9.1.2. 
For a discussion of efficacy assessments, see Section 9.12.2 and Section 9.12.3; exploratory 
efficacy assessments, Section 9.12.4; safety assessments, Section 9.12.6; and PK variables, 
Section 9.12.5. The 111-206 study design is presented in Figure 9.1.1.   


 
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Figure 9.1.1:  Study Design 
 


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Table 9.1.1:  Schedule of Events 
Procedurea 
Screening/
Baseline 
Day -30 to 
Day -1b 
Day 
1 
Day 
2 
Day 
3 
Day 
8 
(±1d) 
Week 
3 
(±7d) 
Week 
6 
(±7d) 
Week 
13 
(±7d) 
Week 
20 
(±7d) 
Week 
26 
(±7d) 
Week 
39 
(±7d) 
Week 
52 
(±7d) 
Week 56 
Safety 
Follow-Up 
( + 7d)aa 
Early 
Term 
Visit 
Informed consent 
X 
Medical historyc 
X 
Parental height (optional)d 
X 
Diagnostic genetic testing 
to confirm achondroplasia 
(if needed)e 
X 
Physical examinationf
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogramh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Echocardiogrami 
X 
X 
Xi 
Anthropometric 
measurementsj 
X 
X 
X 
X 
X 
X 
X 
Xj 
Clinical laboratory 
assessments (hematology, 
chemistry, urinalysis)k 
X 
X 
X 
X 
X 
X 
X 
X 
Thyroid function tests 
X 
X 
Vitamin D, 25-hydroxy 
test 
X 
X 
Salivary cortisol 
X 
X 
X 
X 
Serum prolactin 
X 
X 
X 
X 
Plasma PK and cGMP 
assessmentsl 
X 
X 
X 
X 
X 
Anti-BMN 111 
immunogenicitym 
X 
X 
X 
X 
X 
X 


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Procedurea 
Screening/
Baseline 
Day -30 to 
Day -1b 
Day 
1 
Day 
2 
Day 
3 
Day 
8 
(±1d) 
Week 
3 
(±7d) 
Week 
6 
(±7d) 
Week 
13 
(±7d) 
Week 
20 
(±7d) 
Week 
26 
(±7d) 
Week 
39 
(±7d) 
Week 
52 
(±7d) 
Week 56 
Safety 
Follow-Up 
( + 7d)aa 
Early 
Term 
Visit 
Genomic biomarkers 
(optional)n 
X 
Bone metabolism blood 
biomarkersn 
X 
X 
X 
X 
X 
X 
Bone metabolism urine 
biomarkerso 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BMN 111 PD urine 
biomarkerso 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine chemistryo 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hip monitoringp 
X 
X 
X 
MRI brain/skullq 
X 
X 
X 
Sleep studyr 
X 
X 
X 
Clinical outcome 
assessment: Bayley-III 
X 
X 
X 
X 
Clinical outcome 
assessment: Wee-FIMs 
X 
X 
X 
X 
Clinical outcome 
assessment: ITQOLs 
X 
X 
X 
X 
Safety assessment: CBCLs 
X 
X 
X 
X 
DXA (BMD and BMC) of 
whole body [less head], 
spine)t 
X 
X 
Xt 
AP and lateral X-rays of 
spineu 
X 
X 
Xu 
AP X-rays of lower 
extremitiesu  
X 
X 
Xu 
Clinical photographs 
(optional)v 
X 
X 
X 


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Procedurea 
Screening/
Baseline 
Day -30 to 
Day -1b 
Day 
1 
Day 
2 
Day 
3 
Day 
8 
(±1d) 
Week 
3 
(±7d) 
Week 
6 
(±7d) 
Week 
13 
(±7d) 
Week 
20 
(±7d) 
Week 
26 
(±7d) 
Week 
39 
(±7d) 
Week 
52 
(±7d) 
Week 56 
Safety 
Follow-Up 
( + 7d)aa 
Early 
Term 
Visit 
Capture concomitant 
procedures/interventions/ 
surgeries 
All visits 
X 
X 
BMN 111 or placebo 
administrationw 
All visits 
BMN 111 or placebo 
accountability  
All visits 
X 
Adverse eventsx 
All visits 
X 
X 
Concomitant medicationsy 
X 
All visits 
X 
X 
Phone callz 
Weekly calls for 6 months and then every 2 weeks for the remainder of the study 
Home health visit 
Home health visit is not required at any point but may be provided if the caregiver is unable or 
unavailable to administer the study drug.  
a 
Clinic visits (except Days 1, 2, 3, and 8) have a ± 7-day window.  Anthropometric measurement and imaging assessments can be conducted either pre-dose 
or post-dose. 
b 
If the 111-901 visit at which the subject enters Study 111-206 and the 111-206 Screening visit are on the same day, the procedures common to both visits 
will be performed one time only.  All blood tests at Screening visit should be obtained between Day  − 30 and Day  − 14. 
c 
Medical history, including growth history and ACH-related history, should elicit all major illnesses, diagnoses, and surgeries that the subject has ever had; 
any prior or existing medical conditions that might interfere with study participation or safety. 
d 
Standing height of the participant’s biological parents may be assessed.  Prior to the measurement being taken, each parent is required to complete an ICF 
specific to parent height assessment.  The ICF will be signed prior to the assessment, which can be done at any point in the study.  If biological parent is not 
available during the course of the study to take their standing height, the parent can provide their stated height instead if consent has been given. 
e 
If subjects had previous genetic testing, subjects must have a lab certification documenting the specific mutation required for the 111-206 study, including 
the identification of FGFR3 mutation (G346E, G375C, G380R, or “other”). 
f 
Complete physical exam includes major body systems, including assessment of general appearance; CV; dermatologic; head, eyes, ears, nose, and throat; 
lymphatic; respiratory; gastrointestinal (GI); musculoskeletal; and neurological/psychological and genitourinary. 
g 
All treatment visits have pre-dose vital sign assessments.  Vital signs at pre-dose include: body temperature in degrees Celsius (°C), heart rate, BP, and 
respiratory rate.  Post-dose measurements include heart rate, BP, and respiratory rate. 


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Vital Sign Assessment Frequency 
Screening 
After at least 5 min of rest, subject’s vital signs are taken, preferably in sitting or supine position.  Vital sign measurements should be repeated 
and documented 3 times with at least 5 min intervals between assessments.   
Assessment Frequency 
Dosing Visits 
0-1 hr post-dose 
0-2 hr post-dose 
2-4 hr post-dose 
4-8 hr post-dose 
Days 1, 2 
q 15 min (± 5 min) 
q 30 min (± 5 min) 
q 60 min (± 10 min) 
Days 3, 8 
q 15 min (± 5 min) 
q 30 min (± 5 min) 
Subsequent dosing visits 
q 15 min (± 5 min); 
final assessment prior to end of visit 
(if longer than 1 hr) 
1.
Vital sign measurements are taken once per time point, preferably in a sitting or supine position, after at least 5 minutes of rest.
2.
Heart rate, blood pressure, and respiratory rate should be taken and recorded at each indicated time point.
3.
When blood samples and vital sign assessments are scheduled at the same time or within the same time window, vital signs should be measured before blood samples are
drawn.
4.
If a vital sign measurement must be taken after a blood draw, ensure adequate analgesia for the blood draw and wait several minutes before measuring vital signs.
5.
Vital signs may be monitored more frequently or for longer duration post-dose as clinically indicated.
6.
If a subject has a hypotensive event, or signs potentially consistent with hypotension, or a decrease of 20 mm Hg systolic BP or more from baseline (defined by pre-dose
vitals collected that day), vital signs should be measured and recorded approximately every 15 minutes (± 5 minutes) for the first hour and every 30 minutes (± 5 minutes)
thereafter until the BP returns to baseline (or within the normal range for this subject as defined by PI) and signs (if present) resolve.
7.
If the decision is made to adjust the dose, vital signs will be obtained for at least 4 hr following the first dose at the adjusted dose level, similar to the Day 3, 8 schedule.
8.
If a dose adjustment visit coincides with a visit at which a full PK is drawn, vital signs will be obtained for 8 hours, similar to the Day 1, 2 schedule.
h 
A standard 12-lead ECG will include heart rate, rhythm, intervals, axis, conduction defects, and anatomic abnormalities. The time of collection will be 
recorded. ECGs should be performed in triplicate with the subject supine at the visits indicated in the Schedule of Events.  ECGs will be performed post-
dose on study day visits at which a dose is given; in addition, on Day 1, ECGs will be performed pre-dose.  On days when PK samples are being drawn, 
ECGs should be performed within a 5-minute window prior to 30-minute PK assessment. 
i 
Echocardiogram is obtained at the early termination visit only if the previous assessment was done more than 3 months prior to early termination. 
j 
Growth measures may be collected in triplicate approximately the same time each day (± 2 hr around the time when the first measurement assessment was 
taken at Screening). Measurements may include but are not limited to length, standing height (if able to stand unsupported), crown-to-rump length, head 
circumference, upper and lower arm and leg, and arm span. Measurements not taken in the midsagittal plane should be taken on the right side of the body if 
possible and should always be taken on the same side of the body throughout the study. Anthropometric measurements will be taken at the ETV only if 
subject discontinues after Week 6 and if > 2 weeks have elapsed since the previous assessment. 


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k 
Clinical labs (hematology, chemistry, and urinalysis) are all pre-dose draws/samples and can be collected anytime during the visit if there is no drug 
administration. 
l 
Plasma samples will be collected pre-dose and at 5 (± 2 min), 15 (± 2 min), 30 (± 5 min), 45 (± 5 min), 60 (± 5 min), 90 (± 5 min), and 120 (± 5 min) 
minutes post-dose. On Day 1, additional PK samples will be collected at 180 (± 5 min) and 240 (± 5 min) minutes. Samples with volume remaining after 
pharmacokinetic assessment will be used for cGMP pharmacodynamics assessment. NOTE: In the event of interruption of study drug administration for a 
sentinel patient on Day 1 when PK samples are scheduled, the collection of PK samples should be delayed until the subsequent day and only performed after 
successful administration of study drug has been completed in a single injection. 
m 
Antibodies:  Total anti-BMN 111 (TAb), TAb cross-reacting with endogenous natriuretic peptides, and neutralizing antibody (NAb) samples (serum) will be 
drawn pre-dose at each time point listed on the SOE. TAb cross-reacting with endogenous natriuretic peptides and NAb testing will be performed only on 
baseline and TAb positive samples from subjects weighing ≥ 7.0 kg and waived for subjects < 7.0 kg. Drug-specific IgE will be drawn pre-dose on Day 1 for 
subjects weighing ≥ 7.0 kg and waived for subjects < 7.0 kg to stay within the limits of permitted blood volume collections in infants. Total immunoglobulin 
E (IgE) and drug-specific IgE will be drawn in the event of Grade 3 hypersensitivity adverse event) or at Investigator or Sponsor discretion. If such an event 
occurs, the drug-specific IgE sample should be drawn at least 8 hours after the event start time or before the next dose. A sample for total IgE and serum 
tryptase should be drawn within an hour of the start of the event when possible or during an unscheduled safety visit.  
n 
For optional genomic biomarkers, if the sample is not collected on Day 1, it may be drawn at any time during the study. The sample will be used for 
exploratory genomics including, but not limited to, NPR-B, BRAF, and other genes associated with CNP signalling. Bone metabolism blood biomarkers will 
be waived at screening for subjects weighing < 7.0 kg to limit the blood volume on the smallest subjects at this visit. Serum samples for bone metabolism 
biomarkers will be collected pre-dose on the indicated visits. Bone metabolism blood biomarkers include bone-specific alkaline phosphatase and collagen 
type X. 
o
Urine biomarkers and urine chemistry (urine creatinine test) should be obtained pre- and post-dose (approximately 2-4 hours after study drug administration)
for subjects when possible at the indicated visits. The time of collection will be recorded. Urine biomarkers include cGMP and C-terminal telopeptide of
cross-linked collagen type II (CTX-II).
p 
Hip monitoring: this assessment will include medical history of the hip and physical exam to determine changes in hip function or pain with hip range of 
motion. Adverse changes from baseline will trigger further evaluation. 
q 
MRI is obtained at the early termination visit only if the previous assessment was done more than 3 months prior to early termination (unless additional 
study is recommended by Investigator, BioMarin, or DMC). Efforts to obtain a satisfactory image can be discontinued after 3 unsuccessful attempts.   
r 
If sleep study is uninterpretable, subject may need to repeat assessment.  Obtained at the early termination visit only if the previous assessment was done 
more than 3 months prior to early termination (unless additional study is recommended by Investigator, BioMarin, or DMC). 
s 
Wee-FIM is waived for children < 6 months old; CBCL is waived for children < 18 months old. ITQOL and CBCL should be performed before any other 
assessments during the study visit.  
t 
Efforts to obtain a satisfactory image can be discontinued after 3 unsuccessful attempts. DXA will be obtained at ETV only if subject discontinues after 9 
months to reduce unnecessary radiation exposure (unless additional scans are recommended by investigator, BioMarin, or DMC).   
u 
AP and lateral lumbar spine, and AP lower extremities are obtained at the early termination visit only if the previous assessment was done more than 9 
months prior to early termination (unless additional study is recommended by Investigator, BioMarin, or DMC). Obtained at  ETV only if subject 
discontinues after 9 months to reduce unnecessary radiation exposure (unless additional X-rays are recommended by investigator, BioMarin, or DMC). 


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v 
To document the physical and phenotypic findings of achondroplasia with and without treatment with study drug, clinical photography of the full body, face, 
spine, and extremities will be conducted. This assessment is optional. If the parents/caregivers decline clinical photography, the assessment will be waived 
for the duration of the study. 
w  The injection site should be rotated as described in the BMN-111 Injection Guide. Following administration of each dose at clinic visits, subjects should be 
observed for 8 hours after the injection on Days 1 and 2; 4 hours on Days 3 and 8; and 1 hour on subsequent dosing visits. Subjects should be observed for 
30 minutes after every injection that is not administered at the clinic. If interruption of study drug injection occurs, the remainder of the assigned dose should 
be administered immediately (and no later than within 5 minutes) in a different location. The same syringe should be used and newly reconstituted 
investigational drug should be used to draw the remainder of the dose. 
x 
After written informed consent but before study treatment initiation, only SAEs associated with protocol-imposed interventions will be recorded. After study 
drug initiation, all AEs and SAEs will be recorded until 4 weeks after either the last administration of study drug or the Early Termination visit. If a subject 
is discontinued from the study prematurely, AEs and SAEs will be recorded at the Early Termination visit.   
y 
All medications (prescription, over-the-counter, herbal, topical) and nutritional supplements taken 30 days prior to screening and throughout the study should 
be documented. 
z 
During the call study staff will ask the caregiver about correct administration procedures, record adverse events (AEs), record concomitant medications, and 
answer questions.  
aa 
The 4-week safety follow up visit will be waived for subjects who enter another BMN 111 study or registry within the 4-week period following last dose of 
study drug. 


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Table 9.1.2:  Schedule of Events Observational Period for Cohort 3 (infants between birth and < 3 months old) 
Assessments 
Screeninga 
Day 1a 
(Month 0) 
3 Months (± 10 days) 
Informed consent 
X 
Medical history, including growth history and ACH related history 
X 
Concomitant medications 
X 
X 
X 
Physical examinationb 
X 
Vital signsc 
X 
X 
X 
Anthropometric measurementsd 
X 
X 
Vitamin D, 25-hydroxye 
X 
X 
Alkaline phosphatasee 
X 
X 
Bone metabolism blood biomarkers 
X 
X 
Bone metabolism urine biomarkers 
X 
X 
Genomic biomarkers (optional)f 
X 
Weight 
X 
X 
Body mass index (calculated) 
X 
X 
Clinical outcome assessment: Bayley-IIIg 
X 
Clinical outcome assessment: ITQOLg 
X 
Capture concomitant procedures/interventions/surgeries 
X 
X 
Adverse eventsh 
X 
X 
X 
a 
Screening and Day 1 (Month 0) assessments may be performed on the same calendar day at the discretion of the investigator. If Screening and Day 1 (Month 
0) are done on the same day, vital signs are taken only once. Please refer to eCRF Completion Instructions.
b 
A complete physical examination will be performed at Screening. Complete physical exam includes major body systems, including assessment of general 
appearance; CV; dermatologic; head, eyes, ears, nose, and throat; lymphatic; respiratory; gastrointestinal (GI); musculoskeletal; and 
neurological/psychological and genitourinary. 
c 
Vital signs will be measured with appropriate blood pressure cuffs for achondroplasia children following detailed instructions in Study Reference Manual. 
At screening, blood pressure should be taken with subject in a supine position, after the subject has been resting for at least 5 minutes. At all other visits, 
blood pressure should be taken one time after at least 5 minutes of rest, with subject in a supine position. Heart rate should be taken at each time point that 
blood pressure is measured. Left brachial arm should be the first method of assessment considered, and the same site should be used for blood pressure 
measurement in each subject throughout the study. The method and site of blood pressure measurement will be recorded and should be utilized consistently 
throughout the remainder of the study. 


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d 
Growth parameters (anthropometric measurements) may include but are not limited to height, standing height, sitting or supine height, weight, upper and 
lower arm and leg length, and arm span. Body proportion measurements may include but are not limited to upper:lower body segment ratio, upper 
arm:forearm length ratio, upper leg:lower leg length ratio, and arm span:standing height ratio. Refer to the Anthropometric Measurement Guidelines for 
specific instructions regarding the collection of growth measurements. All age-appropriate physical measurements will be collected at approximately the 
same time each visit ( ± 2 hours) by a trained study staff member; every effort will be made to have the measurements collected by the same study staff 
member, if possible, throughout the study. Each measurement will be taken in triplicate (excluding weight, taken once).  
e 
Vitamin D (25-hydroxy) and alkaline phosphatase will be measured during Screening and at the 3-month visit. 
f 
If sample is not collected at Day 1, it may be drawn at any time during the study. The sample will be used for exploratory genomics including, but not 
limited to, NPR-B, BRAF, and other genes associated with CNP signaling.  
g 
Bayley-III is waived for subjects < 1 month old; ITQOL is waived for subjects < 2 months old.  
h 
AEs will be collected at screening.  For subjects enrolled in Cohort 3 (0 to  < 6 months old), the collection period for all AEs begins after informed consent is 
obtained. 


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9.1.1 Dose Adjustments 
Analysis of available PK data from studies 111-101 and 111-202 indicated that differences in 
subject body weight did not directly translate to differences in total body clearance of 
BMN 111.  The same weight-based dose in the pediatric population of Study 111-202 
(5-12 years old) yielded lower exposure (Cmax and AUC) than that characterized in the adult 
population of Study 111-101.  Therefore, the same weight-based dose in the young pediatric 
population in this study may yield exposure less than the target exposure range characterized 
to be safe and effective in Study 111-202 at the 15 µg/kg dose. Since this is the first 
experience with BMN 111 in this young pediatric population, it is also possible the exposure 
at 15 µg/kg could be greater than the target exposure range, and dose adjustment may be 
warranted. Thus, an option for adjustment of the weight-based dose is provided to ensure that 
the appropriate target exposure for safety and efficacy is reached for the young subjects in 
this study.   
The need for dose adjustment will be evaluated as follows: three sentinel subjects in Cohort 1 
will receive an initial dose of 15 µg/kg. After all three sentinel subjects reach Day 8, the 
Sponsor will review and evaluate all available safety and PK data (at minimum). If the 
criteria for dose adjustment are met, the three sentinel subjects will be started on the new 
adjusted dose at their next scheduled visit, and vital signs will be obtained for at least 4 hours 
post-dose. 
The remainder of the subjects in the age cohort will also be enrolled starting at the new 
adjusted dose. After the third sentinel subject reaches Week 12 post dose adjustment, a DMC 
review will occur to evaluate all safety and PK data and, upon endorsement, the three 
sentinel subjects from the next younger cohort will be enrolled starting at the new adjusted 
dose.  The three sentinel subjects for the second and third cohorts will be evaluated similarly 
to the sentinel subjects in the first cohort for potential dose adjustment. 
As subjects age on study, they will be administered the dose determined to be appropriate for 
their current age.  For example, if a subject enrolls into Cohort 2 at age 20 months, they will 
receive the recommended dose for subjects aged ≥ 6 to < 24 months until they turn 24 months 
in age.  When they turn 24 months in age, they will begin to receive the recommended dose 
for subjects aged ≥ 24 to < 60 months. 
Criteria for Dose Adjustment 
The criteria for dose adjustment are based on obtaining equivalent exposure characterized to 
be safe and effective with the 15 µg/kg dose in Study 111-202 in each of the age cohorts 
evaluated in this study. BMN 111 dose may be adjusted if the mean observed AUC0-120 from 


 
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sentinel subjects is less than the 25th percentile for AUC0-120 in Cohort 3 (15 μg/kg) of Study 
111-202 or greater than the 75th percentile in Cohort 3 of Study 111-202. If these criteria are 
met, an allometric scaling coefficient, α, for BMN 111 clearance by subject body weight will 
be determined using a population PK modelling approach and available data from this study 
and Studies 111-202 and 111-101. The recommended adjusted dose will be determined using 
the following expression: 
 
 
where WTref and Doseref are the typical (i.e., median) subject body weight and total dose, 
respectively, at the 15 μg/kg dose level in Cohort 3 of Study 111-202, and WTch is the 
anticipated median weight in the age cohort being studied. As such, the recommended 
adjusted dose will target the median AUC0-120 observed at the 15 μg/kg dose level of Study 
111-202. The recommended adjusted dose, Dosech, will be normalized by WTch, to provide 
the recommended adjusted weight-based dose. The following rules will be used for dose 
adjustment: 
• A maximum of a 2-fold increase in dose/kg will be permitted between dose 
adjustments regardless of exposure. 
• The total dose will not exceed the highest total dose administered in Study 111-202. 
9.1.2 Stopping Criteria 
Individual Subject Stopping Criteria  
For individual subjects treated with BMN 111, DMC will be informed if any of the following 
individual subject stopping criteria should occur. Temporary dosing suspension, permanent 
discontinuation of dosing, or dose reduction for the individual subject will be considered. 
• Any treatment-emergent adverse event (AE) assessed as at least Grade 4 by the 
Investigator and/or Sponsor Medical Monitor  
• Any treatment-emergent AE of at least Grade 3 assessed as related to study drug by 
the Investigator and/or Sponsor Medical Monitor  
• Any two treatment-emergent Grade 2 symptomatic hypotension events within 7 days 
(non-urgent medical intervention indicated) or any Grade 3 hypotensive event (urgent 
medical intervention or hospitalization indicated) assessed by the Investigator and/or 
Sponsor’s Medical Monitor  


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•
Clinically significant finding or arrhythmia on electrocardiogram (ECG) that
indicates abnormal cardiac function or conduction or prolongation of
QTc-F > 500 msec
•
Clinically significant new or worsening signs of cervicomedullary compression as
determined by the Investigator and in consultation with Sponsor medical monitor and
neurosurgical specialist (if needed)
•
Adverse findings on clinical hip exam or hip imaging assessments that are determined
to be clinically significant as determined by the Investigator and in consultation with
Sponsor Medical Monitor and orthopedic specialist (if needed)
If the subject meets any stopping criterion, after Investigator consultation with the BioMarin 
Medical Monitor and DMC, the subject may be re-challenged at the same dose. If the subject 
meets stopping criteria on re-challenge or if re-challenge at same dose is not clinically 
indicated, other options that may be considered include:  
•
Re-challenge at lower dose with consideration given to upward titration to tolerated
dose
•
Permanent treatment discontinuation (with an option of ongoing assessment in the
study)
Cohort Stopping Criteria 
For each cohort, a DMC review will be conducted if any of the following cohort stopping 
criteria occur in subjects treated with BMN 111.  Temporary dosing suspension, permanent 
discontinuation of dosing, or dose reduction for the cohort(s) will be considered and the 
impact on all other age cohorts will be assessed.  
•
Any treatment-emergent AE assessed as at least Grade 4 by the Investigator and/or
Sponsor Medical Monitor
•
Any two subjects have a treatment-emergent AE of at least Grade 3 assessed as
related to study drug by the Investigator and/or Sponsor Medical Monitor
•
Any two subjects have two treatment-emergent Grade 2 symptomatic hypotension
events within 7 days (non-urgent medical intervention indicated) or any two subjects
cohort have a Grade 3 hypotensive event (urgent medical intervention or
hospitalization indicated) assessed by the Investigator and/or Sponsor’s Medical
Monitor
•
Any two subjects have a clinically significant finding or arrhythmia on ECG that
indicates abnormal cardiac function or conduction or prolongation of
QTc-F >500 msec


 
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• Any two subjects have adverse findings on clinical hip exam or hip imaging 
assessments that are determined to be clinically significant as decided by principal 
investigator and in consultation with Sponsor medical monitor and orthopedic 
specialist (if needed)  
9.2 
Discussion of Study Design, Including Choice of Control Group 
Study 111-206 is a Phase 2 randomized, double-blind, placebo-controlled clinical trial of 
BMN 111 in infants and younger children with a diagnosis of ACH who are age 0 to 
< 60 months. Identification of efficacy at this age range is congruent with mechanism of 
action of BMN 111, because BMN 111 is expected to act at open epiphyseal growth plates. 
Therefore, to have a potential therapeutic benefit for subjects with ACH, specifically for the 
foramen magnum and spine, treatment is expected to be required prior to growth plate 
closure. 
In terms of the study design, a randomized double-blind placebo control will be used to 
mitigate the risk of selection bias and any potential bias in data collection and study conduct.  
Additionally, this design provides a framework for interpretation of any endpoints with a 
subjective component, e.g. health-related quality of life (HRQoL) and activities of daily 
living (ADL) questionnaires and any subjective assessment of safety. 
9.3 
Selection of Study Population 
Subjects age 0 months to < 60 months old, with documented ACH confirmed by genetic 
testing, and who meet the study eligibility criteria will participate. 
Additional criteria for participation in the study are provided in Sections 9.3.1 and 9.3.2. 
9.3.1 Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Diagnosis of ACH, confirmed by genetic testing.  If subjects had previous genetic 
testing, subjects must have a lab report from a certified laboratory with the study 
specific mutation documented. 
2. Age 0 to < 60 months, at study entry (Day 1) 
3. Cohort 1 and 2 subjects must have at least a 6-month period of pretreatment growth 
assessment in Study 111 901 immediately before screening, and have one 
documented measurement of height/body length a minimum of 6 months prior to the 
screening visit for 111-206.  Cohort 3 subjects must have a minimum of 3 months of 
observation prior to treatment.  This observational period can be obtained either (1) 
via prior enrollment in Study 111-901 or (2) via enrollment in this Study 111 206 for 
a minimum of 3 months of non-treatment observation prior to commencement of 
treatment.  


 
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4. Parent(s) or guardian(s) (and the subjects themselves, if required by local regulations 
or ethics committee) are willing and able to provide written, signed informed consent 
after the nature of the study has been explained and prior to performance of any 
research-related procedure 
5. Willing and able to perform all study procedures as physically possible 
6. Parent(s) or caregiver(s) are willing to administer daily injections to the subjects and 
complete the required training 
9.3.2 Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1. Have hypochondroplasia or short-stature condition other than achondroplasia 
(e.g., trisomy 21, pseudoachondroplasia, etc.) 
2. Subject weighs < 5.0 kg (Cohort 1 and 2) or < 4.0 kg (Cohort 3) 
3. Have any of the following: 
• Hypothyroidism or hyperthyroidism 
• Insulin-requiring diabetes mellitus 
• Autoimmune inflammatory disease (including celiac disease, systemic lupus 
erythematosus, juvenile dermatomyositis, scleroderma, etc.) 
• Inflammatory bowel disease 
• Autonomic neuropathy 
4. Have a history of any of the following: 
• Renal insufficiency defined as serum creatinine > 2 mg/dL 
• Chronic anemia or Hgb  < 10.0 g/dL (based on screening clinical laboratory 
testing) 
• Baseline systolic blood pressure (BP) below age and gender specified normal 
range or recurrent symptomatic hypotension (defined as episodes of low BP 
generally accompanied by symptoms e.g., dizziness, fainting) or recurrent 
symptomatic orthostatic hypotension 
• Cardiac or vascular disease, including the following 
o Cardiac dysfunction (abnormal echocardiogram determined to be 
clinically significant by principal investigator [PI] and medical monitor) at 
Screening Visit  
o Hypertrophic cardiomyopathy 
o Pulmonary hypertension 
o Congenital heart disease with ongoing cardiac dysfunction  
o Cerebrovascular disease 
o Aortic insufficiency or other clinically significant valvular dysfunction 
o Clinically significant atrial or ventricular arrhythmias 


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6. Have a clinically significant finding or arrhythmia that indicates abnormal cardiac
function or conduction or QTc-F  > 450 msec on screening ECG
7. Have evidence of cervicomedullary compression (CMC) likely to require surgical
intervention within 60 days of Screening as determined by the Investigator and
informed by the following assessments:
•
Physical exam (e.g., neurologic findings of clonus, opisthotonus, exaggerated
reflexes, dilated facial veins)
•
Polysomnography (e.g., severe central sleep apnea)
•
MRI indicating presence of severe CMC or spinal cord damage
8. Have an unstable medical condition likely to require surgical intervention in the next
6 months, or planned spine or long-bone surgery (i.e., surgery involving significant
disruption of bone cortex) during the study period
9. Have documented uncorrected Vitamin D deficiency: 25(OH)D   ≤ 15 ng/mL
(37.5 nmol/L)
10. Require any other investigational product prior to completion of the study period
11. Have received another investigational product or investigational medical device
within 30 days prior to the Screening visit
12. Have used any other investigational product or investigational medical device for the
treatment of achondroplasia or short stature at any time
13. Require current chronic therapy with antihypertensive medication or any medication
that, in the investigator’s judgment, may compromise the safety or ability of the
subject to participate in this clinical study (Table 9.3.5.1)
14. Have been treated with growth hormone, insulin-like growth factor 1 (IGF-1), or
anabolic steroids in the 6 months prior to screening, or long-term treatment
(> 3 months) at any time
15. Have had regular long-term treatment (> 1 month) with oral corticosteroids (low-dose
ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable) in the
12 months prior to screening
16. Have ever had cervicomedullary decompression surgery (Cohorts 2 and 3 only), spine
or long-bone surgery (i.e., surgery involving disruption of bone cortex) or have ever
had bone-related surgery with chronic complications
NOTE: Subjects with prior cervicomedullary decompression may be allowed into
Cohort 1 only after discussion and agreement with Medical Monitor.
17. Have ever had limb-lengthening surgery or plan to have limb-lengthening surgery
during the study period
18. Have had a fracture of the long bones or spine within 6 months prior to screening


 
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19. Have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or total 
bilirubin greater than upper limit of normal (ULN) at screening (except for subjects 
with a known history of Gilberts or newborns entering screening in Cohort 3) 
20. Have evidence of severe untreated sleep apnea; or have newly initiated sleep apnea 
treatment (eg, continuous positive airway pressure [CPAP] or sleep apnea-mitigating 
surgery) in the 2 months prior to screening 
21. Have current malignancy, history of malignancy, or currently under work-up for 
suspected malignancy 
22. Have known hypersensitivity to BMN 111 or its excipients 
23. Have a history of hip surgery or severe hip dysplasia 
24. Have a history of clinically significant hip injury in the 30 days prior to screening  
25. Have a history of slipped capital femoral epiphysis or avascular necrosis of the 
femoral head  
26. Have abnormal findings on baseline clinical hip exam or imaging assessments that are 
determined to be clinically significant as determined by the Investigator 
27. Have a condition or circumstance that, in the view of the Investigator, places the 
subject at high risk for poor treatment compliance or for not completing the study 
28. Have any concurrent disease or condition that, in the view of the Investigator, would 
interfere with study participation or safety evaluations, for any reason 
9.3.3 
Inclusion Criteria for Cohort 3 Observation Period 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Parent(s) or guardian(s) willing and able to provide signed informed consent after the 
nature of the study has been explained and prior to performance of any 
research-related procedure. Also, willing and able to provide written assent (if 
applicable) after the nature of the study has been explained and prior to performance 
of any research-related procedure. 
2. Birth to ≤ 3 months of age at study entry.  
3. Have ACH, documented by genetic testing 
4. Are willing and able to perform all study procedures as physically possible 
After completing the observation period, subjects must fulfill the general eligibility criteria 
prior to receiving treatment with study drug.  
9.3.4 Exclusion Criteria for Cohort 3 Observation Period 
Individuals who meet any of the following exclusion criteria are not eligible to participate in 
the study: 


 
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1. Have hypochondroplasia or short stature condition other than ACH (e.g., trisomy 21, 
pseudoachondroplasia) 
2. Have any of the following disorders: 
• Hypothyroidism 
• Insulin-requiring diabetes mellitus 
• Autoimmune inflammatory disease (including celiac disease, lupus (SLE), 
juvenile dermatomyositis, scleroderma, and others) 
• Inflammatory bowel disease 
• Autonomic neuropathy 
3. Have an unstable clinical condition likely to lead to intervention during the course of 
the study, including progressive cervical medullary compression  
4. Have a history of any of the following: 
• Renal insufficiency  
• Anemia  
5. Have a history of cardiac or vascular disease, including the following: 
• Cardiac dysfunction  
• Hypertrophic cardiomyopathy 
• Congenital heart disease 
• Cerebrovascular disease, aortic insufficiency 
• Clinically significant atrial or ventricular arrhythmias 
6. Current treatment with antihypertensive medications, ACE inhibitors, angiotensin II 
receptor blockers, diuretics, beta-blockers, calcium-channel blockers, cardiac 
glycosides, systemic anticholinergic agents, any medication that may impair or 
enhance compensatory tachycardia, drugs known to alter renal function that is 
expected to continue for the duration of the study 
7. Have had regular long-term treatment (> 1 month) with oral corticosteroids (low-dose 
ongoing inhaled steroid for asthma is acceptable) in the previous 3 months 
8. Concomitant medication that prolongs the QT/QTc interval within 14 days or 
5 half-lives, whichever is longer, before the Screening visit 
9. Have used any other investigational product or investigational medical device for the 
treatment of ACH or short stature 
10. Planned or expected bone-related surgery (ie. surgery involving disruption of bone 
cortex), during the study period.  
11.  Planned or expected to have limb-lengthening surgery during the study period.   
12. Have any condition that, in the view of the Investigator, places the subject at high risk 
of poor compliance with the visit schedule or of not completing the study. 


 
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13. Concurrent disease or condition that, in the view of the Investigator, would interfere 
with study participation 
After completing the observation period, subjects must fulfill the general eligibility criteria 
prior to receiving treatment with study drug.  
9.3.5 Current Chronic Therapy with Restricted Medications 
Table 9.3.5.1 lists the medications that are restricted in Study 111-206. 
Table 9.3.5.1:  Current Chronic Therapy with Restricted Medications 
Restricted Medications 
• 
Antihypertensive medications 
• 
Angiotensin-converting enzyme (ACE) inhibitors 
• 
Angiotensin II receptor blockers 
• 
Diuretics 
• 
Beta-blockers 
• 
Calcium-channel blockers 
• 
Cardiac glycosides 
• 
Systemic anticholinergic agents 
• 
GnRH agonists 
• 
Growth hormone (and analogs) 
• 
Any medication that may impair or enhance compensatory tachycardia, diuretics, or 
other drugs known to alter renal or tubular function 
• 
Any medication that in the investigator’s judgment, may compromise the safety or 
ability of the subject to participate in the clinical trial 
 
9.3.6 Removal of Subjects from Treatment or Assessment 
Subjects (or their legally authorized representative) may withdraw their consent to participate 
in the study at any time without prejudice. The Investigator must withdraw from the study 
any subject who requests to be withdrawn. A subject’s participation in the study may be 
discontinued at any time at the discretion of the Investigator and in accordance with his/her 
clinical judgment. When possible, the tests and evaluations listed for the termination visit 
should be carried out.  BioMarin must be notified of all subject withdrawals as soon as 
possible.  
Investigators may discontinue administration of BMN 111 or placebo at any time. Subjects 
discontinued from the study by the investigator must return to the clinic for a termination 
visit. Reasons for which the investigator or BioMarin will withdraw a subject from study 
treatment include, but are not limited to, the following:  


 
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1. Subject experiences a serious or intolerable AE due to BMN 111 as determined by the 
subject, investigator, or sponsor 
2. Subject requires medication or medical procedure prohibited by the protocol 
3. Subject does not adhere to study requirements specified in the protocol 
4. Subject is lost to follow-up 
If a subject fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the subject cannot be reached by telephone, a certified letter should 
be sent to the subject (or the subject’s legally authorized representative, if appropriate) 
requesting contact with the Investigator. This information should be recorded in the study 
records.  
The Investigator or designee must explain to each subject, before enrollment into the study, 
that for evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with the study sponsor, regulatory agencies, and IRB/IEC/REB. It is 
the Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as HIPAA in the US, from each 
subject, or if appropriate, the subject’s legally authorized representative. If permission to use 
protected health information is withdrawn, it is the Investigator’s responsibility to obtain a 
written request, to ensure that no further data will be collected from the subject and the 
subject will be removed from the study. 
It is a priority of the study to maximize study subject retention and adherence to 
study-specific procedures. The completeness of the study data may affect the integrity and 
accuracy of the study results.  Therefore, subjects who discontinue study treatment should be 
encouraged to continue to undergo as many of the protocol-specified procedures and 
assessments as possible for the remainder of the study, as long as such continued 
participation does not detrimentally affect the health, safety, or welfare of the subject, and 
consent remains in place. It is important that following treatment discontinuation the original 
visit schedule is strictly adhered to.  
For subjects who discontinue BMN 111 or placebo but remain in the study, PK and 
BMN 111 activity assessments will be waived completely; vital signs and clinical 
labs/biomarkers will be obtained only once at each visit subsequent to BMN 111 or placebo 
discontinuation.  Pre-and post-dose designations will not apply as the subject has 
discontinued dosing and vital sign and clinical lab/biomarkers assessments previously 
designated as “post-dose” will be waived.  All other assessments at each visit should be 
completed if possible and the subject is willing.  Data from the study procedures and 
assessments may be used to further characterize the natural progression of ACH.  


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BioMarin reserves the right to discontinue the study at any time.  Premature termination of 
the study may occur because of regulatory authority decision, a change in the opinion of the 
IRB/IEC/REB, clinical or safety reasons, or at the discretion of the Sponsor.  The Sponsor 
reserves the right to discontinue the development of BMN 111 at any time, or to discontinue 
participation by an individual Investigator or site for poor enrollment or 
noncompliance.  Any decision to terminate the study will be promptly communicated to 
Investigators, regulatory authorities, and IRB/IEC/REB.  The Investigator is responsible for 
communicating any decision to terminate a study to hospital staff involved in the conduct of 
the study and the participating subjects (and their families). 
9.3.7 Subject Identification 
Each subject will be assigned a unique subject identifier. This unique identifier will be on all 
eCRF pages. In legal jurisdictions where use of initials is not permitted, a substitute identifier 
will be used. 
9.3.8 Duration of Subject Participation 
Duration of the study is 52 weeks of treatment with a safety follow up at Week 56. Following 
completion of the study, subjects in both treatments groups may be eligible to receive 
BMN 111 in an open-label extension study, to assess safety and efficacy of BMN 111 over 
the longer term. For subjects enrolling into the extension study, safety follow up visit at 
Week 56 will be waived.  
Subjects who are not eligible to receive BMN 111 in a separate study will return at Week 56 
for the Safety Follow-Up visit to assess for any AEs that may have occurred following 
completion of dosing. 
Follow-up assessments and procedures should be performed as outlined in the Study 111-206 
Schedule of Events (Table 9.1.1 and Table 9.1.2).  
Subjects who discontinue from study treatment will be asked to complete study assessments 
and procedures for the remainder of the study.  If subjects discontinue from study treatment 
and decline to participate for the remainder of the study, they will be asked to return for a 
final follow-up visit 4 weeks after their last dose, and the agreement should be documented. 
Subjects will participate in the study until completion or until one of the following occurs: 
the subject withdraws consent and discontinues from the study, the subject is discontinued 
from the study at the discretion of the investigator or BioMarin (upon consultation and in 
agreement with the investigator) or the study is terminated. 


 
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9.4 
Treatments 
9.4.1 Treatments Administered 
BioMarin and/or its designee will provide the study site with a supply of IP sufficient for the 
completion of the study. 
Sentinel subjects will receive BMN 111 at a daily dose of 15 µg/kg (subject to adjustment 
per protocol). Subjects will be randomized to BMN 111 or placebo at a daily dose of 
15 µg/kg (subject to adjustment per protocol) for the duration of the study. The normal 
dosing schedule is a single daily subcutaneous injection given 7 days a week.  
If a recent acute illness associated with volume depletion (e.g., nausea, vomiting, diarrhea) 
has not completely resolved prior to the first dose of BMN 111 or placebo, the dosing will be 
delayed until hydration status has improved (up to the maximum period allowed for the visit 
window). 
9.4.1.1 
Study Drug Administration 
During the study, BMN 111 or placebo will be administered as a single 15 µg/kg SC 
injection given daily at approximately the same time each day whenever possible. The same 
injection site should not be used 2 days in a row, and sites should be rotated. Study drug 
should be administered at age-appropriate locations (upper thigh, upper back of arm, 
abdomen or buttocks). Determination of appropriate injection sites will be left to the 
discretion of the investigator. Doses may be administered in any of the common SC areas 
(upper arm, thigh, abdomen, buttocks). 
9.4.1.1.1 Observation Period 
Following administration of each dose at clinic visits, subjects should be observed for 
8 hours after the injection on Days 1 and 2; 4 hours on Days 3 and 8; and 1 hour on 
subsequent dosing visits. Subjects should be observed for 30 minutes after every injection 
that is not administered at the clinic.  Instructions for home administration of BMN 111 or 
placebo for subjects who qualify for parent/caregiver administration are provided in the 
Study Drug Injection Guide and Injection media. 
9.4.2 Identity of BMN 111 
BMN 111 is cloned into the pJexpress401 vector, expressed in E. coli and then purified. 
The drug substance is a modified CNP peptide that retains wild-type activity and specificity. 
The modified CNP sequence is: 
PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC 


 
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The amino acid sequence is an analogue of the naturally occurring tissue-expressed form of 
C-type natriuretic peptide (CNP-53). BMN 111 is a recombinant 39 amino acid peptide that 
includes the 37 C-terminal amino acids of the human CNP-53 sequence, and is engineered to 
include two additional amino acids (Pro-Gly) on the N-terminus, which renders the peptide 
more resistant to degradation. It is a cyclic peptide formed by an intramolecular disulfide 
bond. The molecular weight of the purified product is 4.1 kDa. 
9.4.2.1 
Product Characteristics and Labeling 
The clinical drug product will be supplied in sterile, single-dose, Type I glass vials with 
coated stopper and flip-off aluminum cap. BMN 111 drug product is supplied as a 0.8-mg or 
2-mg lyophilized, preservative-free, white-to-yellow powder for reconstitution with sterile 
water for injection (WFI). The reconstituted solution is colorless to yellow and contains 
0.8 mg/mL to 2 mg/mL of BMN 111, as well as citric acid, sodium citrate, trehalose, 
mannitol, methionine, polysorbate 80, and sterile WFI. The target pH of the reconstituted 
solution is 5.5. Sterile WFI will be commercially sourced. All reconstitution and dose 
preparation steps will be performed as indicated in the BMN 111 Injection Guide and 
Injection video. 
BMN 111-placebo lyophilized product will be supplied in sterile, single-dose, Type I glass 
vials with coated stopper and flip-off aluminum cap. The placebo is designed to be 
comparable in appearance to the drug product and contains all of the components of the drug 
product including commercially sourced sterile WFI except the drug substance. 
The BMN 111 or placebo kit label includes the following information: the contents, 
directions, lot number, quantity, subject ID, vial ID, investigator, the required storage 
conditions, a precautionary statement, the expiry date, the study number, and BioMarin 
Pharmaceutical name and location. This may vary based on country requirements. 
9.4.3 Storage 
At the study site, all IP must be stored under the conditions specified in the Investigator’s 
Brochure in a secure area accessible only to the designated pharmacists and clinical site 
personnel. All IP must be stored and inventoried and the inventories must be carefully and 
accurately documented according to applicable state, federal and local regulations, ICH GCP, 
and study procedures. 
Specific information for storage and return of BMN 111 or placebo is provided in the 
Pharmacy Binder, Study Drug Injection Guide, and Injection media. 


 
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9.4.4 Directions for Administration 
Refer to the Study Drug Injection Guide for complete BMN 111 or placebo preparation 
instructions.  
The injection will be administered as a daily dose of BMN 111 15 µg/kg or placebo given as 
a single subcutaneous injection. The dose should be given at approximately the same time 
every day whenever possible.  Following administration of each dose at clinic visits, subjects 
should be observed for 8 hours after the injection on Days 1 and 2; 4 hours on Days 3 and 8; 
and 1 hour on subsequent dosing visits. Subjects should be observed for 30 minutes after 
every injection that is not administered at the clinic. Subjects should have adequate food 
intake prior to dosing.  All subjects should have been well hydrated and fed in the hour prior 
to administration of BMN 111 or placebo. 
Caregivers will administer BMN 111 or placebo at home once approved by the investigator 
and adequate training is demonstrated. Instructions on how to complete and document the 
training can be found in the Study Reference Manual.   
A caregiver will be eligible to administer BMN 111 or placebo if he or she meets all of the 
following criteria: 
• The subject has been on a stable dosing regimen for a minimum of 3 days  
• PI has approved administration of BMN 111 or placebo by the caregiver 
• The caregiver has completed the Administration Training conducted by qualified 
study site personnel and has been observed by the study site personnel to be able to 
adequately prepare the proper dose and perform the injections safely 
For dosing between planned clinic visits prior to caregiver approval, a home health nurse 
may administer BMN 111 or placebo, or subjects may be administered BMN 111 or placebo 
in the clinic by study staff or trained caregiver.   
The caregiver will be provided with a paper or electronic study diary and will be asked to 
record daily dosing information, changes in health status, medications and injection sites 
used, date and time of the injection, and injection site reactions, if any. 
A subject’s suitability for continued at-home drug administration will be evaluated by the 
investigator and the Sponsor’s Medical Monitor if a subject experiences a CTCAE Grade 3 
or higher AE that is considered possibly or probably drug-related, and/or a hypersensitivity 
reaction during the study.   


 
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9.4.5 Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized using an interactive voice/response system (IXRS) in a 1:1 ratio, 
i.e., injection with placebo:15 µg/kg of BMN 111.  An independent third-party vendor will 
develop the randomization schedule so that BioMarin and site personnel are blinded to 
treatment assignments.  NOTE: In Japan, subjects are randomized separately within each 
cohort. 
9.4.6 Selection of Dose and Dosing Schedule Used in the Study 
Study 111-202, the second clinical trial in humans and the first in children with ACH, is an 
ongoing Phase 2, open-label, sequential-cohort, dose-escalation study that assesses daily SC 
BMN 111 in pediatric subjects with ACH aged 5-14 years with doses ranging from 2.5 µg/kg 
to 30 µg/kg.  
Analysis of safety data from the 6-month initial phase of Study 111-202 showed that 
treatment with BMN 111 for 6 months at the doses of 2.5, 7.5, 15, and 30 µg/kg was 
generally well tolerated. The most common AEs across all cohorts were injection site 
reactions, asymptomatic hypotension, headache, and nasopharyngitis. Based on previous 
experience of the ongoing Phase 2 clinical trial, including the 24-month data cut at 15 µg/kg, 
injection site reactions have been identified as risks associated with BMN 111 injections. For 
a detailed summary of risks, please refer to the current version of the Investigator’s Brochure 
supplied by BioMarin.  
Analysis of efficacy data from the 6-month initial phase of Study 111-202 showed that 
subjects treated with BMN 111 for 6 months at doses ranging from 2.5 to 15 µg/kg daily had 
a dose-dependent improvement in AGV, with ~50% improvement in AGV seen at the 
15 µg/kg dose. The data from Cohort 4 (30 µg/kg) show an apparent greater than dose-
proportional increase in BMN 111 plasma exposure (Cmax and AUC0-t), with a marginal 
improvement in both absolute AGV and change from baseline AGV after 6 months of 
BMN 111 treatment when compared with Cohort 3 (15 µg/kg). 
Efficacy/toxicity studies have been conducted in neonatal and very young animals (7-day 
postpartum mouse and rat) in both a disease (TD mouse) and non-disease (rat) model. 
Given that this is the first study in infants and young children, an age-based cohort study 
design is used to assess safety and PK in young children (Cohort 1, ≥ 24 to < 60 months) 
prior to dosing toddlers (Cohort 2, ≥ 6 to < 24 months) and infants (Cohort 3, 
0 to  <  6 months). PK will be monitored and evaluated; Day 1 PK data from the sentinel 
subjects will inform dose selection modification for the sentinel subjects and for the rest of 
the cohort to target the observed exposure of the 15-µg/kg dose group in Study 111-202. 


 
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Safety, efficacy and PK data from Study 111-202, a Phase 2 study in children with ACH, 
where a dose of 15 µg/kg has been and continues to be studied, are expected to be the most 
relevant, and translatable to this study (111-206).   
9.4.6.1 
Selection of Timing of Dose for Each Subject 
9.4.7 Blinding 
An independent third-party vendor will develop the randomization schedule so that site 
personnel will not know treatment assignments. BMN 111 or placebo will be labeled with the 
study number and a unique identification number. Subjects and the participating site 
members will be blinded to the two study treatments (15 µg/kg BMN 111 or placebo). The 
investigator and other members of staff involved with the study will remain blinded to the 
treatment randomization code during the assembly procedure. In the event of an emergency 
medical situation where subject management would be determined or significantly altered by 
knowing the treatment assignment, the investigator may be unblinded without prior written 
approval from the Medical Monitor.  Following such an emergency unblinding, the 
investigator will contact the medical monitor and provide written rationale according to the 
unscheduled unblinding procedure set forth in the Study Manual.  The Medical Monitor will 
review the rationale, evaluate whether there are any additional safety considerations that need 
to be implemented for the subject and/or the study, and determine whether the investigator 
requires further guidance on unblinding.  The Medical Monitor may also communicate with 
the investigator advice on the care of the subject and define the plan for the subject’s future 
participation in the study. 
9.4.8 Prior and Concomitant Medications 
All medications (prescription, over-the-counter [OTC] and herbal), and nutritional 
supplements 30 days prior to screening and throughout the study will be recorded on the 
designated eCRF.  The Investigator may prescribe additional medications during the study, as 
long as the prescribed medication is not prohibited by the protocol. In the event of an 
emergency, any needed medications may be prescribed without prior approval, but the 
medical monitor must be notified of the use of any contraindicated medications immediately 
thereafter. Any concomitant medications added or discontinued during the study should be 
recorded on the eCRF. 
9.5 
Treatment Compliance 
Subjects will be instructed to return all used and unused BMN 111 or placebo kits at each 
study visit. Subject compliance with the dosing regimen will be assessed by reconciliation of 


 
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the used and unused vials. The quantity dispensed, returned, used, lost, etc. must be recorded 
on the dispensing log provided for the study. 
The date, time, and volume of each dose of BMN 111 or placebo administered to each 
subject must be recorded. These data will be used to assess treatment compliance.  
9.6 
Investigational Product Accountability (BMN 111 or Placebo) 
The Investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of IP(s) received, subjects to whom IP is dispensed (subject-by-subject dose 
specific accounting), and IP lost or accidentally or deliberately destroyed. The Investigator or 
designee must retain all unused or expired study supplies until the study monitor (on-site 
CRA) has confirmed the accountability data. 
9.6.1 Return and Disposition of Clinical Supplies 
Unused BMN 111 or placebo must be kept in a secure location for accountability and 
reconciliation by the study monitor. The Investigator or designee must provide an 
explanation for any destroyed or missing BMN 111 or placebo kits/vials. 
Unused BMN 111 or placebo may be destroyed on site, per the site’s standard operating 
procedures, but only after BioMarin has granted approval for destruction. The study monitor 
must account for all BMN 111 or placebo kits/vials in a formal reconciliation process prior to 
destruction. The site must document all BMN 111 or placebo destroyed on site, and 
documentation must be provided to BioMarin and retained in the investigator study files. If a 
site is unable to destroy BMN 111 or placebo appropriately, the site can, upon request, return 
unused BMN 111 or placebo to the BioMarin contracted facility. The return of all BMN 111 
or placebo kits/vials must also be documented and accounted for per instructions provided by 
BioMarin. 
All BMN 111 or placebo and related materials should be stored, inventoried, reconciled, and 
destroyed or returned according to applicable state and federal regulations and study 
procedures. 
9.7 
Dietary or Other Protocol Restrictions 
BMN 111 will be administered as a single daily dose of 15 µg/kg SC injection given daily at 
approximately the same time each day whenever possible. Placebo will be administered as a 
single SC injection given daily at approximately the same time each day whenever possible. 
Following administration of each dose, subjects will be observed for at least 2 hours after the 
injection for observation for Days 1 to 3, and 30 minutes for all other days of dose 
administration.  


 
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Subjects should have adequate food intake prior to dosing.  All subjects should have been 
well hydrated and fed in the hour prior to administration of BMN 111 or placebo. 
9.8 
Demographic Data and Medical History  
Demographic data and a detailed medical history will be obtained at Screening. This medical 
history, including growth history and ACH-related history, should elicit all major illnesses, 
diagnoses, and surgeries that the subject has ever had; any prior or existing medical 
conditions that might interfere with study participation or safety; and evaluation for knee, 
thigh, hip or groin pain, or change in gait/activity.   
9.9 
Biological Parental Standing Height 
Standing height of the subject’s biological parents (optional) may be assessed via height 
measurement or stated height. Height measurement can be done at any point in the study.  
Prior to the measurement being taken, each parent is required to complete an ICF specific to 
parent height assessment.  The ICF will be signed prior to the assessment, which can be done 
at any point in the study. If the biological parent is not available during the course of the 
study to take his/her standing height, if consented, the biological parent can provide his/her 
stated height.  
9.10 
Physical Examination Findings 
Physical examination will include assessment of general appearance; CV; dermatologic; 
head, eyes, ears, nose, and throat; lymphatic; respiratory; GI; musculoskeletal; and 
neurological/psychological and genitourinary. Other body systems may be examined. 
Screening results will be the baseline values and clinically significant changes from baseline 
will be recorded as an AE or SAE and study drug related or unrelated when appropriate 
based on the investigator’s clinical judgment. 
9.11 
Echocardiogram 
Cardiac anatomy and function will be evaluated by a standard 2-dimensional Doppler 
echocardiogram by a cardiologist. Echocardiograms will be performed at screening, and 
provide information regarding cardiac anatomy and function prior to enrollment in the study. 
9.12 
Efficacy and Safety Variables 
9.12.1 Efficacy and Safety Measurements Assessed 
The Schedule of Events (Table 9.1.1 and Table 9.1.2) describes the timing of required 
evaluations. 


 
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9.12.2 Primary Efficacy Variables 
The primary efficacy endpoint is change from baseline in length/height Z-score. 
Growth measures may be collected approximately the same time each visit (± 2 hr from the 
time when the first measurement assessment was taken at Screening) by a study staff 
member, preferably the same person throughout the study, who has been trained by a 
BioMarin representative. Standardized measuring equipment and detailed measurement 
techniques are detailed in the Anthropometric Measurement Guidelines.  
9.12.3 Secondary Efficacy Variables 
The secondary efficacy endpoints include change from baseline in AGV (annualized to 
cm/yr), biomarker samples to evaluate the effect of BMN 111 on bone metabolism, 
BMN 111 pharmacodynamic biomarkers, growth parameters and body proportions, sleep 
apnea, skull and brain morphology, and clinical outcome assessments 
(developmental/functional/HRQoL status). 
Weight will be measured at Screening and at study visits as indicated on the Schedule of 
Events (Table 9.1.1 and Table 9.1.2). 
Biomarkers may include but are not limited to assessment of changes in bone and collagen 
metabolism (serum bone-specific alkaline phosphatase, serum collagen type X, and urine 
C-terminal telopeptide of collagen type II [CTX-II]) and BMN 111 bioactivity (plasma and 
urine cGMP). BioMarin or designee will perform analysis, and samples may also be used for 
assay development.   
Samples for blood and/or urine biomarkers will be collected at the time points presented in 
the Schedule of Events (Table 9.1.1 and Table 9.1.2). Refer to the Study Laboratory Manual 
for instructions regarding obtaining and shipping samples. The sample type will also be 
included in the Study Laboratory Manual. 
9.12.3.1 
Body Proportion Ratios of the Extremities 
Change from baseline in body proportion ratios of the extremities will be evaluated using 
anthropometric measurements and measurement ratios.  Refer to the Anthropometric 
Measurement Guidelines for specific instructions regarding the collection of growth 
measurements. All age-appropriate physical measurements will be collected at approximately 
the same time each visit (±2 hours around the time when the first measurement assessment 
was taken at Screening) by a trained study staff member; every effort will be made to have 
the measurements collected by the same study staff member, if possible, throughout the 
study. Each measurement will be taken in triplicate (excluding weight, taken once). 


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Anthropometric measurement can be conducted either pre-dose or post-dose. Measurements 
may include but are not limited to length, standing height (if able to stand unsupported), 
crown-to-rump length, head circumference, upper and lower arm and leg, and arm span. 
Measurements not taken in the midsagittal plane should be taken on the right side of the body 
if possible and should always be taken on the same side of the body throughout the study 
Body proportion measurements may include but are not limited to upper arm:forearm length 
ratio, upper leg:lower leg length ratio, and armspan:standing height ratio. 
9.12.3.2 
MRI Assessments 
MRIs are performed to evaluate the effect of BMN 111 on skull and brain morphology, 
including foramen magnum, ventricular, and brain parenchymal dimensions. MRI assessment 
procedures for all visits must be performed as described in the Imaging Manual and can be 
conducted either pre-dose or post-dose.  
9.12.3.3 
Sleep Study 
Given that sleep apnea is a finding in children with ACH (Waters, 1993) and has implications 
on functional and health outcomes, a sleep study will be performed in a limited number of 
qualified sleep centers. A sleep-testing device will be used to assess the presence and severity 
of sleep-disordered breathing by measurement of blood oxygen saturation, pulse rate, and 
airflow during overnight monitoring. Assessment of episodes of sleep apnea will include, but 
may not be limited to, the number of episodes of apnea and hypopnea per hour 
(Apnea/Hypopnea Index).   
9.12.3.4 
Clinical Outcome Assessments 
Clinical outcome assessments will be administered to assess the HRQoL of study subjects. 
Functional Independence will be assessed.  Clinical outcome assessments will be performed 
at the time points indicated in the Schedules of Events (Table 9.1.1 and Table 9.1.2) and the 
ITQoL should be administered prior to any other assessments.  The Wee-FIM and the 
Bayley-III may be administered at any point deemed convenient during the visit. The age 
ranges for clinical outcome assessment tools are shown in Figure 9.12.3.4.1.  The clinical 
outcome assessments are not to be considered as source data for AEs. 


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Figure 9.12.3.4.1:  Clinical Outcomes Assessment Tools 
9.12.3.4.1 Bayley-III 
The Bayley-III is a performance-based outcome assessment for use in children from 1 to 
42 months. It is individually administered by the trained clinician to the subject/child. 
The time required varies from 15-60 minutes depending on the child’s developmental level 
and cooperation.  
Scales include Cognitive subscale, Receptive and Expressive subscales, and Gross and Fine 
Motor subscales. The two language scales make up a composite Language Scale score and 
the Gross and Fine Motor subscales yield a composite Motor Scale score.  
The scales have clinical and research utility as a diagnostic assessment for young children 
with varied disorders and disabilities, and reflect current professional standards for early 
childhood assessment (Bayley, 2006).  
In addition to its use for subjects ranging from 1 to 42 months old, the Bayley-III assessment 
will be administered to those entering the study between 42 and 60 months old 
(Figure 9.12.3.4.1) and for the remainder of the duration of this study, as this assessment can 
capture ongoing developmental issues associated with Achondroplasia.  Bayley-III is waived 
for subjects  < 1 month old. 
9.12.3.4.2 Functional Independence Measure (Wee-FIM) 
The Wee-FIM instrument is an assessment tool that measures functional performance across 
three domains (self-care, mobility and cognition) (Ireland, 2011; Ireland, 2012). 
The Wee-FIM instrument has been used in previous research in children with ACH, and has 
identified ongoing limitations in functional performance across these domains extending 


 
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beyond the age of 7 years (Ireland, 2011). Because the Wee-FIM considers the child’s 
performance from a caregiver’s perspective (Ireland, 2012), this tool in turn gives an 
indication of “burden of care” for families and caregivers of children with ACH.  Wee-FIM 
is waived for children < 6 months old. 
9.12.3.4.3 Infant and Toddler Quality of Life Questionnaire (ITQOL) 
The Infant Toddler Quality of Life questionnaire (ITQOL) is an observer-reported outcome 
tool developed for use in children from 2 months to 5 years old that attempts to capture 
physical, mental and social well-being. The ITQOL adopts the World Health Organization’s 
definition of health as a state of complete physical, mental and social well-being, and not 
merely the absence of disease. The ITQOL also assesses the quality of the parent/guardians 
life.  The 97-item full-length version (ITQOL) will be used for this study. Completion time 
varies.  ITQOL is waived for subjects < 2 months old. The ITQOL should be administered 
prior to any other study assessments. 
9.12.4 Exploratory Efficacy Variables 
9.12.4.1 
Clinical Photography 
To document the physical and phenotypic findings of achondroplasia with and without 
treatment with study drug, clinical photography of the full body, face, spine, and extremities 
will be conducted. This assessment is optional. If the parents/caregivers decline clinical 
photography, the assessment will be waived for the duration of the study. 
9.12.4.2 
Exploratory Biomarker Research Sample Analyses 
All samples collected in this study may be used for on-study exploratory biomarker research 
once the primary use has been completed.  
For each portion of the blood and urine samples reserved for protocol-specified analyses, 
there may be multiple sample aliquots. Once samples have been successfully analyzed during 
the study, unused sample portions may be used during the study for assay development or 
other purposes stated in this section. No exploratory genomic research will be conducted 
without consent from the subject and his/her legally authorized representative (parent or legal 
guardian). 
9.12.4.3 
Genomic Biomarker Analysis 
While the inherited FGFR3 mutations associated with achondroplasia are well characterized, 
disease phenotype in monogeneic diseases is often modified by variants in other genes. 
Exploratory genomics will include, but are not limited to NPR-B, BRAF, and other genes 
associated with CNP signaling. Exploratory genomic analysis may inform understanding of 


 
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the BMN 111 mechanism of action in achondroplasia. This analysis will not be conducted 
without express consent from the subject and his/her legally authorized representative (parent 
or legal guardian). 
9.12.5 Pharmacokinetics Variables 
PK plasma samples will be collected pre-dose and at 5 (± 2 min), 15 (± 2 min), 30 (± 5 min), 
45 (± 5 min), 60 (± 5 min), 90 (± 5 min), and 120 (± 5 min) minutes post-dose. On Day 1, 
additional PK samples will be collected at 180 (± 5 min) and 240 (± 5 min) minutes.  In the 
event of interruption of study drug administration for a sentinel patient on Day 1 when PK 
samples are scheduled, the collection of PK samples should be delayed until the subsequent 
day and only performed after successful administration of study drug has been completed in a 
single injection. 
Whenever possible, the following PK parameters for sentinel subjects and for subjects 
randomized to BMN 111 will be estimated by non-compartmental analysis: 
• Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) 
• Area under the plasma concentration-time curve from time 0 to the time of last 
measurable concentration (AUC0-t) 
• Maximum observed plasma concentration (Cmax) 
• Time to reach Cmax (Tmax) 
• Elimination half-life (t1/2) 
• Apparent clearance (CL/F) 
• Apparent volume of distribution (Vz/F) 
Refer to the Study Laboratory Manual for additional instructions regarding obtaining and 
shipping samples. BioMarin will perform sample analysis, and samples may also be used for 
assay development.  
9.12.6 Safety Variables 
Safety will be evaluated by the incidence of AEs, SAEs, and clinically significant changes in 
vital signs, physical examination, ECG, imaging, and laboratory test results (urinalysis, 
chemistry, hematology). Additionally, imaging, hip monitoring, biomarker, immunogenicity, 
cortisol and prolactin levels, and physical measurement data will be utilized for safety-related 
reviews and analysis.  


 
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9.12.6.1 
Adverse Events 
The occurrence of AEs will be assessed continuously from the time the subject receives study 
drug. The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10.2.1. Assessments of AEs will occur at the time points shown in the Schedule of 
Events (Table 9.1.1 and Table 9.1.2). Additionally, contact by a study staff member to the 
caregiver will be required every week for 6 months, and then every 2 weeks for the 
remainder of the study. During these contacts, study staff will ask the caregiver about dose 
administration and seek information on AEs and SAEs by specific questioning. Information 
on all AEs and SAEs should be recorded in the subject’s medical record and on the AE 
eCRF.  
9.12.6.2 
Procedures During the Study 
All concomitant procedures/interventions/surgeries will be recorded after informed consent is 
obtained and after the first administration of study drug, until end of study. 
9.12.6.3 
Imaging Assessment Procedures (per Schedule of Events) 
Imaging assessment procedures for all visits must be performed using the same instruments.  
Imaging assessments can be conducted either pre-dose or post-dose. 
• Bilateral X-rays of entire lower extremity, anterior-posterior (AP) view, to assess 
long bone growth and pathology as well as growth plate morphology. 
• Lumbar spine X-rays to measure changes from baseline in bone morphology and 
pathology.   
• DXA of whole body [less head], spine, to assess bone mineral density (BMD) and 
bone mineral content (BMC). 
Additional imaging may be conducted should there be any issues or concerns with the 
subject’s imaging assessments. Imaging assessments will be collected and interpreted by a 
central reader. If clinically significant abnormalities are noted, the investigator or designee is 
required to assess whether it is appropriate to report an AE and if the subject should continue 
in the study. Refer to the vendor Imaging Guidelines for detailed imaging assessment 
requirements and procedures. 
9.12.6.4 
Clinical Laboratory Assessments 
Specific visits for obtaining clinical laboratory assessment samples are provided in 
Table 9.1.1 and Table 9.1.2. The scheduled clinical laboratory tests are listed in 
Table 9.12.6.4.1. Refer to the Study Reference Manual for instructions on obtaining and 
shipping samples. 


 
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Any abnormal test results determined to be clinically significant by the Investigator should 
be repeated (at the Investigator’s discretion) until the cause of the abnormality is determined, 
the value returns to baseline or to within normal limits, or the Investigator determines that the 
abnormal value is no longer clinically significant. 
The investigator should assess all abnormal clinical results and include a comment on 
whether or not the result is clinically significant. Each clinically significant laboratory result 
should be recorded as an adverse event. 
The diagnosis, if known, associated with abnormalities in clinical laboratory tests that are 
considered clinically significant by the Investigator will be recorded on the AE eCRF. 
Table 9.12.6.4.1: Clinical Laboratory Tests  
Blood Chemistry 
Hematology 
Urinalysis 
Albumin 
Hemoglobin 
Appearance 
Alkaline phosphatase, total 
Hematocrit 
Color 
ALT (SGPT) 
WBC count 
pH 
AST (SGOT) 
RBC count 
Specific gravity 
Direct bilirubin 
Platelet count 
Ketones 
Total bilirubin 
Differential cell count 
Protein 
BUN 
 
Glucose 
Calcium 
 
Bilirubin 
Chloride 
 
Nitrite 
Potassium 
 
Urobilinogen 
Sodium 
 
Hemoglobin 
Glucose 
 
 
Bicarbonate 
 
Urine Chemistry  
Urine creatinine 
Urine sodium 
Urine potassium 
LDH 
Phosphorus 
 
 
Total protein 
25-hydroxy Vitamin D  
 
 
Creatinine 
Thyroid function (TSH, FT4; if either TSH and 
FT4 are abnormal then T3 may be measured in 
addition) 
 
 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; FT4, free thyroxine; LDH, 
lactate dehydrogenase; RBC, red blood cell; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-
pyruvic transaminase; T3, triiodothyronine; TSH, thyroid stimulating hormone; WBC, white blood cell. 
 


 
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9.12.6.5 
Other Laboratory Assessments  
Subjects will be asked to provide blood and urine at the times indicated in the Schedule of 
Events (Table 9.1.1 and Table 9.1.2).  Blood volume for testing has been reduced to the 
minimum necessary for adequate evaluation of efficacy and safety of BMN 111. 
For subjects who have not previously had genetic testing confirming diagnosis of ACH, 
molecular genetic diagnosis to identify the FGFR3 mutation (G346E, G375C, G380R, or 
“other”) will be performed.  If subjects had previous genetic testing, subjects must have a lab 
report from a certified laboratory with the study specific mutation documented. 
Salivary cortisol and serum prolactin will be collected at the times indicated in the Schedule 
of Events (Table 9.1.1). 
Scheduled biomarker and anti-BMN 111 antibody tests are listed in Table 9.12.6.5.1. 
Table 9.12.6.5.1:  Biomarkers and Anti-BMN 111 Antibodies 
Blood Special Chemistry 
Urine Biomarkers 
Exploratory bone metabolism biomarkers: 
bone-specific alkaline phosphatase and collagen 
type X 
Exploratory bone metabolism urine biomarkers: 
C-terminal telopeptide of collagen type II 
Genomic biomarkers 
BMN 111 pharmacodynamics biomarkers (cGMP) 
Anti-BMN 111 antibodies 
 
BMN 111 pharmacodynamics biomarker (cGMP) 
BMN 111 pharmacodynamics biomarker (cGMP) 
cGMP, cyclic guanosine monophosphate 
 
9.12.6.6 
Child Behavior Checklist  
The Child Behavior Checklist (CBCL) is for use in children from 1.5-5 years old, and will be 
administered for those entering the study at less than 5 years old and for the remainder of the 
duration of the study.  The CBCL comprises 99 questions addressing symptoms related to 
mood, behavior issues, and sleep disturbance.  It is completed by the parent or primary 
caregiver.  
The form requires approximately 15 minutes to complete. The checklist yields scores in the 
following areas: reactivity, anxiety, depression, somatic complaints, withdrawal, sleep 
problems, attention problems, and aggressive behavior. CBCL is waived for 
children < 18 months old. The CBCL should be administered prior to any other study 
assessments. 


 
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9.12.6.7 
Vital Signs, Physical Examinations and Other Observations Related to Safety 
Vital signs assessed pre-dose will include seated or supine systolic blood pressure (SBP) and 
diastolic blood pressure (DBP) measured in mm Hg, heart rate in beats per minute, 
respiration rate in breaths per minute, and temperature in degrees Celsius (°C). All treatment 
visits have pre-dose vital sign assessments. Post-dose measurements include heart rate and 
BP. For all dosing visits, assessment frequency is detailed in Table 9.12.6.5.1 (and Schedule 
of Events Table 9.1.1 and Table 9.1.2). 
At Screening, after at least 5 minutes of rest, subject’s BP is taken in sitting or supine 
position. Vital sign measurements should be repeated and documented 3 times, with at least 
5-minute intervals between assessments.  Left brachial arm should be the first method of 
assessment considered, and the same site should be used for blood pressure measurement in 
each subject throughout the study. The method and site of blood pressure measurement will 
be recorded and should be utilized consistently throughout the remainder of the study. 
At other visits, vital sign measurements are taken once per time point in a sitting or supine 
position after at least 5 minutes of rest. Heart rate should be taken at each time point that BP 
is measured. When blood samples and BP assessments are scheduled at the same time or 
within the same time window, BP should be measured before blood samples are drawn. If a 
BP measurement must be taken after a blood draw, ensure adequate analgesia for the blood 
draw and wait several minutes before measuring BP. Pre-dose vital signs should always be 
taken and recorded prior to pre-dose blood draw. Vital signs may be monitored more 
frequently or for longer duration post-dose as clinically indicated.   
If a subject has signs potentially consistent with hypotension or a decrease in systolic BP of 
20 mm Hg or more from pre-dose systolic BP, blood pressure and heart rate (BP/HR) should 
be measured and recorded approximately every 15 minutes for the first hour and every 
30 minutes thereafter until the systolic BP returns to pre-dose systolic BP (or within the 
normal range for this subject as defined by PI) and signs (if present) resolve.  If the 
hypotension resolves within the first hour and returns to the normal range, additional BP 
monitoring as described above is not required. Detailed guidance for blood pressure 
measurements is provided in the Blood Pressure Instrument and Technique Guidelines.  


 
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Table 9.12.6.5.1:  Vital Sign Assessment Frequency  
Vital Sign Assessment Frequency  
Screening 
After at least 5 min of rest, subject’s vital signs are taken, preferably in sitting or supine 
position.  Vital sign measurements should be repeated and documented 3 times with at 
least 5 min intervals between assessments.   
 
Assessment Frequency 
Dosing Visits 
0-1 hr post-dose 
0-2 hr post-dose 
2-4 hr post-dose 
4-8 hr post-dose 
Days 1, 2 
 
q 15 min (± 5 min) 
q 30 min (± 5 min) 
q 60 min (± 10 min) 
Days 3, 8 
 
q 15 min (± 5 min) 
q 30 min (± 5 min) 
 
Subsequent dosing 
visits 
q 15 min (± 5 min); 
final assessment prior 
to end of visit (if 
longer than 1 hr) 
 
 
 
1. Vital sign measurements are taken once per time point, preferably in a sitting or supine position, after at 
least 5 minutes of rest.   
2. Heart rate, blood pressure, and respiratory rate should be taken and recorded at each indicated time 
point.   
3. When blood samples and vital sign assessments are scheduled at the same time or within the same time 
window, vital signs should be measured before blood samples are drawn.   
4. If a vital sign measurement must be taken after a blood draw, ensure adequate analgesia for the blood 
draw and wait several minutes before measuring vital signs.   
5. Vital signs may be monitored more frequently or for longer duration post-dose as clinically indicated. 
6. If a subject has a hypotensive event, or signs potentially consistent with hypotension, or a decrease of 
20 mm Hg systolic BP or more from baseline (defined by pre-dose vitals collected that day), vital signs 
should be measured and recorded approximately every 15 minutes (± 5 minutes) for the first hour and 
every 30 minutes (± 5 minutes) thereafter until the BP returns to baseline (or within the normal range for 
this subject as defined by PI) and signs (if present) resolve.  
7. If the decision is made to adjust the dose, vital signs will be obtained for at least 4 hr following the first 
dose at the adjusted dose level, similar to the Day 3, 8 schedule. 
8. If a dose adjustment visit coincides with a visit at which a full PK is drawn, vital signs will be obtained 
for 8 hours, similar to the Day 1, 2 schedule. 
 
9.12.6.8 
Mitigating the Risk of Potential Hypotension  
Study personnel and caregivers should be made aware of the potential risk of hypotension 
with BMN 111 administration.  Subjects must be well hydrated and at a minimum be fed 
prior to administration of BMN 111 or placebo.  If a recent acute illness associated with 
volume depletion (e.g., nausea, vomiting, diarrhea) has not completely resolved prior to the 
first dose of BMN 111 or placebo, BMN 111 or placebo dosing may be delayed until 
hydration status has improved (up to the maximum period allowed for the screening 
window). 
Caregivers should be trained to observe and recognize the signs of dehydration (e.g. from 
fever, vomiting, diarrhea, etc.) and contact the investigator prior to BMN 111 or placebo 


 
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administration if dehydration is suspected. Site personnel and caregivers should be trained to 
identify the signs of hypotension and, if they occur, should implement first-aid strategies at 
the discretion of the investigator such as having the subject lie down supine, elevating the 
lower extremities, and administering fluids. For guidelines on how to report adverse events 
associated with hypotension, refer to Section 10.3.1.4. 
9.12.6.9 
Electrocardiography 
A standard 12-lead ECG will include heart rate, rhythm, intervals, axis, conduction defects, 
and anatomic abnormalities. The time of collection will be recorded. ECGs should be 
performed in triplicate with the subject supine at the visits indicated in the Schedule of 
Events (Table 9.1.1 and Table 9.1.2).  ECGs will be performed post-dose on study day visits 
at which a dose is given; in addition, on Day 1, ECGs will be performed pre-dose.  On days 
when PK samples are being drawn, ECGs should be performed within a 5-minute window 
prior to 30-minute PK assessment.  If clinically significant abnormalities are noted, the 
investigator or designee is required to assess whether it is appropriate for the subject to 
continue in the study. 
9.12.6.10 Hip Clinical Assessment 
The hip clinical assessment should be completed by an appropriately qualified physical 
therapist or a physician (MD) i.e., the investigator or the sub-investigator at the time points 
indicated in the Schedule of Events (Table 9.1.1 and Table 9.1.2). Medical history will be 
obtained to evaluate for hip, thigh, or knee pain, or change in gait. The physical exam 
(including observation of gait when possible) identifies and evaluates any changes in hip 
function or pain with assessment of active and passive range of motion. Changes from 
baseline may trigger further evaluation based on the investigator’s clinical assessment, which 
may include hip imaging and/or orthopedic consultation. If findings on clinical hip exam are 
determined to be clinically significant by the investigator and in consultation with Sponsor’s 
Medical Monitor and orthopedic specialist (if needed), the DMC will be notified of AEs 
resulting from clinically significant abnormal hip monitoring assessments. DMC may 
provide recommendations as to if/when BMN 111 or placebo treatment should be 
temporarily or permanently discontinued.  
9.12.6.11 Pediatric Blood Volume 
Clinical labs and immunogenicity samples are necessary to perform to adequate safety 
assessment in this study.  The objectives of testing pharmacodynamics biomarkers are to 
demonstrate biologic activity of BMN 111 and to understand the impact of immune 


 
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responses on drug activity; and for blood biomarkers, to investigate the effects of treatment 
on changes in bone metabolism and endogenous CNP production. 
To minimize blood collection volumes, assay technologies were chosen that are capable of 
sensitively detecting analytes using the lowest possible volume of blood for analysis.  
Additionally, assays capable of detecting analytes in urine rather than blood have been 
selected where possible. 
9.12.6.12 Anti-BMN 111 Immunogenicity Assessments 
Subjects randomized to receive BMN 111 or placebo will undergo immunogenicity testing. 
Blood (serum) samples for immunogenicity assessments will be collected at the time points 
indicated in the Schedule of Events (Table 9.1.1), and testing performed using validated 
assays. Neutralizing antibody (NAb) testing will be performed on Baseline and TAb positive 
samples drawn from subjects weighing ≥ 7.0 kg and waived for subjects < 7.0 kg.  
Scheduled samples will be tested in one or more of the following assessments: 
• Anti- BMN 111 total antibody (TAb) 
• Anti-BMN 111 antibody cross-reactive with endogenous CNP, ANP, and BNP (TAb) 
• Anti-BMN 111 NAb 
Testing for the presence of cross-reactive antibodies that bind to endogenous CNP, ANP, or 
BNP and for the presence of BMN 111 NAbs will be performed on baseline samples and 
anti- BMN 111 TAb-positive samples. Baseline NAb sample and cross-reactive TAb sample 
testing will be done at any time prior to the end of study. 
9.12.6.13 HPA Axis Assessments 
To address potential effects of BMN 111 on activation of the hypothalamic pituitary adrenal 
(HPA) axis, assessment of salivary cortisol and serum Prolactin levels will be analyzed at the 
time points indicated in the Schedule of Events (Table 9.1.1). Both tests will be done at 
Baseline, Week 26, and Week 52.  
9.12.6.14 IgE Safety Assessments 
Samples for total immunoglobulin E (IgE) and drug-specific IgE testing will be drawn on 
Day 1 and in the event of a significant hypersensitivity AE, or at the discretion of the 
investigator and/or BioMarin. A significant hypersensitivity AE is defined as an event that is 
grade 3 or higher, requires temporary or permanent cessation of BMN 111, or is determined 
to be significant at the discretion of investigator and/or BioMarin (excluding reactions that 
are solely a localized injection site reaction). If a hypersensitivity AE occurs, an unscheduled 


 
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safety visit should occur no later than 48 hours of the start of the reaction, including 
inspection of the injection site and clinical laboratory tests.  
Blood (serum) samples should be collected and tested in one or more of the following 
assessments: 
•  Drug-specific IgE 
• Total IgE 
• Serum tryptase 
If feasible, a sample for drug-specific IgE should be drawn no sooner than 8 hours after the 
event start time or before the next dose. A sample for total IgE and serum tryptase should 
also be drawn within 1 hour of the start of the event when possible or during the unscheduled 
safety visit.  
A localized injection site reaction is defined as skin signs or signs restricted to one affected 
primary location, i.e., hives, wheals, or swelling or an area of erythema, redness, induration, 
pain, or itching at or near the site of injection. Management of such localized reactions 
should be determined by the investigator’s clinical judgment in consultation with the 
Sponsor’s Medical Monitor (if warranted). 
9.12.6.15 Unscheduled Safety Visits 
Unforeseen circumstances may arise in which an unscheduled visit may be needed. In such a 
case, the procedures performed at the unscheduled visit will be completed on a case-by-case 
basis. 


 
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10 
REPORTING ADVERSE EVENTS 
10.1 
Safety Parameters and Definitions 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified hematology, clinical chemistry, and urinalysis variables; 
measurement of protocol-specified vital signs; and other protocol-defined events of special 
interest that are deemed critical to the safety evaluation of the study drug. 
10.1.1 Adverse Events 
For this protocol, a reportable adverse event (AE) is any untoward medical occurrence 
(e.g., sign, symptom, illness, disease or injury) in a subject administered the study drug or 
other protocol-imposed intervention, regardless of attribution. This includes the following: 
• AEs not previously observed in the subject that emerge during the course of the 
study. 
• Pre-existing medical conditions judged by the Investigator to have worsened in 
severity or frequency or changed in character during the study. 
• Complications that occur as a result of non-drug protocol-imposed interventions 
(eg, AEs related to screening procedures, medication washout, or no-treatment 
run-in). 
An adverse drug reaction is any AE for which there is a reasonable possibility that the 
study-drug caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the study-drug and the AE. 
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series 
of terms relating to a diagnosis. 
10.1.2 Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose meets 
1 or more of the following criteria: 
• Is fatal 
• Is life threatening  
Note: Life-threatening refers to an event that places the subject at immediate risk of 
death. This definition does not include a reaction that, had it occurred in a more 
severe form, might have caused death. 
• Requires or prolongs inpatient hospitalization   
• Results in persistent or significant disability or incapacity 


 
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• Is a congenital anomaly or birth defect in the child or fetus of a subject exposed to IP 
prior to conception or during pregnancy 
• 
Is an important medical event or reaction – that, based on medical judgment, may 
jeopardize the subject or require intervention to prevent one of the above 
consequences (e.g. anaphylaxis) 
All adverse events that do not meet any of the criteria for SAEs should be regarded as 
non-serious AEs. 
10.1.3 Events of Special Interest (EOSI)  
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, 
irrespective of seriousness, severity or causality:  
• 
Fracture 
• 
Slipped Capital Femoral Epiphysis (SCFE) 
• 
Avascular necrosis or Osteonecrosis 
10.2 
Methods and Timing for Capturing and Assessing Safety Parameters 
10.2.1 Adverse Event Reporting Period 
For subjects enrolled in Cohort 1 ( ≥  24 to < 60 months old) and Cohort 2 ( ≥ 6 to   < 24 months 
old), the study AE reporting period is as follows: after informed consent but prior to initiation 
of study treatment, only SAEs associated with any protocol-imposed interventions will be 
reported.  After informed consent is obtained and the first administration of study drug, all 
non-serious AEs and SAEs reporting period begins and continues until 4 weeks following 
either the last administration of study drug or the early termination visit, whichever is longer 
(refer to Section 12.1.11). The criteria for determining, and the reporting of, SAEs is 
provided in Section 10.1.2.  For subjects enrolled in Cohort 3 (0 to <  6 months old), the 
collection period for all AEs begins after informed consent is obtained. 
10.2.2 Eliciting Adverse Events 
Investigators will seek information on AEs and SAEs and EOSI, if applicable at each subject 
contact by specific questioning and, as appropriate, by examination.  Information on all AEs 
and SAEs and EOSI, if applicable should be recorded in the subject’s medical record and on 
the AE Electronic Case Report Form (eCRF). 
10.2.3 Assessment of Seriousness, Severity, and Causality 
The Investigator or qualified designee responsible for the care of the subject will assess AEs 
for severity, relationship to study drug, and seriousness (refer to Section 10.1.2 for SAE 


 
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definitions).  These assessments should be made by a study clinician with the training and 
authority to make a diagnosis (e.g., MD/DO, physician’s assistant, nurse practitioner, or 
DDS). 
10.2.3.1 
Seriousness 
The investigator will assess if an AE should be classified as “serious” based on the 
seriousness criteria enumerated in Section 10.1.2.  Seriousness serves as a guide for defining 
regulatory reporting obligations. 
10.2.3.2 
Severity 
Severity (as in mild, moderate, or severe headache) is not equivalent to seriousness, which is 
based on subject/event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning.  The severity of each will be assessed using the 
defined categories in Table 10.2.3.2.1. 
The Investigator or qualified designee will determine the severity of each AE and SAE, and 
EOSI using the NCI CTCAE v4. Adverse events that do not have a corresponding CTCAE 
term will be assessed according to the general guidelines for grading used in the CTCAE v4 
as stated below. 
Table 10.2.3.2.1:  Adverse Event Grading (Severity) Scale 
Grade 
Description 
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
2 
Moderate: minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)a 
3 
Severe or medically significant but not immediately life-threatening: hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADLb 
4 
Life threatening or debilitating: consequences; urgent 
intervention indicated 
Grade 4 and 5 AEs 
should always be 
reported as SAEs 
5 
Death related to AE 
a Instrumental ADL refer to the following examples: preparing meals, shopping for groceries or clothes, using the 
telephone, managing money. 
b Self-care ADL refer to the following examples: bathing, dressing and undressing, feeding oneself, using the toilet, 
taking medications, not bedridden. 
 


 
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10.2.3.3 
Causality 
The Investigator will determine the relationship of an AE to the study drug and will record it 
on the source documents and AE eCRF.  To ensure consistency of causality assessments, 
Investigators should apply the guidance in Table 10.2.3.3.1. 
Table 10.2.3.3.1:  Causality Attribution Guidance 
Relationship 
Description 
Not Related 
• 
Exposure to the IP has not occurred 
OR 
• 
The administration of the IP and the occurrence of the AE are not 
reasonably related in time  
OR 
• 
The AE is considered likely to be related to an etiology other than the use 
of the IP; that is, there are no facts, evidence, or arguments to suggest a 
causal relationship to the IP. 
Related 
• 
The administration of the IP and the occurrence of the AE are reasonably 
related in time 
AND 
• 
The AE could not be explained by factors or causes other than exposure 
to the IP 
                                                  OR 
 
• 
The administration of IP and the occurrence of the AE are reasonably 
related in time  
AND 
• 
The AE is more likely explained by exposure to the IP than by other factors 
or causes. 
Factors suggestive of a causal relationship could include (but are not limited to): 
• Plausible temporal relationship 
• Absence of alternative explanations 
• Rarity of event in a given subject or disease state 
• Absence of event prior to study drug exposure 
• Consistency with study product pharmacology 
• Known relationship to underlying mechanism of study drug action 
• Similarity to adverse reactions seen with related drug products 
• Abatement of AE with discontinuation of study drug, and/or recurrence of AE with 
reintroduction of study drug 


 
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The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the Investigator’s assessment of causality for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities. 
10.3 
Procedures for Recording Adverse Events 
10.3.1 Recording Adverse Events on a eCRF 
Investigators should use precise medical terminology when recording AEs or SAEs on an 
eCRF.  Avoid colloquialisms and abbreviations. 
Record only one diagnosis, sign, or symptom per event field on the AE eCRF (e.g., nausea 
and vomiting should not be recorded in the same entry, but as 2 separate entries). 
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor to the 
original terms entered on the eCRF, using MedDRA (Medical Dictionary for Regulatory 
Activities) terminology. 
10.3.1.1 
Diagnosis versus Signs and Symptoms 
Using accepted medical terminology, enter the diagnosis (if known).  If not known, enter 
sign(s) and/or symptom(s).  If a diagnosis subsequently becomes available, then this 
diagnosis should be entered on the AE form, replacing the original entries where appropriate. 
10.3.1.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events) should be 
identified by their primary cause.  For example, if severe diarrhea is known to have resulted 
in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the eCRF.  
However, medically important events that may be linked and/or separated in time should be 
recorded as independent events on the eCRF.  For example, if severe hemorrhage leads to 
renal failure, both events should be recorded separately on the eCRF. 
10.3.1.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between subject 
evaluation time points.  Such an event should be recorded only once on the eCRF unless its 
severity increases or decreases (in which case it should be recorded again on the AE eCRF). 
A recurrent AE is one that occurs and resolves between subject evaluation time points, but 
then subsequently recurs.  All recurrences of the AE should be recorded on the AE eCRF. 


 
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10.3.1.4 
Hypotension 
If an asymptomatic drop in blood pressure meets the protocol definition of AE per clinical 
judgment of the reporter, report the event as “blood pressure decreased.”  If the drop in blood 
pressure is associated with signs or symptoms, complete the symptomatic hypotension eCRF 
and use the following guidance to report the corresponding AE eCRF: If a unifying diagnosis 
is available to explain the event of hypotension, report the diagnosis as an AE and capture 
signs and symptoms on the symptomatic hypotension eCRF page. If no other unifying 
diagnosis is available, report “hypotension” as the event and capture signs and symptoms on 
the symptomatic hypotension eCRF page.  
10.3.1.5 
Injection Site Reactions 
If an injection site reaction is associated with a single sign or symptom, report the event on 
AE eCRF page (e.g., redness at injection site, AE is injection site redness). If the injection 
site reaction is associated with multiple signs or symptoms, report injection site reaction as 
the adverse event on the AE page, and individual signs and symptoms will be reported on the 
ISR eCRF page (e.g., if the subject experiences redness and induration, report “Injection site 
reaction” on the AE page, and in the corresponding Injection eCRF page, report erythema 
and induration).  If the injection site reaction appears after 24 hours, add “delayed” to the 
term used to describe the event. 
10.3.1.6 
Abnormal Laboratory Values 
Laboratory test results will be recorded on the laboratory results pages of the eCRF, or 
appear on electronically produced laboratory reports submitted directly from the central 
laboratory, if applicable. 
Any laboratory result abnormality fulfilling the criteria for a SAE should be reported as such, 
in addition to being recorded as an AE in the eCRF. 
A clinical laboratory abnormality should be documented as AE if it is not otherwise refuted 
by a repeat test to confirm the abnormality and any one or more of the following conditions 
is met: 
• Accompanied by clinical symptoms 
• Leading to a change in study medication (e.g. dose modification, interruption or 
permanent discontinuation)  
• Requiring a change in concomitant therapy (e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment). 


 
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• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management (e.g., change of dose, 
discontinuation of study drug, more frequent follow-up assessments, further 
diagnostic investigation, etc.) 
This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria. 
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 
explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported.  
10.3.1.7 
Pre-existing Conditions 
A pre-existing condition is one that is present at the start of the study.  Such conditions 
should be recorded as medical history on the appropriate eCRF. 
A pre-existing condition should be recorded as an AE or SAE during the study only if the 
frequency, intensity, or character of the condition worsens during the study period.  It is 
important to convey the concept that a pre-existing condition has changed by including 
applicable language in the verbatim description of the event (e.g., more frequent headaches). 
10.3.1.8 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition (refer to Section 10.3.1.7).  During the study, any new clinically significant 
findings and/or abnormalities discovered on physical examination that meet the definition of 
an AE (or an SAE) must be recorded and document as an AE or SAE on the AE eCRF. 
10.3.1.9 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol (refer to 
Section 10.1.2). 
There are some hospitalization scenarios that do not require reporting as an SAE when there 
is no occurrence of an AE.  These scenarios include planned hospitalizations or prolonged 
hospitalizations to: 
• Perform a protocol-mandated efficacy measurement 


 
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• Undergo a diagnostic procedure 
• Elective surgical procedure for a pre-existing medical condition that has not changed 
• Receive scheduled therapy (study drug or otherwise) for the study indication 
10.3.1.10 Deaths 
All deaths that occur during the AE reporting period (refer to Section 10.2.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the Sponsor as an 
SAE. 
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF.  If the cause of death 
is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the eCRF.  If the death is attributed to progression of the 
disease or condition being studies, record “-” as the SAE term on the eCRF. 
10.4 
Reporting Requirements 
The Sponsor is responsible for identifying, preparing, and reporting all suspected unexpected 
serious adverse reactions (SUSARs) to the relevant competent authorities, ethics committees, 
and investigators in accordance with requirements identified in the Clinical Trials 
Regulations. 
10.4.1 Expedited Reporting Requirements 
All SAEs and EOSI, if applicable that occur during the course of the AE Reporting Period 
(refer to Section 10.2.1), whether or not considered related to study drug, must be reported by 
entering the information in the AE eCRF and submitting to BPV within 24 hours of the site 
becoming aware of the event.  Each SAE must also be reported on the appropriate eCRF.  
Investigators should not wait to collect information that fully documents the event before 
notifying BPV of an SAE.  BioMarin may be required to report certain SAEs to regulatory 
authorities within 7 calendar days of being notified about the event; therefore, it is important 
that Investigators submit any information requested by BioMarin as soon as it becomes 
available. 
If the electronic data capture (EDC) is unavailable, all SAEs should be reported to BPV by 
completing the SAE Report Form and faxing or emailing the completed form to BPV within 
24 hours of the site becoming aware of the event. Once the EDC is available, the information 
should be entered in the AE eCRF.  


 
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The reporting period for SAEs begins after informed consent is obtained and continues until 
4 weeks following either the last administration of study drug or study 
discontinuation/termination, whichever is longer.  
10.4.2 IRB Reporting Requirements 
Reporting of SAEs to the IRB will be done in compliance with the standard operating 
procedures and policies of the IRB and with applicable regulatory requirements. Adequate 
documentation must be obtained by BioMarin showing that the IRB was properly and 
promptly notified as required. 
10.5 
Follow-up of Subjects after Adverse Events 
The Investigator should follow all unresolved AEs/SAEs until the events are resolved or have 
stabilized, the subject is lost to follow-up, or it has been determined that the study treatment 
or participation is not the cause of the AE/SAE.  Resolution of AEs and SAEs (with dates) 
should be documented on the AE eCRF and in the subject’s medical record to facilitate 
source data verification. 
For some SAEs, the Sponsor may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details (eg, hospital discharge summary, consultant 
report, or autopsy report) deemed necessary to appropriately evaluate the SAE report. 
10.6 
Post-Study Adverse Events 
At the last scheduled visit, the Investigator should instruct each subject to report, to the 
Investigator and/or to BPV directly, any subsequent SAEs that the subject’s personal 
physician(s) believes might be related to prior study treatment. 
The Investigator should notify the study Sponsor of any death or SAE occurring at any time 
after a subject has discontinued or terminated study participation, if the Investigator believes 
that the death or SAE may have been related to prior study treatment. The Sponsor should 
also be notified if the Investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a subject who participated in 
this study.  
10.7 
Urgent Safety Measures 
The regulations governing clinical trials state that the sponsor and Investigator are required to 
take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the EU Clinical Trial 
Directive 2001/20/EC, “…in the light of the circumstances, notably the occurrence of any 


 
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new event relating to the conduct of the trial or the development of the investigational 
medicinal product where that new event is likely to affect the safety of the subjects, the 
sponsor and the Investigator shall take appropriate urgent safety measures to protect the 
subjects against any immediate hazard. The sponsor shall forthwith inform the competent 
authorities of those new events and the measures taken and shall ensure that the 
IRB/EC/REB is notified at the same time.”  
The Sponsor is responsible for identifying, preparing and reporting all SUSARs to the 
relevant competent authorities, ethics committees and investigators in accordance with the 
requirements identified in the Clinical Trials Regulations. 
The reporting period for these events which may require the implementation of urgent safety 
measures is the period from the time of signing of the ICF through the completion of the last 
study visit or at the Early Termination Visit (ETV). Investigators are required to report any 
events which may require the implementation of urgent safety measures to BioMarin within 
24 hours. 
Examples of situations that may require urgent safety measures include discovery of the 
following: 
• 
Immediate need to revise the IP administration (eg, modified dose amount or frequency 
not defined in protocol) 
• 
Lack of study scientific value, or detrimental study conduct or management 
• 
Discovery that the quality or safety of the IP does not meet established safety 
requirements 


 
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10.8 
BioMarin Pharmacovigilance Contact Information 
Contact information for BioMarin Pharmacovigilance is as follows: 
BioMarin Pharmaceutical Inc. 
Address 
105 Digital Drive 
 
 
Novato, CA 94949 
Phone:  
 
Fax: 
 
 
E-mail: 
drugsafety@bmrn.com 
The Investigator is encouraged to discuss with the medical monitor any AEs for which the 
issue of seriousness is unclear or questioned. Contact information for the medical monitor is 
as follows: 
Name:  
, MD 
 
 
 
 
 
BioMarin Pharmaceutical Inc. 
Address: 
105 Digital Drive 
 
 
Novato, CA 94949L 
Phone:  
 
 
Fax: 
 
  
E-mail: 
 
 
PI
PI
PI
PI
PI
PI
PI


 
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11 
APPROPRIATENESS OF MEASUREMENTS 
The parameters to be evaluated in this study reflect the combined experience in the clinical 
study 111-202 and reflect the need to further define the efficacy and safety profile of 
BMN 111 in the context of ACH, a complex skeletal dysplasia disorder with multiple clinical 
manifestations. 
The efficacy parameters to be evaluated in this study reflect the sponsor’s experience in the 
clinical study 111-202 and of previous studies of approved growth products (Kemp, 2009; 
Bright, 2009).  Evaluation of the parameters proposed in this study will document the effect 
of BMN 111 treatment on AGV in young children with ACH and are relevant to assessing 
the medical complications of ACH in this patient population.   
The PK assessments in this study are generally recognized as reliable, accurate, and relevant. 
Bone-related biomarkers and other biochemical markers of the pharmacological activity of 
BMN 111 in the blood or urine are secondary assessments. Genomic biomarkers are 
exploratory assessments. 


 
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12 
STUDY PROCEDURES 
An ICF must be signed and dated by subject’s legally authorized, the investigator or 
designee, and witness (if required) before any study-related procedures are performed. 
12.1 
Treatment Visit(s) 
12.1.1 Screening/Baseline Day -30 to Day -1  
• Medical history 
• Parental height 
• Diagnostic genetic testing to confirm achondroplasia (if needed) 
• Physical examination 
• Weight 
• Vital signs 
• Electrocardiogram 
• Echocardiogram 
• Anthropometric measurements 
• Clinical laboratory assessments (hematology, chemistry, urinalysis) 
• Thyroid function tests 
• Vitamin D, 25-hydroxy test 
• Salivary cortisol 
• Serum prolactin 
• Genomic blood biomarkers (optional) 
• Bone metabolism blood biomarkers  
• MRI brain/skull 
• Sleep study 
• Clinical outcome assessment: Bayley-III  
• Clinical outcome assessment: Wee-FIM  
• Clinical outcome assessment: ITQOL 
• Safety assessment: CBCL 
• DXA 
• AP and lateral X-rays of spine 


 
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• AP X-rays of lower extremities  
• Clinical photographs (optional)  
• Concomitant medications 
12.1.2 Day 1 and Week 13 (±7d) 
• Physical examination 
• Weight 
• Vital signs 
• Electrocardiogram 
• Anthropometric measurements 
• Plasma pharmacokinetics and cGMP assessments 
• Anti-BMN 111 immunogenicity 
• Bone metabolism urine biomarkers 
• BMN 111 pharmacodynamic urine biomarkers 
• Urine chemistry 
• Capture concomitant procedures/interventions/surgeries 
• BMN 111 or placebo administration 
• BMN 111 or placebo accountability  
• Adverse events 
• Concomitant medications 
• Phone call or home health visit 
12.1.3 Days 2 and 3 
• Physical examination 
• Weight 
• Vital signs 
• Bone metabolism urine biomarkers 
• BMN 111 pharmacodynamic urine biomarkers 
• Urine chemistry 
• Capture concomitant procedures/interventions/surgeries 
• BMN 111 or placebo administration 


 
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• BMN 111 or placebo accountability  
• Adverse events 
• Concomitant medications 
• Phone call or home health visit 
12.1.4 Day 8 (±1d) and Week 20 (±7d) 
• Physical examination 
• Weight 
• Vital signs 
• Electrocardiogram 
• Clinical laboratory assessments (hematology, chemistry, urinalysis) 
• Bone metabolism blood biomarkers 
• Capture concomitant procedures/interventions/surgeries 
• BMN 111 or placebo administration 
• BMN 111 or placebo accountability  
• Adverse events 
• Concomitant medications 
• Phone call or home health visit 
12.1.5 Week 3 (±7d) 
• Physical examination 
• Weight 
• Vital signs 
• Clinical laboratory assessments (hematology, chemistry, urinalysis) 
• Anti-BMN 111 immunogenicity 
• Bone metabolism urine biomarkers 
• BMN 111 pharmacodynamic urine biomarkers 
• Urine chemistry 
• Capture concomitant procedures/interventions/surgeries 
• BMN 111 or placebo administration 
• BMN 111 or placebo accountability  


 
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• Adverse events 
• Concomitant medications 
• Phone call or home health visit 
12.1.6 Week 6 (±7d) 
• Physical examination 
• Weight 
• Vital signs 
• Electrocardiogram 
• Anthropometric measurements 
• Clinical laboratory assessments (hematology, chemistry, urinalysis) 
• Bone metabolism blood biomarkers 
• Capture concomitant procedures/interventions/surgeries 
• BMN 111 or placebo administration 
• BMN 111 or placebo accountability  
• Adverse events 
• Concomitant medications 
• Phone call or home health visit 
12.1.7 Week 26 (±7d) 
• Physical examination 
• Weight 
• Vital signs 
• Electrocardiogram 
• Anthropometric measurements 
• Salivary cortisol 
• Serum prolactin  
• Plasma pharmacokinetics and cGMP assessments 
• Anti-BMN 111 immunogenicity 
• Bone metabolism urine biomarkers 
• BMN 111 pharmacodynamic biomarkers 


 
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• Urine chemistry 
• Hip monitoring 
• Clinical outcome assessment: Bayley-III  
• Clinical outcome assessment: Wee-FIM  
• Clinical outcome assessment: ITQOL 
• Safety assessment: CBCL 
• Capture concomitant procedures/interventions/surgeries 
• BMN 111 or placebo administration 
• BMN 111 or placebo accountability  
• Adverse events 
• Concomitant medications 
• Phone call or home health visit 
12.1.8 Week 39 (±7d) 
• Physical examination 
• Weight 
• Vital signs 
• Electrocardiogram 
• Anthropometric measurements 
• Clinical laboratory assessments (hematology, chemistry, urinalysis) 
• Plasma pharmacokinetics and cGMP assessments 
• Bone metabolism blood biomarkers 
• Bone metabolism urine biomarkers 
• BMN 111 pharmacodynamic urine biomarkers 
• Urine chemistry 
• Capture concomitant procedures/interventions/surgeries 
• BMN 111 or placebo administration 
• BMN 111 or placebo accountability  
• Adverse events 
• Concomitant medications 


 
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• Phone call or home health visit 
12.1.9 Week 52 (±7d) 
• Physical examination 
• Weight 
• Vital signs 
• Electrocardiogram 
• Anthropometric measurements 
• Clinical laboratory assessments (hematology, chemistry, urinalysis) 
• Thyroid function tests 
• Vitamin D, 25-hydroxy test 
• Salivary cortisol 
• Serum prolactin  
• Plasma pharmacokinetics and cGMP assessments 
• Anti-BMN 111 immunogenicity 
• Bone metabolism urine biomarkers 
• BMN 111 pharmacodynamic urine biomarkers 
• Urine chemistry 
• Hip monitoring 
• MRI brain/skull 
• Sleep study 
• Clinical outcome assessment: Bayley-III  
• Clinical outcome assessment: Wee-FIM  
• Clinical outcome assessment: ITQOL 
• Safety assessment: CBCL 
• DXA 
• AP and lateral X-rays of spine 
• AP X-rays of lower extremities  
• Clinical photographs (optional)  
• Capture concomitant procedures/interventions/surgeries 


 
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• BMN 111 or placebo administration 
• BMN 111 or placebo accountability  
• Adverse events 
• Concomitant medications 
• Phone call or home health visit 
12.1.10  Week 56 Safety Follow-up ( + 7d) 
• Physical examination 
• Vital signs 
• Electrocardiogram 
• Echocardiogram 
• Capture concomitant procedures/interventions/surgeries 
• Adverse events 
• Concomitant medications 
12.1.11  Early Termination Visit 
• Physical examination 
• Weight 
• Vital signs 
• Electrocardiogram 
• Echocardiogram (obtained at the early termination visit only if the previous 
assessment was done more than 3 months prior to early termination) 
• Anthropometric measurements 
• Clinical laboratory assessments (hematology, chemistry, urinalysis) 
• Salivary cortisol 
• Serum prolactin  
• Anti-BMN 111 immunogenicity 
• Bone metabolism blood biomarkers 
• Bone metabolism urine biomarkers 
• BMN 111 pharmacodynamic urine biomarkers 
• Urine chemistry 


 
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• Hip monitoring 
• MRI brain/skull (obtained at the early termination visit only if the previous 
assessment was done more than 3 months prior to early termination) 
• Sleep study (obtained at the early termination visit only if the previous assessment 
was done more than 3 months prior to early termination) 
• Clinical outcome assessment: Bayley-III  
• Clinical outcome assessment: Wee-FIM  
• Clinical outcome assessment: ITQOL 
• Safety outcome assessment: CBCL 
• DXA 
• AP and lateral X-rays of spine (obtained at the early termination visit only if the 
previous assessment was done more than 6 months prior to early termination) 
• AP X-rays of lower extremities (obtained at the early termination visit only if the 
previous assessment was done more than 6 months prior to early termination) 
• Clinical photographs (optional) 
• Capture concomitant procedures/interventions/surgeries  
• BMN 111 or placebo accountability  
• Adverse events 
• Concomitant medications 
12.2 
Observational Period for Cohort 3 (Infants between birth and  < 3 months old 
[0 days to   < 13 weeks]) 
12.2.1 Screening Visit 
• Medical history, including growth history and ACH-related history 
• Concomitant medications 
• Physical examination 
• Vital signs 
• Vitamin D, 25-hydroxy 
• Alkaline phosphatase 
• Bone metabolism blood biomarkers 
• Bone metabolism urine biomarkers 


 
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• Adverse events 
12.2.2 Day 1 (Month 0) 
• Concomitant medications 
• Vital signs 
• Anthropometric measurements 
• Genomic biomarkers (optional) 
• Weight 
• Body mass index (calculated) 
• Clinical outcome assessment: Bayley-III  
• Clinical outcome assessment: ITQOL 
• Capture concomitant procedures/interventions/surgeries 
• Adverse events 
12.2.3 3 Months (± 10 days) 
• Concomitant medications 
• Vital signs 
• Anthropometric measurements 
• Vitamin D, 25-hydroxy 
• Alkaline phosphatase 
• Bone metabolism blood biomarkers 
• Bone metabolism urine biomarkers 
• Weight 
• Body mass index (calculated) 
• Capture concomitant procedures/interventions/surgeries 
• Adverse events 


 
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13 
DATA QUALITY ASSURANCE 
BioMarin personnel or designees will visit the study site prior to initiation of the study to 
review with the site personnel information about the IP, protocol and other regulatory 
document requirements, any applicable randomization procedures, source document 
requirements, eCRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs.  
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on eCRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records.  
Sites will enter study data into eCRFs into the study EDC system.  Data Quality Control will 
be performed by BioMarin Clinical Data Management or designee through implementation 
of quality control checks specified in the study data management plan and edit check 
specifications. Additional subject-reported study data may be entered into the study EDC 
system via electronic diary. 


 
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14 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE  
14.1 
Statistical and Analytical Plans 
The statistical analysis plan (SAP) will provide additional details on the planned statistical 
analysis. Unless otherwise stated, all analyses will be performed using SAS v. 9.4. 
14.1.1 Interim Analyses 
An interim analysis will be carried out to support NDA/MAA filing. The study team, 
subjects, and investigators will have no access to the individual subject treatment allocation, 
and blinded pooled safety outputs will be provided for the randomized subjects. 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data 
Because the completeness of the data affects the integrity and accuracy of the final study 
analysis, every effort will be made to ensure complete, accurate and timely data collection 
and, therefore, avoid missing data. In addition, a subject who prematurely discontinues study 
drug should be asked if they are willing to continue to participate in the study assessments for 
remaining duration of the study, as long as in the judgment of the investigator such continued 
participation would not detrimentally affect the health, safety, or welfare of the subject. 
No missing data will be imputed for any analysis, except for unless otherwise specified for 
the efficacy analyses or for the missing dates for AEs and concomitant medications. Missing 
dates or partially missing dates will be imputed conservatively to ensure that an AE is 
considered treatment emergent and has the longest possible duration, if the partial 
information available indicates that the AE is likely treatment emergent.  
Additional details regarding the handling of missing data will be provided in the SAP. 
14.2 
Safety Analysis 
The safety analysis will be performed on safety population as defined in Section 14.7.2 and 
will be considered descriptive.  
All AEs will be coded using the most current version of MedDRA will be used by the 
Sponsor to assign system organ class and preferred term classification to events and diseases, 
based on the original terms entered on the CRF. 
All AEs will be coded using MedDRA. The incidence of AEs will be summarized by system 
organ class, preferred term, relationship to study treatment (as assessed by investigator), and 
severity. All AEs, including SAEs and AEs that lead to permanent discontinuation from the 
study and from the study treatment, will be listed. Hypersensitivity reactions and 


 
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symptomatic hypotension are of interest, and the percentage of subjects who report these AEs 
will be presented. Hypersensitivity reactions will be defined in the SAP. 
Clinical laboratory data will be summarized by the type of laboratory test. For each clinical 
laboratory test, descriptive statistics will be provided on baseline as well as all subsequent 
visits. 
All other safety measures including laboratory tests, vital signs, ECG, echocardiogram, hip 
clinical assessment, and concomitant medication data will also be summarized descriptively. 
Data summaries will be presented by treatment group (when applicable) for each cohort and 
overall. All safety results will be listed. 
14.3 
Efficacy Analysis 
Efficacy analysis will be performed on the efficacy population as defined in Section 14.7.1. 
Efficacy endpoints include length/height AGV and length/height standard score (Z-score) at 
Week 52.  
For a given interval [Date1, Date2], the AGV is defined as follows: 
AGV = Length/standing height at Day 2 − Length/standing height at Day 1
Interval Length (Days)
 × 365.25 
 
where the interval length in days is calculated as Date2 – Date1. AGV will be calculated for 
the following visits/intervals: 
• Baseline: [Date of last length/height measurement in study 901 at least 6 months prior 
to Day 1 in study 206, Date of Day 1] 
• Week 13: [Date of Day 1, Date of Week 13] 
• Week 26: [Date of Day 1, Date of Week 26] 
• Week 39: [Date of Day 1, Date of Week 39] 
• Week 52 (12-month): [Date of Day 1, Date of Week 52] 
The baseline of the AGV is established in the natural history study of Study111-901, based 
on the standing height measurements in the last 6 months prior to enrollment to Study 
111-206. AGV will be summarized using descriptive statistics (mean, SD, median, minimum, 
and maximum). Results will be summarized by treatment group and cohort. 


 
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The measurement of length/standing height will be converted to age-and sex-appropriate 
standard score (SDS), also referred to as Z-score, by comparison with normal reference 
standards (not ACH). The Z-score will be summarized similarly to growth velocity. 
Comparisons between treatment groups by cohort on these variables will be carried out 
where appropriate. Statistical comparisons will be considered descriptive. Additional details 
regarding efficacy analysis will be provided in the SAP. 
14.4 
Pharmacokinetic Analyses  
Subjects randomized to receive BMN 111 or placebo will undergo pharmacokinetic testing. 
For subjects randomized to BMN 111, PK parameters generated over the course of the study 
will be evaluated and summarized with descriptive statistical measures (mean, standard 
deviation, CV%, min, median and max). Correlative analyses of some of the PK parameters 
with efficacy, safety and immunogenicity measures may be conducted.  
14.5 
Immunogenicity Analysis 
Immunogenicity will be summarized as change from baseline as well as by study time point 
in subjects randomized to receive BMN 111 or placebo.  Results will be summarized as 
incidence and titer for all cohorts. Additionally, immunogenicity may be assessed for 
correlations with measures of safety, PK, and efficacy. 
14.6 
Determination of Sample Size 
Approximately 70 subjects age 0 to < 60 months at study entry will participate in this study. 
No formal sample size calculations were performed. The number of subjects is considered 
appropriate to evaluate the safety and efficacy of BMN 111 in the target population.  
14.7 
Analysis Populations 
14.7.1 Efficacy Population 
All randomized subjects who receive at least one dose of double-blinded BMN 111 or 
placebo in this study. 
14.7.2 Safety Population   
All subjects who received at least one dose of double-blinded BMN 111 or placebo in this 
study. 


 
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15 
DATA MONITORING COMMITTEE 
In addition to safety and PK monitoring by BioMarin personnel, an independent DMC will 
act as an advisory body to BioMarin and will monitor the safety and PK of subjects in the 
study. After the sentinel subjects complete 12 weeks of dosing, a DMC review will occur to 
evaluate all available safety and PK data.  Upon approval by the DMC, the next younger 
cohort will be opened and the 3 sentinel subjects will be enrolled. 
The DMC will make recommendations for stopping or continuing the study on an individual 
subject level and/or on a cohort level per the pre-specified stopping criteria. Based on criteria 
outlined in the protocol, the DMC may also make endorsements for dose adjustments if 
needed.  
Please see DMC Charter for further details. 
 


 
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16 
COSTS, COMPENSATION, AND SUBJECT INJURY 
There will be no charge to study subjects to be in this study. BioMarin will pay all costs of 
tests, procedures, and treatments that are part of this study. In addition, after IRB/IEC/REB 
approval, BioMarin may reimburse the reasonable cost of travel for study-related visits in 
accordance with BioMarin’s study-specific travel and reimbursement policy. BioMarin will 
not pay for any hospitalizations, tests, or treatments for medical problems of any sort related 
solely to the study subject’s disease. Costs associated with such hospitalizations, tests, and 
treatments should be billed and collected in the way that such costs are usually billed and 
collected outside the study. 
The Investigator should contact BioMarin immediately upon notification that a study subject 
has been injured by the study drug or by procedures performed as part of the study. 
Any subject who experiences a study-related injury should be instructed by the Investigator 
to seek immediate medical treatment at a pre-specified medical institution if possible, or at 
the closest medical treatment facility if necessary. The subject should be given the name of a 
person to contact to seek further information about, and assistance with, treatment for 
study-related injuries. The treating physician should bill the subject’s health insurance 
company or other third party payer for the cost of this medical treatment. If the cost of the 
medical treatment is not covered by health insurance or another third party that usually pays 
these costs, then either BioMarin or the institution may pay for reasonable and necessary 
medical services to treat the injuries caused by the study drug or study procedures. In some 
jurisdictions, BioMarin is obligated by law to pay for study-related injuries without prior 
recourse to third party payer billing and/or regardless of fault. If this is the case, BioMarin 
will comply with the law. 


 
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17 
CASE REPORT FORMS AND SOURCE DOCUMENTS 
Electronic case report forms will be provided for each subject. The Investigator must review 
and electronically sign the completed eCRF casebook to verify its accuracy. 
eCRFs must be completed using a validated web-based application. Study site personnel will 
be trained on the application and will enter the clinical data from source documentation, 
except in instances when electronic subject-reported data is transmitted directly into EDC, as 
referenced in the study specific vendor management plan. Unless explicitly allowed in the 
eCRF instructions, blank data fields are not acceptable.  
In the event of an entry error, or if new information becomes available, the value will be 
corrected by deselecting the erroneous response and then selecting or entering the factual 
response. In compliance with 21 CFR Part 11, the system will require the personnel making 
the correction to enter a reason for changing the value. The documented audit trail will 
include the reason for the change, the original value, the new value, the time of the correction 
and the identity of the operator. 
BioMarin’s policy is that study data on the eCRFs must be verifiable to the source data, 
which necessitates access to all original recordings, laboratory reports, and subject records. 
In addition, all source data should be attributable (signed and dated). The Investigator must 
therefore agree to allow direct access to all source data. Subjects (or their legally authorized 
representative) must also allow access to their medical records, and subjects will be informed 
of this and will confirm their agreement when giving informed consent. If direct source 
document verification of study data by the site monitor is prohibited by institutional policy or 
local law, then the Investigator must make available facilities and/or personnel to allow 
GCP-compliant source verification to occur. Examples of such methods include certified 
copies of records which have study data visible but sensitive information redacted, or other 
GCP-compliant means agreed between the Investigator and the Sponsor. 
A CRA designated by BioMarin will compare the eCRFs with the original source documents 
at the study site and evaluate them for completeness and accuracy before designating them as 
“Source Data Verified” (SDV). Electronic Subject-reported data transferred directly into 
EDC will not be SDV’d or queried. If an error is discovered at any time or a clarification is 
needed, the CRA, or designee, will create an electronic query on the associated field. Site 
personnel will then answer the query by either correcting the data or responding to the query. 
The CRA will then review the response and determine either to close the query or re–query 
the site if the response does not fully address the question. This process is repeated until all 
open queries have been answered and closed.  


 
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Before a subject’s eCRF casebook can be locked, data fields must be source data verified and 
all queries closed. Refer to the Study Monitoring Plan for details on which fields must be 
source data verified.  The Investigator will then electronically sign the casebook, specifying 
that the information on the eCRFs is accurate and complete. The Data Manager, or designee, 
will then set the status of the forms, visits, and the entire casebook to Locked. Upon 
completion of the CSR, an electronic copy of each site’s casebooks will be copied to a 
compact disk (CD) and sent to each site for retention with other study documents. 


 
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18 
STUDY MONITORING AND AUDITING 
Qualified individuals designated by BioMarin will monitor all aspects of the study according 
to GCP and standard operating procedures for compliance with applicable government 
regulations. The Investigator agrees to allow these monitors direct access to the clinical 
supplies, dispensing, and storage areas and to the clinical files, including original medical 
records, of the study subjects, and, if requested, agrees to assist the monitors. The 
Investigator and staff are responsible for being present or available for consultation during 
routinely scheduled site visits conducted by BioMarin or its designees. 
Members of BioMarin’s GCP Compliance Department or designees may conduct an audit of 
a clinical site at any time before, during, or after completion of the study. The Investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Representatives of the FDA or other Regulatory Agencies may also conduct an audit of the 
study. If informed of such an inspection, the Investigator should notify BioMarin 
immediately. The Investigator will ensure that the auditors have access to the clinical 
supplies, study site facilities, original source documentation, and all study files. 


 
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RETENTION OF RECORDS  
The Investigator must retain all study records required by BioMarin and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a BioMarin 
representative before disposal of any study records, and must notify BioMarin of any change 
in the location, disposition or custody of the study files. The Investigator /institution must 
take measures to prevent accidental or premature destruction of essential documents, that is, 
documents that individually and collectively permit evaluation of the conduct of a study and 
the quality of the data produced, including paper copies of study records (e.g., subject charts) 
as well as any original source documents that are electronic as required by applicable 
regulatory requirements.  
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the U.S. or an ICH region or (2) at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP. The Investigator /institution 
should retain subject identifiers for at least 15 years after the completion or discontinuation 
of the study. Subject files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution or private practice, but not less than 15 years. 
These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirements or by a BioMarin agreement. BioMarin must be notified 
and will assist with retention should Investigator /institution be unable to continue 
maintenance of subject files for the full 15 years. It is the responsibility of BioMarin to 
inform the Investigator/institution as to when these documents no longer need to be retained. 


 
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USE OF INFORMATION AND PUBLICATION 
BioMarin recognizes the importance of communicating medical study data and therefore 
encourages the publication of these data in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, manuscripts, 
and presentations based on the data from this study will be described in the Clinical Trial 
Agreement between BioMarin and the Investigator/Institution. Consideration for authorship 
of all publications will be based on compliance with the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals (“Uniform Requirements”) of the 
International Committee of Medical Journal Editors (ICMJE) 
(http://www.icmje.org/about-icmje/faqs/icmje-recommendations/) and good publication 
practices (GPP). 


 
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21 
REFERENCES 
Bartels, CF, Bukulmez, H, Padayatti, P, Rhee, DK et. al. Mutations in the transmembrane natriuretic 
peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. 
Am J Hum Genet 75[1], 27-34. 2004. 
Bayley, N. Bayley Scales of Infant Development, Third Ed. Psychological Corporation, New York, 
NY. 2006. 
Bocciardi, R, Giorda, R, Buttgereit, J, Gimelli, S. et al. Overexpression of the C-type natriuretic 
peptide (CNP) is associated with overgrowth and bone anomalies in an individual with balanced 
t(2;7) translocation. Hum Mutat 28[7], 724-731. 2007. 
Bright, GM, Mendoza, JR, Rosenfeld, RG. Recombinant human insulin-like growth factor-1 
treatment: ready for primetime. Endocrinol Metab Clin North Am. 38[3]:625-38. 2009. 
Chusho, H, Tamura, N, Ogawa, Y, Yasoda, A et. al. Dwarfism and early death in mice lacking C-type 
natriuretic peptide. Proc Natl Acad Sci U S A 98[7], 4016-4021. 2001. 
Foldynova-Trantirkova, S, Wilcox, WR, Krejci, P. Sixteen years and counting: the current 
understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias. Hum 
Mutat 33[1], 29-41. 2012. 
National Institutes of Health. Genetics Home Reference Achondroplasia 2012.  Available at: 
https://ghr.nlm.nih.gov/condition/achondroplasia. 
Horton, WA, Hall, JG, Hecht, JT. Achondroplasia. Lancet 370[9582], 162-172. 2007. 
Ireland PJ, Johnson S, Donaghey S, Johnston L, McGill J, Zankl A, Ware RS, Pacey V, Ault J, 
Savarirayan R, Sillence D, Thompson E, Townshend S. Developmental milestones in infants and 
young Australasian children with achondroplasia. J Dev Behav Pediatr. Jan;31(1):41-7. 2010. 
Ireland PJ, McGill J, Zankl A, Ware RS, Pacey V, Ault J, Savarirayan R, Sillence D, Thompson EM, 
Townshend S, Johnston  LM. Functional performance in young Australian children with 
achondroplasia. Dev Med Child Neurol. Oct;53(10):944-50. 2011. 
Ireland P, Johnston LM. Measures of self-care independence for children with osteochondrodysplasia: 
a clinimetric review. Phys Occup Ther Pediatr. 32(1):80-96. 2012. 
Kemp, SF. Insulin-like growth factor-I deficiency in children with growth hormone insensitivity: 
current and future treatment options. BioDrugs 23[3]:155-63. 2009. 
Krejci, P, Masri, B, Fontaine, V, Mekikian, PB et. al. Interaction of fibroblast growth factor and C-
natriuretic peptide signaling in regulation of chondrocyte proliferation and extracellular matrix 
homeostasis. J Cell Sci 118[Pt 21], 5089-5100. 2005. 
Little, R. J. A. (1993), “Pattern-Mixture Models for Multivariate Incomplete Data,” Journal of the 
American Statistical Association, 88, 125–134. 


 
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Long, S, Wendt, D, Bell, S. A novel method for the large-scale production of PG-CNP37, a C-type 
natriuretic peptide analogue. J Biotechnol 162[2], 196-201. 2012. 
Lorget, F, Kaci, N, Peng, J, Benoist-Lasselin, C et. al. Evaluation of the therapeutic potential of a 
CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet 91[6], 1108-
1114. 2012. 
Mukherjee D, Pressman BD, Krakow D, Rimoin DL, Danielpour M. Dynamic cervicomedullary cord 
compression and alterations in cerebrospinal fluid dynamics in children with achondroplasia: review 
of an 11-year surgical case series. J Neurosurg Pediatr.  Sep;14(3):238-44. 2014. 
Molenberghs, G. and Kenward, M. G. (2007), Missing Data in Clinical Studies, New York: John 
Wiley & Sons. 
Pauli RM, Scott CI, Wassman ER Jr, Gilbert EF, Leavitt LA, Ver Hoeve J, Hall JG, Partington MW, 
Jones KL, Sommer A, et al. Apnea and sudden unexpected death in infants with achondroplasia. J 
Pediatr. 1984 Mar;104(3):342-8. 
Pejchalova, K, Krejci, P, Wilcox, WR. C-natriuretic peptide: an important regulator of cartilage. Mol 
Genet Metab 92[3], 210-215. 2007. 
Shirley, ED, Ain, MC. Achondroplasia: manifestations and treatment. J Am Acad Orthop Surg 17[4], 
231-241. 2009. 
Waters, KA, Everett, F, Sillence, D, Fagan, E et. al. Breathing abnormalities in sleep in 
achondroplasia. Arch Dis Child 69[2], 191-196. 1993. 
Wendt, DJ, Dvorak-Ewell, M, Bullens, S, Lorget, F et. al. Neutral endopeptidase-resistant C-type 
natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth 
factor receptor 3-related dwarfism. J Pharmacol Exp Ther 353[1], 132-149. 2015. 
White KK, Parnell SE, Kifle Y, Blackledge M, Bompadre V. Is there a correlation between sleep 
disordered breathing and foramen magnum stenosis in children with achondroplasia? Am J Med 
Genet A. Jan;170A(1):32-41. 2016. 
 Wynn, J, King, TM, Gambello, MJ, Waller, DK et. al. Mortality in achondroplasia study: a 42-year 
follow-up. Am J Med Genet A 143A[21], 2502-2511. 2007. 
Yasoda, A, Kitamura, H, Fujii, T, Kondo, E et. al. Systemic administration of C-type natriuretic 
peptide as a novel therapeutic strategy for skeletal dysplasias. Endocrinology . 2009. 
Yasoda, A, Komatsu, Y, Chusho, H, Miyazawa, T et. al. Overexpression of CNP in chondrocytes 
rescues achondroplasia through a MAPK-dependent pathway. Nat Med 10[1], 80-86. 2004. 


 
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INVESTIGATOR RESPONSIBILITIES 
22.1 
Conduct of Study and Protection of Human Subjects  
In accordance with FDA Form 1572 and/or principles of ICH E6 GCP, the Investigator will 
ensure that: 
• He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of subjects. 
• He or she will personally conduct or supervise the study. 
• He or she will inform any potential subjects, or any persons used as controls, that the 
drugs are being used for investigational purposes.  He or she will ensure that the 
requirements relating to obtaining informed consent in 21 CFR Part 50 and/or ICH E6 
Sections 2.9 and 4.8 are met, as well as IRB/IEC review and approval requirements in 
21 CFR Part 56 and/or ICH E6 GCP Section 2.6.  
• He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with 21 CFR 312.64 and/or ICH E6 GCP Section 
4.11. 
• He or she has read and understands the information in the Investigator’s Brochure, 
including potential risks and side effects of the drug. 
• His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments 
• He or she will ensure that adequate and accurate records are in accordance with 
21 CFR 312.62 and/or ICH E6 Section 4.9, and will make those records available for 
inspection in accordance with 21 CFR 312.68 and/or ICH Section 4.9.7. 
• He or she will ensure that the IRB/IEC/REB complies with the requirements of 
21 CFR Part 56, ICH Section 3.0 and other applicable regulations, and conducts 
initial and ongoing reviews and approvals of the study. He or she will also ensure that 
any change in research activity and all problems involving risks to human subjects or 
others are reported to the IRB/IEC/REB. Additionally, he or she will not make any 
changes in the research without IRB/IEC/REB approval, except where necessary to 
eliminate apparent immediate hazards to human subjects. 
• He or she agrees to comply with all other requirements regarding the obligations of 
clinical Investigators and all other pertinent requirements in 21 CFR Part 312 and/or 
ICH E6 R2. 


PI
PI
PI


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24 
PROTOCOL AMENDMENT TEXT REVISIONS 
The following table summarizes the major revisions and administrative changes made to the protocol body (corresponding changes 
have been applied in the synopsis but are not shown here) in Amendment 2, and relates the changes to the appropriate rationale (see 
pages 2-4).  Text that has been added or inserted is indicated by underlined font, and deleted text is indicated by strikethrough font.  
Section No./Title 
Revision 
Rationale 
List of 
Abbreviations and 
Definitions of 
Terms 
ADL 
Activity of Daily Living 
CMC 
cervicomedullary compression 
CPAP 
continuous positive airway pressure 
CTX-II C-terminal telopeptide of cross-linked collagen type II 
CV% 
coefficient of variation 
DXA 
dual X-ray absorptiometry 
EDC 
electronic data capture 
EOSI 
events of special interest 
ERK 
extracellular signal-regulated kinase 
EUEudraCT 
European Union Drug Regulating Authorities Clinical Trials 
HR 
heart rate 
HRQoLHRQOL health-related quality of life 
IXRS 
Interactive Voice/Web Response System 
mg 
milligram 
mL 
milliliter 
PA 
posterior-anterior 
TAF 
human transcription factor 
Wee-FIM WeeFIM 
Functional independence measure for children 
13 
Section 7.3.1/Study 
111-901 
To obtain accurate baseline measurements, at least 6 months of growth data are collected for Cohorts 1 and 2; and at 
least 3 months of data for Cohort 3. 
13 
Section 7.4/Study 
Rationale 
Study 111-202 is an ongoing Phase 2, open-label, sequential cohort, dose escalation study that assesses daily SC 
administration of BMN 111 in pediatric subjects with ACH, in which the primary objective is to evaluate the safety and 
tolerability of BMN 111 administered for 6 months and up to 24 months and includes secondary objectives consisting of 
13 


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Section No./Title 
Revision 
Rationale 
determination of change from baseline in AGV, growth parameters, body proportions, and evaluation of the dose-
exposure and PK profiles of BMN 111 in children with ACH. 
Analysis of safety data from the 6 month initial phase of Study 111-202 showed that treatment with BMN 111 was 
generally well tolerated at all dose levels (refer to current Investigators Brochure for specific details). 
Analysis of efficacy data from Study 111-202 demonstrated that that subjects given BMN 111 at the dose of 15 µg/kg 
daily had an improvement in AGV, with approximately ~50% increase over baseline seen with treatment for 6 months 
which was sustained after continued treatment for 12 months. 
Subjects treated with 30 µg/kg daily also showed similar improvement in mean AGV after 6 months and their mean 
changes from baseline in AGV were similar to subjects treated with 15 µg/kg daily. Safety data for the 30-µg/kg daily 
dose was also similar to the 15-µg/kg daily dose.  Given that no clinically significant difference could be identified 
between the 15 µg/kg and 30-µg/kg daily dose in the Phase 2, 6 month safety and efficacy data, the lower of the two 
doses has been chosen for this Phase 2 study. 
8.0/Overall Study 
Design and Plan 
The secondary objectives of the study are to: 
• Evaluate the effect of BMN 111 on change from baseline in AGV throughout the 52 weeks of the study
• Evaluate the effect of BMN 111 on bone morphology/quality by X-ray and dual X-ray absorptiometry (DXA)
• Evaluate the PK of BMN 111 in children age 0 to < 60 months with ACH
• Evaluate hip function
• Evaluate for hip, thigh, or knee pain, or change in gait
• Evaluate the effect of BMN 111 on health-related quality of life (HRQoL), developmental status, and/ functional
independence using age-specific QoL and functional independence questionnaires/QOL status (Bayley Scales of Infant
and Toddler Development, Third edition [Bayley-III], Activity of Daily Living and Functional Independence Measure
(Wee-FIM), Infant Toddler Quality of Life Questionnaire (ITQOL),,WeeFIM Child Behavior Checklist ([CBCL]),
ITQOL 
• Evaluate immunogenicity of BMN 111 and assess impact on safety, PK, and efficacy measures
• Evaluate the effect of BMN 111 on bone metabolism and BMN 111 pharmacodynamic biomarkers
The exploratory objectives of the study are to: 
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• Evaluate the effect of BMN 111 on growth parameters and body proportions, including change from baseline in
upper:lower body segment ratio 
• Evaluate the effect of BMN 111 on sleep apnea
• Document physical and phenotypic changes with clinical photography (optional)
• Evaluate the effect of BMN 111 on skull and brain morphology, including foramen magnum, ventricular and brain
parenchymal dimensions 
• Describe the incidence of surgical interventions, including cervical decompression, adenotonsillectomy, and
tympanostomy 
The exploratory objectives of the study are to: 
• Document physical and phenotypic changes with clinical photography (optional)
• Evaluate genomic biomarkers (optional)
Section 8.0/Overall 
Study Design and 
Plan 
The exploratory objectives of the study are to: 
•
Document physical and phenotypic changes with clinical photography (optional)
•
Evaluate genomic biomarkers (optional)
13 
Section 8.0/Overall 
Study Design and 
Plan  
•
Evaluate the effect of BMN 111 on change from baseline in AGV throughout the 52 weeks of the study
13 
Section 9.1/Overall 
Study Plan 
Sentinel subjects from each cohort will be enrolled, treated with BMN 111, and studied for short-term safety and PK data, 
after which subjects in all 3 cohorts will be . No two sentinel subjects will be dosed on the same day for any cohort. After 
the sentinel data are evaluated, additional recruited subjects will be randomized to receive BMN 111 or placebo SC daily 
(1:1 ratio) for up to 52 weeks. No two sentinel subjects will be dosed on the same day for any cohort.   
13 
Section 9.1/Overall 
Study Plan 
Cohort 3 subjects must have a minimum of 3 months of observation prior to commencement of treatment.  These subjects 
will have the option to enroll in either 111-901 or 111-206, depending on age at enrollment: 
•
Infants ≥ 3 months and  < 6 months old (≥ 13 weeks and < 26 weeks) will enroll in 111-901 for a 6-month
period of pretreatment growth assessment prior to enrollment in 111 206 for treatment in Cohort 2. 
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•
Infants between birth and < 3 months old (0 weeks and < 13 weeks) will enroll into 111-206 with a 3-month
observational period prior to treatment. 
Table 9.1.1 and 
Table 9.1.2/ 
Schedules of Events 
The schedules of events have been updated to reflect changes made elsewhere in the protocol text and table footnotes. 
4 
Table 9.1.1/ 
footnotes 
j Growth measures may be collected in triplicate approximately the same time each day (± 2 hr around the time when the 
first measurement assessment was taken at Screening). Measurements may include but are not limited to length, 
standing height (if able to stand unsupported), crown-to-rump length, head circumference, upper and lower arm and 
leg, and arm span. Measurements not taken in the midsagittal plane should be taken on the right side of the body if 
possible and should always be taken on the same side of the body throughout the study. Anthropometric measures will 
be taken at the early termination visit only if subject discontinues after Week 6 and if > 2 weeks have elapsed since the 
previous assessment. 
k Clinical labs (hematology, chemistry, and urinalysis) are all pre-dose draws/samples and can be drawn collected 
anytime during the visit if there is no drug administration. 
n For optional genomic biomarkers, if the sample is not collected on Day 1, it may be drawn at any time during the study. 
The sample will be used for exploratory genomics including, but not limited to, NPR-B, BRAF, and other genes 
associated with CNP signalling. Bone metabolism blood biomarkers will be waived at screening for subjects 
weighing  < 7.0 kg to limit the blood volume on the smallest subjects at this visit. Serum samples for bone metabolism 
biomarkers will be collected pre-dose on the indicated visits. Bone metabolism blood biomarkers include bone-specific 
alkaline phosphatase and collagen type X. 
s WeeFim Wee-FIM is waived for children < 6 months old; CBCL is waived for children < 18 months old. ITQOL and 
CBCL should be performed before any other assessments during the study visit. 
t Efforts to obtain a satisfactory image can be discontinued after 3 unsuccessful attempts. DXA at early termination visit 
only if subject discontinues after 9 months to reduce unnecessary radiation exposure (unless additional scans are 
recommended by investigator, BioMarin, or DMC). 
u AP and lateral lumbar spine, and AP lower extremities are obtained at the early termination visit only if the previous 
assessment was done more than 9 months prior to early termination (unless additional study is recommended by 
Investigator, BioMarin, or DMC).  AP lower extremities X-ray at the Week 52 visit is waived for subjects who cannot 
stand upright unsupported.  Although X-rays are preferable for consistency across the study population, if there are 
IRBs or IECs unwilling to allow x-rays in Cohort 3 subjects, contact the MM to discuss alternate non-radiological 
methods for assessment. Obtained at ETV only if subject discontinues after 9 months to reduce unnecessary radiation 
exposure (unless additional X-rays are recommended by investigator, BioMarin, or DMC). 
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Section 
9.2/Discussion of 
Study Design, 
Including Choice of 
Control Group 
Therefore, to have a potential therapeutic benefit for subjects with ACH, specifically for the foramen magnum and spine, 
treatment is expected to be required prior to epiphyseal growth plate closure. 
13 
Section 
9.3.1/Inclusion 
Criteria; Synopsis 
Cohort 1 and 2 subjects must have at least a 6-month period of pretreatment growth assessment in Study 111 901 
immediately before screening study entry, and have one documented measurement of height/body length a minimum of 6 
months (+/ 10 days) prior to the screening visit for 111-206.  Cohort 3 subjects must have a minimum of 3 months of 
observation prior to treatment.  This observational period can be obtained either (1) via prior enrollment in Study 111-901 
or (2) via enrollment in this Study 111 206 for a minimum of 3 months of non-treatment observation prior to 
commencement of treatment. 
13 
Section 
9.3.3/Inclusion 
Criteria for Cohort 3 
Observation Period 
9.3.4/Exclusion 
Criteria for Cohort 3 
Observation Period  
9.3.3 
Inclusion Criteria for Cohort 3 Observation Period 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Parent(s) or guardian(s) willing and able to provide signed informed consent after the nature of the study has been
explained and prior to performance of any research related procedure. Also, willing and able to provide written assent
(if applicable) after the nature of the study has been explained and prior to performance of any research-related
procedure.
2. Birth to ≤ 3 months of age at study entry.
3. Have ACH, documented by genetic testing
4. Are willing and able to perform all study procedures as physically possible
After completing the observation period, subjects must fulfill the general eligibility criteria prior to receiving treatment 
with study drug. 
9.3.4 Exclusion Criteria for Cohort 3 Observation Period  
Individuals who meet any of the following exclusion criteria are not eligible to participate in the study: 
1. Have hypochondroplasia or short stature condition other than ACH (e.g., trisomy 21, pseudoachondroplasia)
. . . 
13. Concurrent disease or condition that, in the view of the Investigator, would interfere with study participation
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After completing the observation period, subjects must fulfill the general eligibility criteria prior to receiving treatment 
with study drug. 
Section 
9.3.6/Removal of 
Subjects from 
Treatment or 
Assessment 
Investigators may discontinue administration of BMN 111 or placebo at any time. Subjects discontinued from the study 
by the investigator must return to the clinic for a termination visit. Reasons for which the investigator or BioMarin will 
withdraw a subject from study treatment include, but are not limited to, the following: . . .    
. . . Therefore, subjects who discontinue study treatment should be encouraged to continue to undergo as many of the 
protocol-specified procedures and assessments as possible for the remainder of the study, as long as such continued 
participation does not detrimentally affect the health, safety, or welfare of the subject, and consent remains in place. It is 
important that following treatment discontinuation the original visit schedule is strictly adhered to.  
13 
Section 
9.4.2.1/Product 
Characteristics and 
Labeling; Synopsis 
The clinical drug product will be supplied in sterile, single-dose, Type I glass vials with coated stopper and flip-off 
aluminum cap. BMN 111 drug product is supplied as a 0.8-mg or 2-mg lyophilized, preservative-free, white-to-yellow 
powder for reconstitution with either a sterile diluent or sterile water for injection (WFI). The reconstituted solution is 
colorless to yellow and contains 0.8 mg/mL to 2 mg/mL of BMN 111, as well as citric acid, sodium citrate, trehalose, 
mannitol, methionine, polysorbate 80, and sterile WFI water for injection. The target pH of the reconstituted solution is 
5.5. Sterile WFI water for injection will be commercially sourced and sterile diluent solution containing all of the above 
excipients will be supplied for reconstitution. All reconstitution and dose preparation steps will be performed as indicated 
in the BMN 111 Injection Guide and Injection video. 
8 
Section 
9.4.4/Directions for 
Administration  
The caregiver will be provided with a paper or electronic study diary and will be asked to record daily dosing 
information, changes in health status, medications and injection sites used, date and time of the injection, and injection 
site reactions, if any. 
13 
Section 
9.4.5/Method of 
Assigning Subjects 
to Treatment Groups 
Subjects will be randomized using an interactive voice/response system in a 1:1 ratio, i.e., injection with placebo:15 
µg/kg of BMN 111, using IXRS.  An independent third party vendor will develop the randomization schedule so that 
BioMarin and site personnel are blinded to treatment assignments.  NOTE: In Japan, subjects are randomized separately 
within each cohort. 
13 
Section 
9.4.7/Blinding 
An independent third-party vendor will develop the randomization schedule so that BioMarin and site personnel will not 
know treatment assignments. BMN 111 or placebo will be labeled with the study number and a unique identification 
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number. Subjects and the participating site members will be blinded to the two study treatments (15 µg/kg BMN 111 or 
placebo). 
Section 
9.8/Biological 
Parental Standing 
Height 
Standing height of the subject’s biological parents (optional) may be assessed (optional) via height measurement or stated 
height. Height measurement can be done at any point in the study. 
13 
Section 
9.11.4.2/Imaging 
Assessment 
Procedures 
•
Bilateral X-rays of entire lower extremity x-rays, anterior-posterior (AP) view, to assess growth plate
morphology.
•
Hip imaging via pelvis Xx-ray to identify hip pathology
•
Lumbar spine Xx-rays to measure changes from baseline in bone morphology and pathology.
•
MRI to evaluate the effect of BMN 111 on skull and brain morphology, including foramen magnum, ventricular
and brain parenchymal dimensions.
•
DXA (BMD and BMC) of whole body [less head], spine, and forearm (including ultra-distal, mid-distal, and
one- third radius regions of interest) to assess bone mineral density (BMD) and bone mineral content (BMC).
13 
Section 
9.12.3/Secondary 
Efficacy Variables 
The secondary efficacy endpoints include change from baseline in AGV (annualized to cm/yr), biomarker samples to 
evaluate the effect of BMN 111 on bone metabolism, and BMN 111 pharmacodynamic biomarkers, growth parameters and 
body proportions, sleep apnea, skull and brain morphology, and clinical outcome assessments 
(developmental/functional/HRQoL status). 
9 
9.12.3.2/MRI 
Assessments 
9.11.4.2 Imaging MRI Assessments  
Imaging assessment procedures for all visits must be performed using the same instruments.  Imaging assessments can be 
conducted either pre-dose or post-dose. 
•
Bilateral lower extremity x-rays, anterior-posterior (AP) view, to assess growth plate morphology.
•
Hip imaging via pelvis x-ray to identify hip pathology
•
Lumbar spine x-rays to measure changes from baseline in bone morphology and pathology.
MRIs are performed to evaluate the effect of BMN 111 on skull and brain morphology, including foramen magnum, 
ventricular, and brain parenchymal dimensions. MRI assessment procedures for all visits must be performed as described 
in the Imaging Manual and can be conducted either pre-dose or post-dose. 
3 
Section 
9.12.3.4/Clinical 
Clinical outcome assessments will be administered to assess the HRQoL health-related quality of life of study subjects. 
Functional Independence ADL questionnaires will be assessed. performed in study subjects to assess functional 
performance. Clinical outcome assessments will be performed at the time points indicated in the Schedules of Events 
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Outcome 
Assessments 
(Table 9.1.1 and Table 9.1.2) and the ITQoL and CBCL should be administered prior to any other assessments.  The 
Wee-FIM and the Bayley-III may be administered at any point deemed convenient during the visit.). The age ranges for 
clinical outcome assessment tools are shown in Figure 9.12.3.3.1 The clinical outcome assessments are not to be 
considered as source data for AEs.  
Figure 9.12.3.3.1 has been modified to remove the CBCL as a Clinical outcome assessment tool. 
9.12.3.4.2 
9.12.4.7.2 9.12.3.4.2 
Activity of Daily Living and Functional Independence Measure (Wee-FIM) 
13 
Section: 
9.12.5/Pharmacokin
etics Variables 
Whenever possible, the following PK parameters for sentinel subjects and for subjects randomized to BMN 111 will be 
estimated by non-compartmental analysis: 
•
Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞)
•
Area under the plasma concentration-time curve from time 0 to the time of last measurable concentration
(AUC0-t)
•
Maximum observed plasma concentration (Cmax)
•
Time to reach Cmax (Tmax)
•
Cmax
•
tmax
•
Elimination half-life (t1/2)
•
Apparent clearance of drug (CL/F)
•
Apparent volume of distribution based upon the terminal phase(Vz/F)
10 
9.12.6.2/Procedures 
During the Study 
All concomitant procedures/intervention/surgery interventions/surgeries will be recorded after informed consent is 
obtained and after the first administration of study drug, until end of study. 
13 
9.12.6.3/Imaging 
Assessment 
Procedures (per 
Schedule of Events) 
9.11.4.2 9.12.3.2 Imaging Assessment Procedures (per Schedule of Events) 
Imaging assessment procedures for all visits must be performed using the same instruments.  Imaging assessments can be 
conducted either pre-dose or post-dose. 
• Bilateral lower extremity x-rays, anterior-posterior (AP) view, to assess long bone growth and pathology as well as
growth plate morphology. 
• Hip imaging via pelvis x-ray to identify hip pathology
• Lumbar spine x-rays to measure changes from baseline in bone morphology and pathology.
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• MRI to evaluate the effect of BMN 111 on skull and brain morphology, including foramen magnum, ventricular and
brain parenchymal dimensions. 
• DXA (BMD and BMC) of whole body [less head], and spine, and forearm (including ultra-distal, mid-distal, and one
third radius regions of interest) to assess bone mineral density (BMD) and bone mineral content (BMC).
Although X-rays are preferable for consistency across the study population, if there are IRBs or IECs unwilling to allow 
X-rays in Cohort 3 subjects, contact the medical monitor to discuss alternate non-radiological methods for assessment. 
Section 
9.12.6.6/Child 
Behavior Checklist 
4.12.3.3 9.12.6.6 Child Behavior Checklist 
The Child Behavior Checklist (CBCL) is for use in children from 1.5-5 years old, and will be administered for those 
entering the study at less than 5 years old and for the remainder of the duration of the study.  The CBCL comprises 99 
questions addressing symptoms related to mood, behavior issues, and sleep disturbance.  It is completed by the parent or 
primary caregiver.  
The form requires approximately 15 minutes to complete. The checklist yields scores in the following areas: reactivity, 
anxiety, depression, somatic complaints, withdrawal, sleep problems, attention problems, and aggressive behavior. CBCL 
is waived for children < 18 months old. The CBCL should be administered prior to any other study assessments. 
6 
Section 9.12.6.10 
Section 9.12.6.12 
Anti-BMN 111 Immunogenicity Assessments and IgE Testing 
Ad Hoc IgE Safety Assessment 
13 
Section 10.8/BPV 
Contact Information 
Name: 
 
 MD, PhD 
 
BioMarin Pharmaceutical Inc. 
Address: 
10 Bloomsbury Way 
London WC1A 2SL105 Digital Drive 
Novato, CA 94949L 
Phone: 
 
13 
PI
PI
PI
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Fax: 
 
 
E-mail: 
 
 
Section 
12.1.1/Screening/ 
Baseline Day -30 to 
Day -1 
•
Serum prolactin
•
Genomic blood biomarkers (optional)
•
Bone metabolism blood biomarkers
•
Screening baseline hip assessment with pelvis x ray
•
MRI brain/skull
•
Sleep study
•
Clinical outcome assessment: Bayley-III
•
Clinical outcome assessment: WeeFIMWee-FIM
•
Clinical outcome assessment: ITQOL
•
Clinical outcomeSafety assessment: CBCL
13 
12.1.2/Day 1/Week 
13 (±7d)/12.1.2 
Days 2 and 3/12.1.4 
Day 8 (±1d)/Week 
20 (±7d)/12.1.5 
Week 3 (±7d;) 
•
Capture allconcomitant procedures/interventions/surgeries
13 
12.1.6/Week 6 (±7d) 
•
Genomic biomarkers (optional)
13 
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•
Bone metabolism blood biomarkers
•
Capture allconcomitant procedures/interventions/surgeries
12.1.7/Week 26 
(±7d) 
•
Clinical outcome assessment: WeeFIMWee-FIM
•
Clinical outcome assessment: ITQOL
•
Clinical outcomeSafety assessment: CBCL
•
Capture allconcomitant procedures/interventions/surgeries
13 
12.1.8/Week 39 
(±7d) 
•
Capture allconcomitant procedures/interventions/surgeries
13 
12.1.9/Week 52 
(±7d) 
•
Genomic biomarkers (optional)
•
Clinical outcome assessment: WeeFIMWee-FIM
•
Clinical outcome assessment: ITQOL
•
Clinical outcomeSafety assessment: CBCL
•
Capture allconcomitant procedures/interventions/surgeries
13 
12.1.10/Week 56 
Safety Follow-up 
(+ 7d) 
•
Capture allconcomitant procedures/interventions/surgeries
13 
12.1.11/Early 
Termination Visit 
•
Clinical outcome assessment: WeeFIMWee-FIM
•
Clinical outcome assessment: ITQOL
•
ClinicalSafety outcome assessment: CBCL
•
Capture allconcomitant procedures/interventions/surgeries
13 
12.2.2/Day 1 
(Month 0) 
•
Capture allconcomitant procedures/interventions/surgeries
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12.2.3/3 Months (± 
10 days) 
•
Capture allconcomitant procedures/interventions/surgeries
13 
Section 13 Data 
Quality Assurance 
Sites will enter study data into eCRFs into the study EDC system.  Data Quality Control will be performed by BioMarin 
Clinical Data Management or designee through implementation of quality control checks specified in the study data 
management plan and edit check specifications. Additional subject-reported study data may be entered into the study EDC 
system via electronic diary. 
11 
Section 
14.1.1/Interim 
Analysis 
An interim analysis will be carried out to support NDA/MAA filing. The report will be provided by a third party to assure 
that the study team, subjects, and investigators will have no access to the individual subject treatment allocation, and 
blinded pooled safety outputs will be provided for the randomized subjects. 
13 
Section 
14.3/Efficacy 
Analysis 
AGV will be calculated for the following visits/intervals: 
Baseline: [Date of last length/height measurement in study 901 at least 6 months prior to screening visitDay 1 in study 
206, Date of Day 1] 
13 
Section 17 Case 
Report Forms and 
Study Documents 
eCRFs must be completed using a validated web-based application. Study site personnel will be trained on the application 
and will enter the clinical data from source documentation, except in instances when electronic subject-reported data is 
transmitted directly into EDC, as referenced in the study specific vendor management plan. Unless explicitly allowed in 
the eCRF instructions, blank data fields are not acceptable. 
A CRA designated by BioMarin will compare the eCRFs with the original source documents at the study site and evaluate 
them for completeness and accuracy before designating them as “Source Data Verified” (SDV). Electronic Subject-
reported data transferred directly into EDC will not be SDV’d or queried. 
11 

SAP_001.pdf: 
 
 
 
 
    
 
 
 
 
 
 
Official Title: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial to 
Evaluate the Safety and Efficacy of BMN 111 in Infants and Young Children with 
Achondroplasia, Age 0 to < 60 Months 
 
NCT Number: NCT03583697 
 
Applicant/MAH: BioMarin Pharmaceutical Inc. 
 
Version Date: 02February2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
CFT-114417-ITEM Rev. 01 
 
Pg. 1 of 76 
 
 
105 Digital Drive 
Novato, CA 94949 
 
Statistical Analysis Plan 
 
Study 111-206 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled 
Clinical Trial to Evaluate the Safety and Efficacy of 
Vosoritide in Infants and Young Children with 
Achondroplasia, Age 0 to < 60 Months 
 
Version 1.1: Final CSR 
Date: 17 November 2021 
The information in this document is considered privileged and confidential by BioMarin 
Pharmaceutical Inc., may not be disclosed to others except to the extent necessary to obtain 
Institutional Review Board approval and informed consent, or as required by Federal and 
State Laws.  Persons to whom this information is disclosed must be informed that this 
information is privileged and confidential and that it should not be further disclosed. 
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Study 111-206 SAP 
 
 
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1 
SAP SYNOPSIS 
TITLES OF STUDY: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial to 
Evaluate the Safety and Efficacy of vosoritide in Infants and Young Children with Achondroplasia, 
Age 0 to < 60 Months. 
PROTOCOL NUMBER: 111-206  
STUDY SITES: Approximately 10-15 clinical centers worldwide 
PHASE OF DEVELOPMENT: Phase 2 
OBJECTIVES:  
The primary objectives of the study are to: 
• 
Evaluate the safety and tolerability of vosoritide in children age 0 to < 60 months with 
Achondroplasia (ACH)  
• 
Evaluate the effect of vosoritide on change from baseline in standing height/body length 
Z-score 
The secondary objectives of the study are to: 
• 
Evaluate the effect of vosoritide on change from baseline in standing height/body length, 
annualized growth velocity (AGV), and upper: lower segment body ratio throughout the 
52-weeks of the study  
• 
Evaluate the effect of vosoritide on other growth parameters and body proportions 
• 
Evaluate the effect of vosoritide on bone morphology/quality by X-ray and dual X-ray 
absorptiometry (DXA) 
• 
Evaluate the Pharmacokinetics (PK) of vosoritide in children age 0 to < 60 months with 
ACH  
• 
Evaluate hip function 
• 
Evaluate for hip, thigh, or knee pain, or change in gait  
• 
Evaluate the effect of vosoritide on health-related quality of life (HRQoL), developmental 
status, and functional independence using age-specific QoL and functional independence 
questionnaires (Bayley Scales of Infant and Toddler Development, Third edition 
[Bayley-III], Activity of Daily Living and Functional Independence Measure (Wee-FIM), 
Infant Toddler Quality of Life Questionnaire (ITQOL), Child Behavior Checklist (CBCL) 
• 
Evaluate immunogenicity of vosoritide and assess impact on safety, PK, and efficacy 
measures  
• 
Evaluate the effect of vosoritide on bone metabolism and vosoritide pharmacodynamic 
(PD) biomarkers 
• 
Evaluate the effect of vosoritide on sleep apnea 
• 
Evaluate the effect of vosoritide on skull and brain morphology, including foramen 
magnum, ventricular and brain parenchymal dimensions 
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• 
Describe the incidence of surgical interventions, including cervical decompression, 
adenotonsillectomy, and tympanostomy 
The exploratory objectives of the study are to: 
• 
Document physical and phenotypic changes with clinical photography (optional) 
• 
Evaluate genomic biomarkers (optional).   
The exploratory objectives of the study are optional and will not be addressed in this SAP.  
STUDY DESIGN AND PLAN: Study 111-206 is a phase 2 randomized, double-blind, placebo-
controlled clinical trial of vosoritide in infants and younger children with a diagnosis of ACH. 
Approximately 70 Subjects will be enrolled into 3 age cohorts: n ≥ 30 total for aged ≥ 24 to 
< 60 months, n ≥ 20 total for aged ≥ 6 to < 24 months, and n ≥ 20 total for aged 0 to < 6 months. 
There will be 3 sentinel subjects for each cohort, and the rest of subjects will be randomized 1:1 to 
treatment or placebo control and stratified by age for Cohorts 1 and 2.  
All subjects who complete the 111-206 study will be eligible to receive vosoritide in the extension 
study 111-208 after the Week 52 visit.  
ANALYSIS POPULATIONS:  
The Full Analysis Set (FAS) is defined according to the intent-to-treat principle and includes all 
enrolled sentinel and randomized subjects with a signed informed consent.  
The Per-Protocol (PP) population is defined as a subset of the FAS population who completed the 
treatment originally allocated (i.e., always received the assigned treatment), with a standing 
height/body length assessment at Week 52 following the protocol window, and with treatment 
compliance of at least 80%. 
The Safety Population is a subset of the FAS who receive at least one dose of vosoritide or placebo 
in this study. 
The PK Population is defined as all sentinel subjects and subjects randomized to vosoritide 
treatment group, who received at least one dose of vosoritide in this study and have at least one 
evaluable PK concentration. 
The Immunogenicity Population is defined as all subjects in the Safety Population who have at 
least one evaluable immunogenicity sample. 
STUDY ENDPOINTS AND ANALYSES:  
Efficacy endpoints and analysis:  
The primary efficacy endpoint is change from baseline in standing height/body-length Z-score at 
Week 52.  
The key secondary efficacy endpoints include change from baseline at Week 52 in standing 
height/body length, AGV, and upper to lower body ratio. Other secondary efficacy endpoints 
include biomarker samples to evaluate the effect of vosoritide on bone metabolism, vosoritide 
pharmacodynamic biomarkers, growth parameters and body proportions, sleep apnea, skull and 
brain morphology, and clinical outcome assessments (developmental/functional/HRQoL status).  
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In addition to the summary statistics analyses for efficacy endpoints, model-based analysis will be 
conducted for change from baseline at Week 52 in standing height/body length Z-Score, standing 
height/body length, AGV, and upper to lower body ratio for all cohorts overall and/or by cohort, as 
appropriate.  
Safety endpoints and analyses: 
Adverse events (AEs) will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) Version 24.1 and presented by System Organ Class (SOC) and Preferred Term (PT). 
Summaries of AE’s will include all AE’s, serious adverse events (SAEs) and events of interest 
(EOI). 
Clinical laboratory tests will be summarized descriptively. Shift tables tabulating Common 
Terminology Criteria for Adverse Events (CTCAE) severity grade at baseline versus worst post-
baseline grade will be provided.  
Vital signs will be summarized descriptively. Shift tables tabulating shifts from pre-dose (diastolic 
blood pressure (BP) < 40 mmHg, diastolic BP ≥ 40mmHg) to lowest post-injection value (diastolic 
BP ≥40mmHg) will be provided. Additional shift tables will describe similar pre/post injection 
shifts in vital signs.  
X-rays and DXA will be performed on the extremities and spine to evaluate changes in bone 
morphology and quality.  
Anti-vosoritide immunogenicity assessments will be summarized descriptively. Behavioral 
assessments with the CBCL will be summarized descriptively.  
Other analyses:  
Additional analyses will be conducted as appropriate to evaluate the impact of the COVID-19 
pandemic on the study conduct. 
  
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TABLE OF CONTENTS 
1 SAP SYNOPSIS ..................................................................................................................2 
2 APPROVAL (SIGNATURE AND DATE) .........................................................................9 
3 LIST OF ABBREVIATIONS ............................................................................................10 
4 INTRODUCTION .............................................................................................................12 
4.1 Objectives of Study ...................................................................................................12 
4.2 Study Design .............................................................................................................13 
4.3 Study Populations .....................................................................................................15 
4.4 Study Dosage and Administration ............................................................................15 
4.5 Sample Size Determination .......................................................................................15 
4.6 Blinding and Randomization Methods .....................................................................15 
4.6.1 
Blinding Method ..........................................................................................15 
4.6.2 
Randomization Method ...............................................................................15 
4.7 Interim Analysis ........................................................................................................16 
5 GENERAL ANALYSIS CONSIDERATIONS ................................................................17 
5.1 Analysis Populations .................................................................................................19 
5.1.1 
Full Analysis Set .........................................................................................19 
5.1.2 
Per-Protocol .................................................................................................19 
5.1.3 
Safety ...........................................................................................................19 
5.1.4 
PK ................................................................................................................19 
5.1.5 
Immunogenicity ...........................................................................................20 
5.2 Pooling of Data from Sites with Small Enrollment ..................................................20 
5.3 Study Day Derivation ................................................................................................20 
5.4 Visit Windows for Analysis ......................................................................................20 
5.5 Handling of Dropouts and Missing Data ..................................................................22 
5.5.1 
Partial Dates ................................................................................................22 
6 SUBJECT DISPOSITION .................................................................................................24 
7 DISCONTINUATION AND COMPLETION ..................................................................25 
8 PROTOCOL EXEMPTIONS AND DEVIATIONS .........................................................26 
9 DEMOGRAPHICS AND BASELINE CHARACTERISTICS.........................................27 
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10 MEDICAL HISTORY .......................................................................................................29 
11 PRIOR AND CONCOMITANT MEDICATIONS ...........................................................30 
12 COMPLIANCE..................................................................................................................31 
13 EXTENT OF EXPOSURE TO STUDY TREATMENT ..................................................32 
14 EFFICACY EVALUATIONS ...........................................................................................33 
14.1 General Approaches for Analyzing Growth Parameters ...........................................33 
14.2 Primary Efficacy Endpoint ........................................................................................35 
14.2.1 Primary Analyses ........................................................................................35 
14.2.2 Sensitivity Analyses ....................................................................................36 
14.3 Secondary Efficacy Endpoint(s) ...............................................................................36 
14.3.1 Standing Height/Body Length .....................................................................36 
14.3.2 Annualized Growth Velocity .......................................................................37 
14.3.3 Upper to Lower Body Segment Ratio .........................................................37 
14.3.4 Body Proportion Ratios ...............................................................................38 
14.3.5 Other Growth Measures ..............................................................................38 
14.4 Health-Related Quality of Life .................................................................................39 
14.4.1 Bayley-III ....................................................................................................40 
14.4.2 Infant and Toddler Quality of Life Questionnaire (itqol-97, 2013) 
(ITQOL) ......................................................................................................41 
14.4.3 Function Independence Measure (WeeFIM) (Wee-FIM II Version 
6.4) ..............................................................................................................42 
14.5 Sleep Study Scores ....................................................................................................43 
15 SAFETY EVALUATIONS ...............................................................................................45 
15.1 Adverse Events .........................................................................................................45 
15.1.1 Treatment-Emergent Adverse Events .........................................................45 
15.1.2 Events of Interest .........................................................................................47 
15.1.3 Injection Site Reaction Symptoms ..............................................................49 
15.2 Clinical Laboratory Tests ..........................................................................................49 
15.3 Vital Signs .................................................................................................................51 
15.4 Biological Parental Standing Height .........................................................................52 
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15.5 Electrocardiogram .....................................................................................................52 
15.6 HPA Axis Assessments .............................................................................................53 
15.7 Child Behavior Checklist (Achenbach, 2000) ..........................................................53 
15.8 Echocardiogram ........................................................................................................54 
15.9 On-Study Procedures, Interventions and Surgeries ..................................................54 
15.10 Hip Monitoring and Rotation ....................................................................................55 
15.11 Body Mass Index and BMI Z-scores ........................................................................55 
15.12 Weight Z-Scores .......................................................................................................55 
16 IMAGING SECONDARY ENDPOINT(S) ......................................................................57 
16.1 Lower Limb X-Rays .................................................................................................57 
16.2 Lumbar Spine X-Rays ...............................................................................................57 
16.2.1 Vertebral Height ..........................................................................................58 
16.2.2 Transverse Diameter (Interpedicle Distance) ..............................................58 
16.2.3 Sagittal Width ..............................................................................................58 
16.2.4 Lumbar Spine Angles ..................................................................................58 
16.3 Dual Energy X-ray Absorptiometry ..........................................................................59 
16.3.1 Whole Body Less Head and Lumbar Spine ................................................60 
16.4 MRI ...........................................................................................................................60 
17 BONE METABOLISM BIOMARKERS ..........................................................................62 
18 VOSORITIDE PD ACTIVITY BIOMARKERS ..............................................................63 
19 IMMUNOGENICITY ASSESSMENT .............................................................................64 
20 PHARMACOKINETICS AND PHARMCODYNAMICS ...............................................68 
21 OTHER ANALYSES ........................................................................................................69 
22 ANALYSES DIFFERENT FROM PROTOCOL-DEFINED ANALYSES .....................70 
23 REFERENCES ..................................................................................................................71 
24 SUMMARY OF KEY CHANGES TO STUDY SAP .......................................................72 
25 APPENDICES ...................................................................................................................73 
25.1 Summary of Growth Measures Derivations ..............................................................73 
25.2 Child Behavior Checklist Domains ...........................................................................75 
 
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LIST OF TABLES  
Table 5.1:  Format for Efficacy Summary Analyses for Cohort 1 ...........................................17 
Table 5.2:  Format for Efficacy Summary Analyses for Cohort 2 ...........................................17 
Table 5.3:  Format for Efficacy Summary Analyses for Cohort 3 ...........................................17 
Table 5.4:  Format for Safety Summary Analyses for Cohort 1* ............................................18 
Table 5.4.1:  Visit Windows for Observed Assessments in BMN 111-901 and 
BMN 111-206 ................................................................................................21 
Table 5.4.2:  Visit Windows for Observed Assessments in 111-206 ......................................22 
Table 15.3.1:  Vital Sign Post-dose Assessment Frequency ....................................................51 
 
LIST OF FIGURES 
Figure 4.2.1:  Study Design .....................................................................................................14 
 
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2 
APPROVAL (SIGNATURE AND DATE) 
 
 
Stat
 
 
 
 
DD MON YYYY 
Dat
 
 
 
 
DD MON YYYY 
Clinical Science Lead 
 
 
 
 
DD MON YYYY 
Pharmacovigilance Lead 
 
 
 
DD MON YYYY 
Head of Statistical Scienc
 
 
 
 
DD MON YYYY 
Head of Cl
 
 
 
 
DD MON YYYY 
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PI
PI
PI
PI
PI
PI


 
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3 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
µg/kg 
microgram/kilogram 
ACH 
achondroplasia 
ADA 
anti-drug antibody 
AE 
adverse event 
AGV 
annualized growth velocity 
ANCOVA 
Analysis of covariance 
ANP 
atrial natriuretic peptide 
ATC 
Anatomical Therapeutic Chemical 
BMC 
bone mineral content 
BMD 
bone mineral density 
BMI 
body mass index 
BMN 
BioMarin 
BNP 
brain natriuretic peptide 
BP 
blood pressure 
BSAP 
bone-specific alkaline phosphatase 
CBCL 
Child Behavior Checklist 
CDC 
Centers for Disease Control and Prevention 
CM 
concomitant medication 
CRF 
case report form 
cGMP 
cyclic guanosine monophosphate 
CNP 
C-type natriuretic peptide 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events (v4.03) 
CTX-II 
C-terminal telopeptide of cross-linked collagen type II 
DBL 
database lock 
DMC 
data monitoring committee 
DXA 
dual x-ray absorptiometry 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
JNDA 
Japan New Drug Application 
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HPA 
hypothalamic pituitary adrenal 
HRQoL 
health-related quality of life 
ISR 
injection site reaction 
ITQoL 
Infant Toddler Quality of Life Questionnaire 
IXRS 
interactive web or voice response system 
MAA 
Marketing Authorization Application 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAb 
neutralizing antibody 
NCI 
National Cancer Institute 
NDA 
New Drug Application 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PP 
per protocol 
PT 
preferred term 
QTc-F 
Fridericia’s corrected QT interval 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
Subcutaneous 
SCFE 
slipped capital femoral epiphysis 
SD 
standard deviation 
SDS 
standard deviation score 
SE 
standard error 
SMQ 
Standardized MedDRA query 
SOC 
system organ class 
TAb 
total anti-drug antibody 
TEAE 
treatment-emergent adverse event 
TLGs 
tables, listings, and graphs 
WeeFIM 
Activity of Daily Living and Functional Independence Measure 
WHO 
World Health Organization 
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4 
INTRODUCTION 
Study 111-206 (original protocol effective date: 06 December 2017) is a Phase 2 randomized, 
double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of vosoritide 
in infants and young children with ACH, aged 0 to < 60 months.  
This final SAP is based on Amendment 2 of Study 111-206 (date: 08 February 2019). It 
describes the analyses and evaluations that will be provided for the final clinical study report 
(CSR). 
Where there are major differences between the protocol-defined analyses, and the SAP-
defined analyses, these will be identified in the SAP. The SAP-defined analyses prevail. 
4.1 
Objectives of Study  
The primary objectives of study are to: 
• Evaluate the safety and tolerability of vosoritide in children age 0 to < 60 months 
with ACH 
• Evaluate the effect of vosoritide on change from baseline in standing height/body 
length Z-score (height Z-Score may be used interchangeable) 
The secondary objectives of study are to: 
• Evaluate the effect of vosoritide on change from baseline in standing height/body 
length, AGV, and upper: lower body segment ratio throughout the 52 weeks of the 
study 
• Evaluate the effect of vosoritide on other growth parameters and body proportions 
• Evaluate the effect of vosoritide on bone morphology/quality by x-ray and DXA 
• Evaluate the PK of vosoritide in children age 0 to < 60 months with ACH 
• Evaluate hip function 
• Evaluate for hip, thigh, or knee pain, or change in gait 
• Evaluate the effect of vosoritide on HRQoL, developmental status, and/functional 
independence using age-specific QoL and functional independence 
questionnaires/QOL status (Bayley-III), Wee-FIM, ITQOL, and CBCL 
• Evaluate immunogenicity of vosoritide and assess impact on safety, PK, and efficacy 
measures 
• Evaluate the effect of vosoritide on bone metabolism and vosoritide PD biomarkers 
• Evaluate the effect of vosoritide on sleep apnea 
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• Evaluate the effect of vosoritide on skull and brain morphology, including foramen 
magnum, ventricular and brain parenchymal dimensions 
• Describe the incidence of surgical interventions, including cervical decompression, 
adenotonsillectomy, and tympanostomy 
The exploratory objectives are to: 
• Documental physical and phenotypic changes with clinical photography (optional) 
• Evaluate genomic biomarkers (optional) 
The exploratory objectives of the study are optional and will not be addressed in this SAP. 
4.2 
Study Design  
Study 111-206 is a phase 2 stratified randomized, double-blind, placebo-controlled clinical 
trial of vosoritide in infants and younger children with a diagnosis of ACH. 
Subjects aged ≥ 6 months to < 60 months old who have documented ACH confirmed by 
genetic testing; at least a 6-month period of pretreatment growth assessment in Study 
111-901 immediately before study entry; and who meet the study eligibility criteria, will 
participate. Eligible subjects ranging from 0 months to < 3 months old may enroll directly 
into 111-206 and have a minimum of 3 months of pre-treatment observation prior to 
commencing treatment with investigational product or may enroll in 111-901 for a minimum 
of 3 months of pretreatment growth assessment immediately before roll-over to 111-206. 
Approximately 70 subjects will be enrolled at approximately 10-15 clinical centers 
worldwide. 
Subjects will be enrolled into 3 age cohorts based on age at study screening starting with the 
eldest population. Within Cohorts 1 and 2, subjects will be stratified by age: 
• Cohort 1 – children aged ≥ 24 to < 60 months (n ≥ 30 total: 3 sentinel subjects who 
receive vosoritide, and at least 27 additional subjects randomized 1:1 to treatment or 
placebo control), stratified by age (≥ 24 months to < 36 months and ≥ 36 months to 
< 60 months) 
• Cohort 2 – children aged ≥ 6 to < 24 months (n ≥ 20 total: 3 sentinel subjects who 
receive vosoritide, and at least 17 additional subjects randomized 1:1 to treatment or 
placebo control), stratified by age (≥ 6 months to < 15 months and ≥ 15 months to 
< 24 months) 
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• Cohort 3 – children aged 0 to < 6 months (n ≥ 20 total: 3 sentinel subjects who 
receive vosoritide, and at least 17 additional subjects randomized 1:1 to treatment or 
placebo control). Treatment begins at ≥ 3 months to < 6 months after 3 months of 
observation.  
Sentinel subjects from each cohort will be enrolled, treated with vosoritide, and studied for 
short-term safety and PK data. After the sentinel data are evaluated within a cohort additional 
recruited subjects will be randomized to receive vosoritide or placebo subcutaneous daily 
(1:1 ratio) for 52 weeks.  
As subjects age on study, they will be administered the dose determined to be appropriate for 
their current age as follows: 
All sentinel and randomized subjects in Cohort 1 received 15 μg/kg dose. Sentinel subjects in 
Cohort 2 initially received 15 μg/kg dose and the dose was escalated to 30 μg/kg while they 
remained < 24 months of age following review of PK data as per protocol. All randomized 
subjects in Cohort 2 will receive 30 μg/kg dose while they remained < 24 months of age. 
All sentinel and randomized subjects in Cohort 3 received 30 μg/kg dose while they 
remained < 24 months of age. The dose for all sentinel and randomized subjects in Cohorts 2 
and 3 will be adjusted to 15 µg/kg/day after they turn 24 months old. 
The 111-206 study design is presented in Figure 4.2.1. All subjects who complete the 
111-206 study will be eligible to receive vosoritide in the extension study 111-208 after the 
Week 52 visit. 
Figure 4.2.1:  Study Design 
 
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4.3 
Study Populations 
Subjects aged 0 to < 60 months old, with documented ACH confirmed by genetic testing, and 
who meet the study eligibility criteria will participate.  
For additional criteria for selection of study population, please refer to inclusion and 
exclusion criteria for the protocol. 
4.4 
Study Dosage and Administration 
In Study 111-206, sentinel subjects in Cohort 1 will receive an initial daily dose of 15 μg/kg. 
All available safety and PK data will be reviewed after 3 sentinel subjects reach Day 8. If the 
criteria for dose adjustment are met, the 3 sentinel subjects will be started on the new 
adjusted dose at their next scheduled visit and the remainder of the subjects in the age cohort 
will also be enrolled starting at the new adjusted dose. The 3 sentinel subjects for the second 
and third cohorts will be evaluated similarly to the sentinel subjects in the first cohort for 
potential dose adjustment. Additional sentinels may be added to any cohort if needed for 
additional safety and/or PK assessment.  
4.5 
Sample Size Determination 
Approximately 70 subjects aged 0 to < 60 months at study entry will participate in 111-206. 
No formal sample size calculations were performed. The number of subjects is considered 
appropriate to evaluate the safety and efficacy of vosoritide in the target population. 
4.6 
Blinding and Randomization Methods 
4.6.1 Blinding Method 
This is a placebo-controlled, double-blind study.  Blinding is strictly maintained during the 
study and a study specific masking plan describes how potentially unblinding data are 
handled during the lifetime of the study. The study will remain blinded until after all data has 
been entered, and the final database has been locked. 
4.6.2 Randomization Method 
The centralized randomization with stratification is managed by an external vendor, using 
IXRS technology.   
Subjects will be enrolled into 3 age cohorts based on age at study screening starting with the 
eldest population. In each cohort, eligible subjects will be randomized in a 1:1 ratio to 
vosoritide or placebo after 3 sentinel subjects are treated. Cohorts 1 and 2 will be stratified by 
age. Subjects are randomized separately within each cohort in Japan.  
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4.7 
Interim Analysis 
No formal interim futility/efficacy analyses are planned. Two informal interim analyses 
including data from both Studies 111-206 and 111-208 were performed for selected domains: 
one for New Drug Application (NDA) to Food and Drug Administration (FDA) and 
marketing authorization applications (MAA) to European Medicines Agency (EMA), dated 
18December 2019, and another for Japan New Drug Application (JNDA), dated 
11November 2020. For these analyses, subjects remained blinded and no efficacy data was 
analyzed for the randomized subjects nor post baseline listings except for serious adverse 
events. 
In addition to safety and PK monitoring by BioMarin Personnel, an independent data 
monitoring committee (DMC) will act in an advisory capacity to BioMarin to monitor 
subject safety and PK of subjects who participate in the study. A DMC review will occur to 
evaluate all available safety and PK data after the sentinel subjects complete 12 weeks of 
dosing, and DMC will make recommendations for stopping or continuing the study, and 
endorse dose adjustments if needed, based on pre-specified criteria. DMC data review 
meetings occur approximately every 6 months during the course of the study. 
 
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5 
GENERAL ANALYSIS CONSIDERATIONS 
The analyses described in this final SAP are based on Amendment 2 of the protocol 
(date: 08 February 2019). 
Individual subject data that is reflected in data summaries will be provided in listings. Unless 
otherwise specified, all listings will be by cohort, by sentinel/randomized subjects, by 
treatment group, and ordered by subject number, where subject number includes the site 
number.  
Unless otherwise specified, summary tables for efficacy variables will use format in 
Table 5.1, Table 5.2, and Table 5.3 for Cohorts 1, 2, and 3, respectively.  Summary tables for 
safety variables will be separated by cohort and overall by treatment group using format in 
Table 5.4.  
Table 5.1:  Format for Efficacy Summary Analyses for Cohort 1 
Sentinel 
Randomized 
All Vosoritide Treated* 
Vosoritide 
Placebo 
≥ 24 to 
< 36 
months 
≥ 36 to 
< 60 months 
Over
all 
≥ 24 to < 
36 
months 
≥ 36 to 
< 60 months 
Over
all 
≥ 24 to < 
36 
months 
≥ 36 to 
< 60 months 
Over
all 
*All vosoritide treated includes sentinel subjects and randomized subjects who received vosoritide. 
 
Table 5.2:  Format for Efficacy Summary Analyses for Cohort 2 
Sentinel 
Randomized 
All Vosoritide Treated* 
Vosoritide 
Placebo 
≥ 6 to 
< 15 
months 
≥ 15 to 
< 24 months 
Over
all 
≥ 6 to < 
15 
months 
≥ 15 to 
< 24 months 
Over
all 
≥ 6 to < 
15 
months 
≥ 15 to 
< 24 months 
Over
all 
*All vosoritide treated includes sentinel subjects and randomized subjects who received vosoritide. 
 
Table 5.3:  Format for Efficacy Summary Analyses for Cohort 3  
Sentinel 
Randomized 
All Vosoritide Treated* 
Vosoritide 
Placebo 
*All vosoritide treated includes sentinel subjects and randomized subjects who received vosoritide. 
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Table 5.4:  Format for Safety Summary Analyses for Cohort 1* 
Sentinel 
Randomized 
All Vosoritide Treated** 
Vosoritide 
Placebo 
* Cohort 2, Cohort 3, and Overall will have the same format as Cohort 1. 
**All vosoritide treated includes sentinel subjects and randomized subjects who received vosoritide. 
 
Baseline growth measures (other than AGV, baseline AGV is defined in Section 14.3.2) and 
baseline weight are those assessed on Day 1 of dosing, regardless of timing relative to 
dosing. (Note: If no assessments are available, then the baseline assessment will be the last 
non-missing assessment prior to Day 1).  Baseline assessments are the last non-missing 
on-study assessments prior to administration of study treatment. Change from baseline is 
calculated as: (post-baseline value – baseline value); Percent change from baseline is 
calculated as: ([post-baseline value – baseline value]/baseline value) x100. 
The screening visit will not be presented in descriptive summaries over time.  When the 
analysis windows have been applied (see Section 5.4), data collected at the screening visit 
may be included in the baseline assessment.  All assessments will be listed, but only those 
assessments assigned to visits according to the windows applied (see Section 5.4) will be 
summarized in tables or graphically.  Exceptions to this are summaries of the worst 
post-baseline laboratory data in shift tables where all assessments are considered. 
Unless otherwise specified, summary statistics n, mean, standard deviation (SD), median, 
25th and 75th percentile, minimum, and maximum will be provided for numerical variables. 
The mean, 25th percentile, median, 75th percentile, and estimates of precision (e.g. SD, 
confidence interval) will be displayed to one more decimal place than the collected data. 
Minimum and maximum values will be presented to the same decimal places as the collected 
data. The number of decimal places to which endpoints are reported follow the project 
programming standards. 
Number and percentage will be provided for categorical variables. When summarizing 
categorical data, for mutually exclusive categories, the sum of the individual categories, 
including a separate “Missing” category, should equal 100%.  Unless otherwise specified, if 
categories have no data, then they will not be displayed.  
All statistical analyses will be performed using SAS® version 9.4 or a later release (SAS 
Institute, North Carolina, USA) and results be presented in the form of tables, listings, and 
graphs (TLGs). All statistical analyses, including dataset creation and output generation, will 
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be performed by Biostatistics and Statistical Programming personnel of BioMarin’s 
Biometrics department. 
5.1 
Analysis Populations 
5.1.1 Full Analysis Set 
The Full Analysis Set (FAS) is defined according to the intent-to-treat principle and includes 
all enrolled sentinel and randomized subjects with a signed informed consent. The FAS will 
be the main analysis population for summaries and/or analyses described in the SAP, 
including but not limited to summaries and/or analyses of demographics, baseline 
characteristics, dispositions, and all efficacy endpoints.   
All listings, excluding screen failures, will be produced on the FAS. 
5.1.2 Per-Protocol 
The Per-Protocol (PP) population is defined as a subset of the FAS population who 
completed the treatment originally allocated (i.e., always received the assigned treatment 
(vosoritide or placebo)), with a standing height/body length assessment at Week 52 following 
protocol window, and with treatment compliance of at least 80%. 
The PP population will be used for sensitivity analysis of the primary and key secondary 
efficacy endpoints only. 
5.1.3 Safety 
The Safety Population is a subset of the FAS who receive at least one dose of vosoritide or 
placebo in the study. The Safety Population will be used to present the safety summaries by 
actual treatment received. Subjects randomized to one treatment group, who only receive the 
study treatment for the other treatment group, will be analyzed in the arm of the study 
treatment they received. 
The Safety Population will be used to present the safety data.   
5.1.4 PK 
The PK Population is defined as all sentinel subjects and subjects randomized to vosoritide 
treatment group, who received at least one dose of vosoritide in this study and have at least 
one evaluable PK concentration. 
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5.1.5 Immunogenicity 
The Immunogenicity Population is defined as all subjects in the Safety Population who have 
at least one evaluable immunogenicity sample. Subjects randomized to one treatment group, 
who only receive the study treatment for the other treatment group, will be analyzed in the 
arm of the study treatment they received. 
5.2 
Pooling of Data from Sites with Small Enrollment 
Not applicable, as there are no analyses by site.  
5.3 
Study Day Derivation 
Study day in 111-206 will be determined by subtracting the initial study treatment start date 
from a visit date plus 1 if the visit date occurs on or after the initial study treatment start date. 
Otherwise, the study day will be the visit date minus the initial study treatment start date. 
Therefore, Study Day 1 will occur on the initial study treatment start date. i.e. 
• Study Day 1 = Day of first dose of study treatment. 
• If Visit Date < Study Treatment Start Date, then Study Day = Visit Date - Study 
Treatment Start Date 
• If Visit Date >= Study Treatment Start Date, then Study Day = Visit Date - Study 
Treatment Start Date +1 
5.4 
Visit Windows for Analysis 
An assessment for a subject will be classified according to the study day of the assessment 
where it falls within a window.   
Observational data in 111-901 for subjects who enrolled in 111-206 and are included in the 
corresponding analysis population will be used in efficacy summary tables and figures. 
For Cohort 3 subjects, data from the observational period in 111-901 or 111-206 will be 
included. The analysis visits and windows for observational assessments in 111-901 and 
111-206 are defined in Table 5.4.1. Unless otherwise specified, only the derived visits listed 
in the table will be included in summary tables and figures. 
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Table 5.4.1:  Visit Windows for Observed Assessments in BMN 111-901 and 
BMN 111-206  
Derived Visit 
Target Daya 
Analysis Windowa 
≥ 3 Months Prior in 111-206 or 111-901 for Cohort 3 subjects* 
-91 
target day +/- 42 days 
≥ 6 Months Prior in 111-901* 
-182 
target day +/- 42 days 
a Target days and analysis windows are relative to the 111-206 Day 1 date defined in Section 5.3 above. 
* In the event a subject does not have an assessment in the 3 months prior or 6 months prior window then the 
closest assessment to the target date will be considered. If the two closest assessments to the target day are 
equidistant from the target day, the latest assessment will be used.  
 
For each subject and growth measure in study 111-901, the record closest to the target day 
within the analysis window will be retained for inclusion in summary tables. 
Spaghetti plots of standing height/body length Z-score will include measures every 6 months 
recorded and including the “≥ 6 months prior”, “≥ 3 months prior” for subjects in Cohort 3 
from Study 111-901 or 111-206. This will allow for all subjects with height assessments ≥ 3 
months prior to Day 1 to have at least one assessment included.  
The analysis windows for assessments in 111-206 are defined in Table 5.4.2. The analysis 
windows are designated to be consecutive for scheduled visits to accommodate delayed visits 
due to impact of COVID-19. The upper bound of each visit window will be target day plus 
half of the difference between the current target day and the next target day, and the lower 
bounds of the window will be the upper bound of the previous window plus 1 except for 
Day 1, Day 2, Day 3, and Week 52. Lower bound, upper bound, and target date are the same 
for Day 1, Day 2, and Day 3. The upper bound of Week 52 will be target day plus 42 days. If 
there are two or more assessments within a designated window, the assessment that is closest 
to the target day will be used for analyses.  If the two closest assessments to the target day are 
equidistant from the target day, the assessments taken on a scheduled visit per case report 
form (CRF) page will be used; if both are scheduled visits but not on the same day, the latest 
assessments will be used; if both are on the same day, the average of the assessments will be 
used.  Unless otherwise specified, all analyses are based on derived visits. 
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Table 5.4.2:  Visit Windows for Observed Assessments in 111-206  
Derived Visit 
Target Daya 
Analysis Windowa 
Baseline 
 
The last assessment prior to the first dose of study treatment unless 
otherwise specified. 
Day 1 
Day 1 
Day 1 
Day 2 
Day 2 
Day 2 
Day 3 
Day 3 
Day 3 
Day 8 
Day 8 
Day 4 - 15 
Week 3 
Day 22 
Day 16 - 33  
Week 6 
Day 43 
Day 34 - 68  
Week 13 
Day 92 
Day 69 -117  
Week 20 
Day 141 
Day 118 - 162  
Week 26 
Day 183 
Day 163 - 229  
Week 39 
Day 274 
Day 230 - 320  
Week 52 
Day 365 
Day 321 - 407  
a Target days and analysis windows are relative to Day 1 date defined in Section 5.3.  
 
5.5 
Handling of Dropouts and Missing Data 
For descriptive summaries, missing data will not be imputed. For model-based analyses, an 
imputation will be conducted for endpoints missed at Week 52. Detailed imputation rules are 
described in Section 14.1.  
Other than for partial/missing dates described below, there will be no imputation for safety 
data. 
5.5.1 Partial Dates 
Where start and stop dates for medications or adverse events are incomplete, imputation rules 
will be applied.  
In the event that the start date of a medication/AE is partial, the following imputation rules 
will be applied: 
• If only day is missing, then the start date will be imputed as the first day of the month. 
If month and year are the same as the month and year of first dose of study treatment, 
then the start date will be imputed as the first dose date in the study in which the AE 
occurred.  
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• If only year is non-missing, then the start date will be imputed as the first day of the 
year. If year is the same as the year of first dose of study treatment, then the start date 
will be imputed as the first dose date in the study in which the AE occurred. 
In the event that the stop date of a medication/AE is partial, the following imputation rules 
will be applied: 
• If only day is missing, then the end date will be imputed as the last day of the month.  
• If only year is non-missing, then the end date will be imputed as the last day of the 
year. If the imputed date is beyond the study completed or discontinued date of the 
study in which the AE occurred, the imputed date will be replaced with the study 
completed or discontinued date. 
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6 
SUBJECT DISPOSITION 
Disposition will be presented based on the FAS. The number of subjects 
enrolled/randomized, the number of subjects who received study treatment, the number of 
subjects who completed study treatment, and the number of subjects who completed the 
study will be reported separately by cohort and overall by treatment group using format as 
specified in Table 5.4.  
Disposition data will be listed for both the sentinels and randomized subjects by cohort and 
treatment group, and will indicate the investigator site. In addition, a listing will be provided 
for those subjects who were screen failures, along with the reason for screen failure. 
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7 
DISCONTINUATION AND COMPLETION  
For subjects who prematurely discontinued from the study, the primary reason for 
discontinuation will be summarized. A similar summary will be provided for subjects who 
discontinued study treatment. 
The number of subjects who completed study treatment and the number of subjects who 
completed the study will be summarized by cohort and overall by treatment group using 
format as specified in Table 5.4. All summaries will be based on the FAS. 
Listing will be provided on the FAS. 
 
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8 
PROTOCOL EXEMPTIONS AND DEVIATIONS  
The number and percentage of subjects with any protocol deviation, any major protocol 
deviation, and any minor protocol deviation will be presented separately by cohort and 
overall by treatment group using format as specified in Table 5.4, according to the categories 
described in the study specific protocol deviation plan. Reasons for major/minor deviations 
will be summarized. Subjects who received the wrong treatment will be identified after data 
base lock and considered as a Major Protocol Deviation. 
All summaries will be based on the FAS. 
All protocol deviations will be listed for sentinel and randomized subjects by cohort. 
sentinel/randomized subjects, treatment group, and subject ID. A separate listing of all major 
deviations which have been classified as a “Dosing Irregularity” will also be provided. 
In addition, a summary and listing of COVID-19 specific protocol deviations will be 
provided.   
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9 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographic and baseline characteristics will be summarized for the FAS, and presented for 
by cohort by treatment group with the format as specified in Table 5.1, Table 5.2, and 
Table 5.3 for Cohorts 1, 2, and 3, respectively and Table 5.4 for Overall. Rules on standing 
height/body length and sitting height/crown to rump length are provided in Section 14.1. 
Demographics will be summarized as: 
• Age at Screening (months with 1 decimal place) 
• Age at Day 1 (months with 1 decimal place) 
• Sex (Male, Female) 
• Race (American Indian or Alaska Native, Asian [Japanese/Other], Black or African 
American, Native Hawaiian or Pacific Islander, White, Multiple, Not Provided Due to 
Patient Privacy Rules) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
Baseline characteristics will be summarized as: 
• Weight (kg) and Weight Z-score 
• Body Mass Index (BMI) (kg/m2), and also BMI Z-score for subjects aged 24 months 
or older  
Baseline growth measures will be summarized as: 
• Height Z-Score (Refer to Section 14.2.1)  
• AGV (cm/yr)  
• Standing Height/Body Length (cm)  
• Sitting Height/Crown to Rump(cm)  
• Lower Body Length (cm) = Standing Height - Sitting Height  
• Head Circumference (cm) 
• Upper Arm Length (cm) 
• Lower Arm (Forearm) Length (cm) 
• Arm Span (cm) 
• Upper Leg Length (Thigh) (cm) 
• Knee to Foot Height (cm) 
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• Tibial Length (cm) 
• Upper to Lower Body Segment Ratio 
• Arm Span to Standing Height Ratio  
• Upper Arm Length to Lower Arm (Forearm) Length Ratio 
• Upper Leg Length to Tibial Length Ratio 
A listing of each sentinel and randomized subject’s demographic/baseline data will be 
provided. 
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10 
MEDICAL HISTORY 
Medical history will be solicited from each subject, including all major illnesses, diagnoses, 
and surgeries that the subject has ever had; any prior or existing medical conditions that 
might interfere with study participation or safety; and evaluation for knee, thigh, hip or groin 
pain, or change in gait/activity.  
All medical history terms will be coded in accordance with MedDRA Version 24.1 that each 
term is assigned a SOC and PT.   
A list of PTs considered to be ACH-related will be reviewed prior to the data cut. A listing 
for the complete list of final terms will be generated, retained in the study file, and 
documented in the CSR.  
All recorded medical history will be summarized on the FAS by SOC and by PT by cohort 
and overall by treatment group using format as specified in Table 5.4, ordered by descending 
order of frequency of SOC in the overall population. In addition, achondroplasia-related 
medical history will be listed and summarized separately by SOC and PT in a similar 
manner. 
The number of subjects with abnormal physical exam results at screening will be 
summarized and listed. 
A listing of each subject’s medical history will be provided, plus a listing of each subject’s 
achondroplasia-related medical history. 
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11 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior and concomitant medications will be summarized for the FAS.  For analysis purposes, 
the following definitions will be used to determine prior and concomitant medications for the 
entire study period: 
• Prior medications: Any medications taken and ended prior to the initial study 
treatment administration date will be considered prior medications. 
• Concomitant medications: Any medications taken on or after the initial study 
treatment administration date up to 30 days after discontinuation of study treatment 
will be considered concomitant medications and included in summary tables. This 
also includes medications initially taken prior to the initial study treatment 
administration date but continued or ended on or after the initial study treatment 
administration date. 
Concomitant medications will be summarized separately by cohort and overall by treatment 
group using format as specified in Table 5.4, and a separate summary will be provided which 
includes only those concomitant medications that were initiated on study.  
All medications will be coded using the latest version available within BioMarin of the 
World Health Organization Drug (WHO Drug) dictionary (Version September 2021).  Prior 
and concomitant medication use will be separately summarized by Anatomical Therapeutic 
Chemical (ATC) medication class (Level 2) and preferred name (i.e., generic medication 
name). If a medication doesn’t have ATC level 2, they are grouped as “ATC Level 2 
classification unavailable”. A subject reporting the same medication more than once will be 
counted once when calculating the number and percentage of subjects who received that 
medication. A listing of prior and concomitant medications will be provided. In addition, a 
listing for COIVD vaccine will be provided.  
 
 
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12 
COMPLIANCE 
Treatment compliance will be calculated based on the study treatment preparation and study 
treatment administration records captured in the eCRF, and summarized separately by cohort 
and overall by treatment group using format as specified in Table 5.4 for the safety 
population.  
For each subject it considers all data up to the last recorded dose. For each column, results 
will be separated for 15 µg/kg, 30 µg/kg, and overall.   
For each daily injection, the amount of study treatment taken will be calculated based on the 
number of units in the syringe pre-injection, minus the number of units remaining in the 
syringe post-injection. For the cases that the number of units in the syringe pre-injection is 
not captured in the eCRF, if response to “Was study drug administrated?” is “Yes”, then it 
will be assumed to be the same as the planned dose; if response to “Was study drug 
administrated?” is “No”, then it will be assumed to be missing and these records will not be 
included in the compliance calculation.  
The total amount of study treatment taken (µg) will be calculated based on the amount of 
study treatment taken (units) in the corresponding treatment duration by using the following 
formula:  
          dose of study treatment (µg) = unit of study treatment * vial concentration/ weight *10. 
The total amount of study treatment planned (µg) is determined based on the duration of 
treatment and the planned dose per day, where dose will be calculated based on the planned 
unit per day by using the same formula as above. 
Percentage compliance for each subject will be derived from the total amount of study 
treatment intake divided by the planned study treatment intake, and multiplied by 100: 
Treatment Compliance (%) = 
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝑜𝑜𝑜𝑜 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 (𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑)
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝑜𝑜𝑜𝑜 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 (𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) x 100 
Treatment compliance will be calculated and summarized separately by cohort and overall by 
treatment group using format as specified in Table 5.4. For each column, results will be 
separated for 15 µg/kg, 30 µg/kg, and overall.   
• Compliance with protocol-specified treatment regimen (%) 
• Compliance with protocol-specified treatment regimen (≥50%, ≥60%, ≥70%, ≥80%, 
≥90%, ≥100%, >=110%, >=120%) 
Listings will be provided for compliance.  
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13 
EXTENT OF EXPOSURE TO STUDY TREATMENT 
Dosing information is recorded by subjects in the paper diary and also by the site on visit 
days.  In the case of duplicate records with the same date, if the investigator confirms the 
date, then investigator reported dosing data will be used.  All summaries will be produced 
based on the safety population, and presented separately by cohort and overall by treatment 
group using format as specified in Table 5.4. For each column, results will be separated for 
15 µg/kg, 30 µg/kg, and overall.   
Descriptive statistics will be provided for the following variables:  
• Duration of treatment (days) 
= Date of last dose – Date of first dose + 1 
• Total number of doses administered 
= Number of doses administered between date of Day 1 and date of last dose 
• Total number of doses missed 
= Number of doses missed between date of Day 1 and date of last dose 
• Total amount of weight adjusted dose administered (µg/kg) by planned dose  
• Average weight-adjusted daily dose administered (µg/kg/day) by planned dose  
The frequency and percent of subjects will be provided for the following variables, where 
missed doses are counted between the date of first dose (Day 1) and date of last dose: 
• Number of subjects who missed at least one dose 
• Number of subjects who missed more than one dose 
• Number of subjects who missed more than 5 consecutive doses 
• Number of subjects who missed more than 10 consecutive doses 
The frequency and percent of events will be provided overall for the following variable: 
• The total number of missed doses and reason for each missed dose (Site Error, 
Parent/Caregiver Error, Home Health Error, Adverse Event, Other, Missing) will be 
provided.   
A listing of each subject’s extent of exposure by planned dose 15 µg/kg and 30 µg/kg will 
also be provided.  
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14 
EFFICACY EVALUATIONS 
14.1 
General Approaches for Analyzing Growth Parameters 
All growth parameters assessed by anthropometric measurements are measured at Baseline, 
Day 1, Week 6, Week 13, Week 26, Week 39, Week 52, and early termination visit.  
Growth parameters are measured 3 times for each assessment. It is the mean of these 3 
assessments that are considered for the summaries and analyses. In the event that all 3 are not 
available, the mean of the 2, or the individual assessment is taken. All measures and means 
of the measures will be included in the listings. 
The general rule when summarizing height (standing and sitting) is that standing 
height/sitting height will be used if subjects ≥ 24 months, body length/crown to rump will be 
used if subjects < 24 months. For subjects with both sets of measurements available, like to 
like will be used based on their measurements available for their age at baseline.  
Thus, in general, for subjects in Cohort 1 standing height and sitting height will be 
summarized. For subjects in Cohorts 2 and 3 body length and crown to rump will be 
summarized.  If body length is not measured and standing height is available, standing height 
will be used. If both sets of measures are available, like to like will be used based on their 
measurements available for their age at baseline.  
These rules will impact the following growth endpoints: standing height/body length 
Z-Score, standing height/body length, AGV, sitting height/crown to rump, lower body length, 
arm span to height ratio, upper to lower body segment ratio, BMI, and BMI Z-score. 
BMI and BMI Z-score will only be derived for subjects aged 24 months or older. 
Body length and crown to rump will not be summarized separately but integrated within the 
summaries for standing height and sitting height. Body length and crown to rump are 
however provided separately in a listing. 
Appendix 25.1 provides details of the derivations used for each endpoint. 
All efficacy endpoints will be assessed using the FAS.  
Visit windows are applied for all assessments (see Section 5.4) and are used to summarize 
the growth measures by visit. 
All parameter assessments are considered for inclusion in analyses.  
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With the exception of AGV (see Section 14.3.2), summary tables for all growth measures 
including standing height/body length Z-score, standing height/body length, upper to lower 
body segment ratio, body proportion ratios, other growth measures (see Section 14.3.5), 
BMI, BMI Z-scores, and weight Z-scores will include assessments at baseline, Week 26 and 
Week 52 from Study 111-206, and 6 months prior in Study 111-901. For subjects in Cohort 3 
assessments at 3 months prior to baseline in Studies 111-206 or 111-901 will be included.  
Each table will include summaries of the absolute observed measures and its change from 
baseline at each of these time points. The tables will summarize data separately by cohort by 
treatment group using format as specified in Table 5.1, Table 5.2, and Table 5.3 for Cohorts 
1, 2, and 3, respectively. 
ANCOVA models will be conducted for change from baseline at Week 52 in standing 
height/body length Z-Score, standing height/body length, AGV, and upper to lower body 
ratio for all cohorts overall and/or by cohort, as appropriate. Unless otherwise specified, all 
models will include the following baseline covariates: age at baseline, baseline AGV, and 
sex. Analyses of standing height/body length Z-Score, standing height/body length, and 
upper to lower body ratio will include their baseline as additional covariate.  
For the model-based analyses, if the required assessment at Week 52 is missing but there are 
height assessments before and after Week 52, a linear interpolation using the measurements 
closest to the before and after Week 52 will be used, otherwise those with no assessment 
after Week 52 will be excluded from the primary analyses.  
In addition to the primary analyses conducted on FAS, sensitivity analyses will also be 
conducted and are described in Section 14.2. 
Results of the statistical analyses will be provided in separate tables, including the least-
squares (LS) mean change from baseline at Week 52 for each treatment group, the treatment 
difference in LS means (calculated as vosoritide - Placebo), the 95% confidence interval (CI) 
for the treatment difference, and corresponding 2-sided p-value. 
Listings for standing height/body length and standing height/body length z-score will include 
all assessments (i.e., all measures and means of the measures) and spaghetti plots for height 
and height Z-score will include assessments every 6 months and will be ordered by cohort, 
sentinel/randomized subject, treatment, subject ID and visit date including 111-901 and 
111-206. 
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14.2 
Primary Efficacy Endpoint 
The primary efficacy endpoint is change from baseline in standing height/body length Z-
score at Week 52.  
Each measurement of derived standing height/body length will be converted to an age-and 
sex-appropriate standard deviation score (SDS), also referred to as a Z-score, by comparison 
with reference data available for average stature children from the CDC. Note no data 
conversions are applied between body length and standing height as recommended for 
average stature.  
Standing height/body length Z-scores will be derived using CDC references and macro 
(CDC, 2019). 
14.2.1 Primary Analyses  
The standing height/body length Z-score at ≥ 6 Months Prior to baseline, ≥ 3 Months Prior  
to baseline for Cohort 3, baseline, Week 26 and Week 52, and it’s change from baseline at 
Week 26 and Week 52 will be summarized and presented separately by cohort by treatment 
group using format as specified in Table 5.1, Table 5.2, and Table 5.3 for Cohorts 1, 2, and 3, 
respectively.  
A spaghetti plot of the height Z-score will be presented for each subject.  
Height Z-scores derived for all visits from 111-901 and 111-206 will be included in data 
listings and height Z-scores derived for every 6 months (including 6-month prior and 3-
month prior) will be included in the spaghetti plots. 
For the model-based ANCOVA analyses, estimand formulation is as follows: 
• Population: FAS  
• Variable: Change from baseline in standing height/body length Z-Score at Week 52 
• Intercurrent event: Regardless of whether or not switching to rescue medication had 
occurred or subjects had discontinued from the treatment. See Section 14.1 for 
handling of missing data 
• Population-level summary: Lsmean difference and 95%CI between the treatment 
groups based on ANCOVA models defined in Section 14.1 
ANCOVA model will include the fixed-effects of treatment (active arm vs. placebo arm) and 
baseline covariates, where baseline covariates include age at baseline, sex, baseline AGV, 
and baseline height Z-score. The following SAS Proc Mixed with option OBSMARGINS for 
lsmeans will be used to perform the analysis:  
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PROC MIXED;  
CLASS Treatment Sex;  
MODEL Change from baseline in height Z-Score at Week 52 = Treatment 
Age_baseline Sex AGV_baseline Height Z-Score_baseline;  
LSMEANS Treatment / DIFF CL OM;  
ESTIMATE 'Active - Placebo' Treatment 1 -1/CL; 
RUN;  
The analysis will be repeated by also including sentinel subjects from the corresponding 
cohort. 
14.2.2 Sensitivity Analyses  
The following sensitivity analyses will be conducted on the primary efficacy endpoint: 
(1) Summary statistics and model-based analyses on the subjects in the PP population  
(2) Model-based analyses using a multiple imputation washout model to derive missing 
data at week 52 for subjects excluded from the primary analysis 
14.3 
Secondary Efficacy Endpoint(s) 
14.3.1 Standing Height/Body Length 
Rules for standing height/body length is described in Section 14.1.  
The standing height/body length and its change from baseline will be summarized and 
presented separately by cohort by treatment group using the format as specified in Table 5.1, 
Table 5.2, and Table 5.3 for Cohorts 1, 2, and 3, respectively.   
Standing height/body length will be analyzed using the same methods and estimand 
formulation as the primary efficacy endpoint analysis and sensitivity analyses. An analysis of 
change from baseline in standing height/body length at Week 52 will be performed using an 
ANCOVA model that includes the fixed-effects of treatment (active arm vs. placebo arm) 
and baseline covariates, where baseline covariates include age at baseline, sex, baseline 
AGV, and baseline standing height/body length.  
Standing height/body length for all visits will be included in data listings including data from 
111-901 and 111-206. 
Spaghetti plots of standing height/body length at every 6 months assessments including 
height assessments collected in the 111-901 study (3-month prior for Subjects in Cohort 3) 
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will be provided for each subject separately by cohort. This plot will include age-sex specific 
reference ranges for average stature children (from CDC, 2019) and age-sex specific 
reference ranges for short stature children (Hoover-Fong, 2008). 
For these plots if only body length is used, it will be indicated in the plot. 
14.3.2 Annualized Growth Velocity 
For a given interval [Date1, Date2], the AGV is defined as follows: 
AGV (cm/yr) = (Derived Standing Height at Date 2-Derived Standing Height at Date 
1)/(Interval Length (Days)) x 365.25 
where the interval length in days is calculated as Date2 - Date1.  
AGV (cm/yr) will be calculated at baseline, Week 26, and Week 52. AGV at baseline will be 
calculated by using height measurements in Study 111-901 at least 6 months prior to Day 1 
of Study 111-206 for subjects in Cohorts 1 and 2, and using height measures in Study 
111-901 or 111-206 at least 3 months prior to Day 1 of Study 111-206 for subjects in Cohort 
3. AGV at other time points will be calculated cumulatively from Day 1 of 111-206 and 
every 6 months interval.  
The absolute values for cumulative AGV and 6-month AGV and their change from baseline 
will be summarized and presented separately by cohort by treatment group using the format 
specified in Table 5.1, Table 5.2, and Table 5.3 for Cohorts 1, 2, and 3, respectively.  
Cumulative AGV will be analyzed using the same methods and estimand formulation as the 
primary efficacy endpoint analysis and sensitivity analyses. An analysis of change from 
baseline in cumulative AGV at Week 52 will be performed using an ANCOVA that includes 
the fixed-effects of treatment (active arm vs. placebo arm) and baseline covariates, where 
baseline covariates include age at baseline, sex, and baseline AGV.  
A box and whisker plot will be provided for AGV (cm/yr) over time by cohort and treatment 
group. 
Listings and individual subject figures for the cumulative AGV and 6 months AGV will 
include AGV for all height assessments at all scheduled visits. 
14.3.3 Upper to Lower Body Segment Ratio 
The upper to lower body segment ratio will be calculated at each visit as follows: 
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Upper to Lower Body Segment Ratio = 
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝑑𝑑 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 ℎ𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝑡𝑡(𝑐𝑐𝑐𝑐)
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 ℎ𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝑡𝑡(𝑐𝑐𝑐𝑐)−𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 ℎ𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝑡𝑡(𝑐𝑐𝑐𝑐). 
The ratio of derived sitting height and derived standing height will also be calculated.  
The upper to lower body segment ratio, the sitting to standing height ratio, and their change 
from baseline will be summarized and presented separately by cohort by treatment group 
using the format as specified in Table 5.1, Table 5.2, and Table 5.3 for Cohorts 1, 2, and 3, 
respectively.   
Upper to lower body segment ratio will be analyzed using the same methods and estimand 
formulation as the primary efficacy endpoint analysis and sensitivity analyses, an analysis of 
change from baseline in the upper to lower body segment ratio at Week 52 will be performed 
using an ANCOVA model that includes the fixed-effects of treatment (active arm vs. placebo 
arm) and baseline covariates, where baseline covariates include age at baseline, sex, baseline 
AGV, and baseline upper to lower body segment ratio.  
Upper to lower body segment ratio and sitting to standing height ratio derived for all visits 
will be included in data listings including data from 111-901 and 111-206. 
14.3.4 Body Proportion Ratios 
Body proportion ratios include:  
• Upper Arm Length to Lower Arm (Forearm) Length Ratio 
• Upper Leg Length (Thigh) to Knee to Heel Length Ratio 
• Upper Leg Length (Thigh) to Tibial Length Ratio 
• Arm Span to Standing Height Ratio 
The absolute values and its change from baseline will be summarized and presented 
separately by cohort by treatment group using the format as specified in Table 5.1, Table 5.2, 
and Table 5.3 for Cohorts 1, 2, and 3, respectively.   
All assessments will be listed. 
14.3.5 Other Growth Measures 
Other growth measures include:  
• Sitting Height (cm)/Crown to Rump (cm) 
• Upper Leg Length (Thigh) (cm) 
• Lower Leg Length: Knee to Foot (cm) 
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• Lower Leg Length: Tibia Length (cm) 
• Head Circumference (cm) 
• Upper Arm Length (cm) 
• Lower Arm (Forearm) Length (cm) 
• Arm Span (cm) 
In addition, derived standing height and derived sitting height will be calculated as specified 
in Section 14.1, and a measure of lower body length will be calculated as follows: 
• Lower Body Length (cm) = Derived Standing height – Derived Sitting height 
Baseline growth measures are those assessed on Day 1, regardless of timing relative to 
dosing. All summaries and analyses will be based on the FAS. 
For each of the above growth measures (including lower body length), the absolute values 
and its change from baseline will be summarized and presented by cohort by treatment group 
using the format as specified in Table 5.1, Table 5.2, and Table 5.3 for Cohorts 1, 2, and 3, 
respectively.   
All assessments will be listed by subject and visit. 
14.4 
Health-Related Quality of Life 
The Health-Related Quality of Life (HRQoL) questionnaires and functional independence 
questionnaires are captured at Baseline, Week 26, Week 52.  All summaries will be 
generated on the FAS. 
Each table will include summaries of the absolute measures at each of these time points and 
change from baseline at every 26 weeks. The tables will be summarized separately by cohort 
by treatment group using the format as specified in Table 5.1, Table 5.2, and Table 5.3 for 
Cohorts 1, 2, and 3, respectively.  
The statistical summaries will include the number of subjects with assessable data, mean, SD, 
median, 25th and 75th percentile, minimum and maximum. Subjects will not be included in a 
summary table if there is no baseline assessment available.  
Separate summary tables will be provided for the total summary scores and the individual 
domains (scales). Individual questions (items) are not included in the summary tables. 
Age-defined versions within the same questionnaire will be summarized together. If subjects 
progress during the course of the study from one age-defined questionnaire to the next age-
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defined questionnaire the results will be summarized together and the baseline assessment 
from the child’s first questionnaire is referred to when summarizing change from baseline. 
If a questionnaire for the wrong age group was filled, outcomes will not be included in the 
summary table but will be included in the listings.  
Self-reports and parent-reports will be summarized separately but together in the bat charts. 
All subject data listings will include total scores, and domain (scale) scores. 
14.4.1 Bayley-III 
The Bayley-III is a performance-based outcome assessment for use in children from 1 to 
42 months.  
Scales include Cognitive scale, Language (Receptive Communication and Expressive 
Communication subscales) scale, and Motor (Gross and Fine Motor subscales) scales. 
In addition to its use for subjects ranging from 1 to 42 months old, the Bayley-III assessment 
will be administered to those entering the study between 42 and 60 months old and for the 
remainder of the duration of this study, as this assessment can capture ongoing 
developmental issues associated with ACH. Bayley-III is waived for subjects < 1 month old. 
Scales/Subscales: 
• Cognitive 
• Language 
o Receptive Communication  
o Expressive Communication  
• Motor 
o Fine Motor  
o Gross Motor   
Each (sub)scale yields a total raw score which is then standardized according to the subject’s 
chronological age (scaled scores). 
Scoring 
Number of items depends on which set is given in each domain. The number of questions 
administered depends in part on the child’s age and on their developmental level. 
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The total raw scores for the Cognitive Scale and the Receptive Communication, Expressive 
Communication, Fine Motor, and Gross Motor subscale are the sums of the number of points 
earned for a (sub)scale. 
The raw scores cannot be accurately compared to each other as each subscale has a different 
number of items resulting in a different range of possible scores. Therefore, the comparisons 
are best based on derived scores: age-based scaled scores or composite scores8. 
Scaled scores represent a child’s performance on a (sub)scale relative to the same age peers. 
They are derived from the total raw scores on each of the subscale and are scaled to a metric 
with a range of 1 to 19, a mean of 10 and a SD of 3. 
Composite scores are scaled to a metric with a mean of 100 and a SD of 15, and range from 
40–160. 
For the Language and Motor Scale, composite scores are derived from the sums of 
age-corrected scaled scores. For each composite, the distribution of the sum of scaled scores 
is used to derive corresponding percentiles which are converted to composite scores with a 
mean of 100 and a standard deviation of 15. 
For the Cognitive subdomain the scaled score to composite equivalent is a linear conversion 
from one scale (mean=10, SD=3) to another (mean=100, SD=15).  
For the scaled scores and composite scores, the absolute values will be summarized 
separately by cohort by treatment group using the format as specified in Table 5.1, Table 5.2, 
and Table 5.3 for Cohorts 1, 2, and 3, respectively. 
The 3 composite scores (Cognitive, Language and Motor) will be displayed by cohort and 
treatment group in a bar chart. 
14.4.2 Infant and Toddler Quality of Life Questionnaire (itqol-97, 2013) (ITQOL) 
The Infant Toddler Quality of Life questionnaire (ITQOL) is an observer-reported outcome 
tool developed for use in children from 2 months to 5 years old that attempts to capture 
physical, mental and social well-being. The ITQOL adopts the World Health Organization’s 
definition of health as a state of complete physical, mental and social well-being, and not 
merely the absence of disease. The ITQOL also assesses the quality of the parents/guardians’ 
life. The 97-item full-length version (ITQOL) will be used for this study. ITQOL is waived 
for subjects < 2 months old. 
Domains 
The following domains are part of the ITQoL: 
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• Overall Health (1item) 
• Physical abilities (10 items) 
• Growth and development (10 items) 
• Pain (3 items) 
• Temperament and mood (18 items) 
• Behavior (12 items) 
• Global behavior (1 items) 
• Getting on with others (15 items) 
• Global health perceptions (11 items) 
• Change in health (1 item) 
• Parental impact emotional (7 items) 
• Parental impact time (7 items) 
• Family cohesion (1 item) 
For the ITQOL, the exact number of items that can be missing differs depending on which 
section is being scored, though the general rule is that a section can be scored if at least half 
the responses in that section were completed. 
Summary scores for the 13 domains (overall score) will be summarized separately by cohort 
by treatment group using the format as specified in Table 5.1, Table 5.2, and Table 5.3 for 
Cohorts 1, 2, and 3, respectively. 
The summary scores for Overall Health, Physical Abilities and Growth and Development 
will be displayed separately for the sentinel and randomized subjects by cohort and treatment 
group in a bar chart. 
14.4.3 Function Independence Measure (WeeFIM) (Wee-FIM II Version 6.4) 
The WeeFIM (Functional Independence Measure for children) instrument is a functional 
independence assessment tool that measures functional performance across three domains 
(self-care, mobility and cognition) from the caregiver’s perspective. 
Performance of a child on each of the individual items within the WeeFIM is assigned to one 
of seven levels on an ordinal scale that represent the function from complete and modified 
independence (levels 7 and 6) without a helping person to modified and complete 
dependence (levels 5 to 1) with a helping person. 
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If individual items (questions) within a domain are missing, the item result is imputed to 1, 
per guidance in The WeeFIM Clinical Guide v 6.49. 
If all items for a domain score are missing the domain score is considered missing. 
If a domain score is missing, the Total score is missing. 
For each of the following domains and the total score, the absolute values at each scheduled 
visit, and change from baseline at each scheduled visit, will be summarized separately by 
cohort by treatment group using the format as specified in Table 5.1, Table 5.2, and Table 5.3 
for Cohorts 1, 2, and 3, respectively: 
• Self-care Score (min score=8, max score=56) 
• Mobility Score (min score=5, max score =35) 
• Cognition Score (min score=5, max score=35) 
• Total WeeFIM rating (min=18, max=126) 
Domain and total scores will be listed by cohort, sentinel/randomized subjects, treatment 
group, and subject number. 
Note: Although each domain will be summarized so that all aspects of this validated scale are 
reported, the cognition aspect of the WeeFIM (cognition subtotal score) is considered not to 
be of concern for subjects with achondroplasia. 
The three domains and Total WeeFIM score will also be displayed by visit in a bar chart and 
presented separately for the sentinel and randomized subjects by cohort and treatment group. 
14.5 
Sleep Study Scores 
A sleep study will be performed in a limited number of qualified sleep centers. A 
sleep-testing device will be used to assess the presence and severity of sleep-disordered 
breathing by measurement of blood oxygen saturation, pulse rate, and airflow during 
overnight monitoring. Assessment of episodes of sleep apnea will include, but may not be 
limited to, the number of episodes of apnea and hypopnea per hour (Apnea/Hypopnea Index).  
Sleep study data is collected at Screening, Week 52, and early termination visit. 
Following episodes of sleep apnea variables will be summarized separately by cohort by 
treatment group using the format as specified in Table 5.1, Table 5.2, and Table 5.3 for 
Cohorts 1, 2, and 3, respectively. 
• Number of episodes of apnea per hour (Apnea Index).   
• Number of episodes of hypopnea per hour (Hypopnea Index).  
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• Number of episodes/Duration of obstructive apneas 
• Number of episodes/Duration of central apneas 
• Number of episodes/Duration of mixed apneas 
• Number of episodes/Duration of obstructive hypopneas 
• Number of desaturations 
Listing of the above episode of sleep apnea variables will be provided.  
 
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15 
SAFETY EVALUATIONS 
The safety population will be used for all safety summaries.  
Summary tables assessing safety parameters at planned visits over time will include all safety 
events up to 30 days following treatment discontinuation. These summary tables will be 
presented separately by cohort and overall by treatment group using format as specified in 
Table 5.4. Listings will include all reported data.  
Safety will be assessed by examining the incidence, frequency, severity (determined using 
the CTCAE version 4.03), and relationship to study treatment of all TEAEs reported during 
the study period. In addition, changes from baseline in clinical laboratory results and vital 
signs will be assessed. 
15.1 
Adverse Events 
Adverse events (AEs) will be coded in accordance with MedDRA Version 24.1 and 
performed prior to DBL. Coding of the severity of AEs is performed by the investigators 
using national cancer institute (NCI) CTCAE version 4.03, where events are coded from 
CTCAE Grade 1 to Grade 5.  
Only TEAEs defined as any adverse event that newly appeared, increased in frequency, or 
worsened in severity following initiation of study treatment administration are reported by 
the investigators and consequently are included in the summary tables. 
In the event that the start date of an AE is incomplete or missing, conservative imputation 
rules are applied so that where there is uncertainty, the event is considered treatment 
emergent. Similarly, the AE end dates are imputed in a conservative manner to a maximum 
length. 
15.1.1 Treatment-Emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) will be summarized separately by cohort and 
overall by treatment group using format as specified in Table 5.4. In summaries by SOC 
and/or PT, subjects with more than one AE of the same SOC or PT will be counted once 
within that SOC/PT. For those AEs that occurred more than once during the study, AEs by 
severity will be summarized by the maximum CTCAE grade and by all CTCAE grades. The 
tables are ordered by the descending frequency of SOC or PT of overall in the table.   
The following summary tables will be provided: 
• Overview of the incidence of TEAEs  
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• Overview of exposure-adjusted event rates of TEAEs  
• Incidence and exposure-adjusted event rates of TEAEs by SOC, PT, and CTCAE 
grade  
• Incidence of TEAEs by SOC, PT and highest CTCAE grade 
• Incidence of and exposure-adjusted event rates TEAEs by PT  
• Incidence of TEAEs by SOC 
• Incidence of and exposure-adjusted event rates treatment related TEAEs by SOC, PT 
and CTCAE grade 
• Incidence of and exposure-adjusted event rates TEAEs with CTCAE Grade >= 3 by 
SOC, PT and CTCAE grade  
• Incidence of serious adverse events (SAEs) by SOC and PT 
• Incidence of non-serious adverse events by SOC and PT 
• Incidence of TEAEs leading to study or study treatment discontinuation by PT 
• Incidence of TEAEs leading to study treatment interruption by PT 
• Incidence of TEAEs leading to study treatment dose reduction by PT 
• Incidence of achondroplasia related TEAEs by SOC and PT* 
* Achondroplasia-related TEAEs will be identified using the PTs identified for 
achondroplasia-related medical history (see Section 10). In addition, all AEs will be reviewed 
prior to DBL and the list updated as required. 
For exposure-adjusted event rates of TEAEs, exposure will be derived to up to the last dose 
reported in the study database.  
Listings: 
In addition to the above tables, the following listings will be provided and ordered by subject 
and AE start date: 
• All TEAEs 
• TEAEs with CTCAE Grade ≥ 3 
• Achondroplasia-related TEAEs 
• SAEs 
• Deaths 
• TEAEs leading to study or study treatment discontinuation 
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• TEAEs leading to study treatment interruption or dose reduction 
• TEAEs of confirmed/suspected COVID-19 
• TEAEs due to COVID-19 Vaccine 
15.1.2 Events of Interest 
Events of interest (EOI) will be summarized by PT separately by cohort and overall by 
treatment group using format as specified in Table 5.4. For those AEs that occurred more 
than once during the study, the maximum severity will be used to summarize the AEs by 
severity. 
The following are identified as events of interest: 
Injection site reactions (ISR) 
• TEAEs with a MedDRA High Level Term (HLT) of “Injection site reaction”. 
Hypotension 
• TEAEs with PT: Blood pressure ambulatory decreased, Blood pressure decreased, 
Blood pressure diastolic decreased, Blood pressure orthostatic decreased, Blood 
pressure systolic decreased, Blood pressure systolic inspiratory decreased, Diastolic 
hypotension, Hypotension, Orthostatic hypotension. 
Heart rate change 
• TEAEs with a PT: Atrial tachycardia, Postural orthostatic tachycardia syndrome, 
Rebound tachycardia, Sinus tachycardia, Supraventricular tachycardia, Tachycardia, 
Tachycardia paroxysmal, Ventricular tachycardia, Bradycardia. 
Hypersensitivity SMQ 
• TEAEs with a PT included in the MedDRA hypersensitivity SMQ 
Algorithmic Anaphylaxis SMQ (with sponsor-defined time restrictions) 
• TEAEs with a PT included in the MedDRA anaphylactic reaction SMQ, with an 
additional time restriction: a narrow scope PT within 48 hours of a dose, or two broad 
scope PTs from different classes where both PTs are within 48 hours of the same 
dose. 
Fractures 
• TEAEs with a PT containing the term “fracture” and also PTs of Bone fragmentation, 
Bone fissure, Scapulothoracic dissociation and Flail chest 
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Slipped Capital Femoral Epiphysis (SCFE) 
• TEAEs with a PT: Epiphyseal disorder, Epiphyseal injury 
Avascular necrosis and osteonecrosis 
• TEAEs with a PT: Osteonecrosis, Osteonecrosis of jaw, Osteonecrosis of external 
auditory canal, Necrosis ischaemic 
Events of interest will be summarized as follows: 
• Incidence and exposure-adjusted event rates of ISR events by PT 
• Incidence and exposure-adjusted event rates of hypotension by PT 
• Incidence and exposure-adjusted event rates of heart rate change events by PT 
• Incidence and exposure-adjusted event rates of hypersensitivity (SMQ) 
• Profile of ISRs 
• Profile of hypotension 
• Profile of heart rate change events 
Profile summaries include: highest CTCAE grade, number of events per subject, time from 
first dose to first event onset, duration of events (days), action taken with study treatment, 
outcome of events. 
Listings: 
In addition to the above tables the following EOI listings are also provided: 
• TEAEs of injection site reaction 
• TEAEs of hypotension 
• TEAEs of documented symptomatic hypotension 
• TEAEs of heart rate change events 
• TEAEs of hypersensitivity (SMQ) 
• TEAEs of algorithmic anaphylaxis (SMQ) with sponsor-defined time restrictions 
• TEAEs of fractures 
• TEAEs of SCFE 
• TEAEs of avascular necrosis and osteonecrosis 
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15.1.3 Injection Site Reaction Symptoms 
Injection site reactions (ISRs) associated with single symptoms are recorded on the AE page 
(as a single symptom). ISRs with multiple symptoms are recorded as an AE of “Injection Site 
Reaction” on the AE page and the associated individual symptoms are recorded on the ISR 
symptom page. 
In order to describe all ISR symptoms recorded, summaries will be based on the data 
collected on the ISR Symptoms page and also those single symptoms recorded as an adverse 
event. 
Incidence and exposure-adjusted event rates of ISR Symptoms will be summarized by PT 
and separately by cohort and overall by treatment group using format as specified in 
Table 5.4.   
ISR Symptoms will be listed. 
15.2 
Clinical Laboratory Tests 
Clinical laboratory tests (hematology, chemistry, and urinalysis) are performed at Screening, 
and pre-dose at Day 1, Day 8, Week 3, Week 6, Week 20, Week 39, Week 52 and early 
termination visit.  
All summary tables will include laboratory assessments from baseline up to 30 days post 
treatment discontinuation. Results will be reported separately as hematology, chemistry, 
urinalysis, and “other laboratory tests”.  
Laboratory tests will be graded as low/normal/high based on laboratory normal ranges.  In 
addition, for laboratory tests with CTC grading available, all non-missing numeric results 
will be used to determine CTC grade programmatically, based on CTCAE v4.03.  
 For the following parameters, the distinction is made between significantly low/high results: 
• Glucose (Hypoglycemia/Hyperglycemia) 
• Hemaglobin (Anemia/Hemaglobin increased) 
• Lymphocytes (Lymphocyte count decreased/Lymphocyte count increased) 
• Potassium (Hypokalemia/Hyperkalemia) 
• Sodium (Hyponatremia/Hypernatremia) 
• Calcium (Hypocalcemia/Hypercalcemia) 
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The absolute values for pre-dose laboratory results at each scheduled visit, change from 
baseline in pre-dose laboratory results, and percent change from baseline in pre-dose 
laboratory results at each scheduled visit will be summarized and presented separately by 
cohort and overall by treatment group using format as specified in Table 5.4.   
Shift tables from baseline to worst post-baseline value (including scheduled and unscheduled 
visits) based on the CTC grading (Normal – Grade 5) will be generated for each Lab 
parameter where CTCAE grading is available, excluding parameters where CTCAE Grade 
does not rely on quantitative results alone (e.g. potassium and uric acid).  Percentages are 
based on the number of subjects with each Baseline CTCAE grade (Normal, Grade 1, Grade 
2, Grade 3, Grade 4, Grade 5, Missing, Overall). Shift tables will be produced separately by 
cohort and overall by treatment group using format as specified in Table 5.4. 
For laboratory tests where grades are not defined by CTCAE, or where CTCAE grading does 
not rely on quantitative results alone (e.g. potassium and uric acid), shift tables will be 
generated using the low/normal/high classification to compare to baseline to the worst post-
baseline value.   
Line plots of the mean results (+/- SD) for the pre-dose windowed absolute values including 
all scheduled visits will be provided for the following parameters by treatment group by 
cohort. Data from the sentinel subjects and randomized subjects received active treatment 
within each cohort will be pooled: 
• Hematology: erythrocytes, hematocrit, hemoglobin, leukocytes, neutrophils, platelets, 
WBC and RBC count. 
• Chemistry: alanine aminotransferase, albumin, alkaline phosphatase, aspartate 
aminotransferase, bicarbonate, bilirubin, blood urea nitrogen, calcium chloride, 
creatinine, direct bilirubin, glucose, lactate dehydrogenase, phosphate, potassium, 
protein, sodium, thyrotropin, vitamin D. 
Listings: 
In addition to the above tables, the following listings will be provided and will contain CTC 
grade and laboratory reference ranges: 
• Hematology results 
• Chemistry results 
• Urinalysis results 
• Urine chemistry results 
• Other laboratory test results 
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• Laboratory results with CTCAE Grade ≥ 3 
Listings will include all reported data and will be ordered by cohort, sentinel/randomized 
subject, subject ID, and assessment date. 
15.3 
Vital Signs 
Vital Signs (heart rate, systolic/diastolic blood pressure, respiratory rate, and body 
temperature) are assessed at Screening, Day 1, Day 2, Day 3, Day 8, Week 3, Week 6, 
Week 13, Week 20, Week 26, Week 39, Week 52, safety follow-up visit, and early 
termination visit. 
All summary tables will include vital signs recorded from baseline up to 30 days post 
treatment discontinuation.  
The vital signs that are collected pre-dose and post-dose. Vital sign assessment frequency is 
shown below.  
Table 15.3.1:  Vital Sign Post-dose Assessment Frequency  
 
 
The absolute values for pre-dose vital signs at each scheduled visit, and change from baseline 
in pre-dose vital signs at each scheduled visit will be summarized and presented separately 
by cohort and overall by treatment group using format as specified in Table 5.4.    
Line plots will be generated, which present the mean pre-dose and post-dose absolute values 
(+/-SD) for each visit by treatment group by cohort. Data from the sentinel subjects and 
randomized subjects received active treatment within each cohort will be pooled. 
The percentage of subjects experiencing at least one instance of a decrease of 20% in 
diastolic blood pressure from pre-dose to same-day post dose will be summarized for overall 
(each subject meeting criteria at any time in the study will be counted only once) for both 
sentinel subjects and randomized subjects. 
Shift tables (Diastolic BP <40mmHg, Diastolic BP ≥40mmHg) from pre-dose to lowest 
same-day post-dose value category (Diastolic BP <40mmHg, Diastolic BP ≥40mmHg) will 
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be generated for overall (each subject meeting criteria at any time in the study will be 
counted only once) for both sentinel subjects and randomized subjects. 
Shift tables (Diastolic BP <30mmHg, Diastolic BP ≥30mmHg) from pre-dose to same-day 
lowest post-dose value category (Diastolic BP <30mmHg, Diastolic BP ≥30mmHg) will be 
generated overall (each subject meeting criteria at any time in the study will be counted only 
once) for both sentinel subjects and randomized subjects. 
Shift tables (Systolic BP < (70mmHg plus 2 x Age), Systolic BP ≥ (70mmHg plus 2 x Age)) 
from pre-dose to lowest same-day post-dose value category ((Systolic BP < (70mmHg plus 2 
x Age), Systolic BP ≥ (70mmHg plus 2 x Age)) will be generated for overall (each subject 
meeting criteria at any time in the study will be counted only once).  Subject’s age used in 
this calculation is the integer value. 
A listing of vital sign data will also be provided. 
15.4 
Biological Parental Standing Height 
If available standing height of the subject’s biological parents will be listed.  
15.5 
Electrocardiogram 
Electrocardiogram (ECG) data are recorded at Screening, Day 1, Day 8, Week 6, Week 13, 
Week 20, Week 26, Week 39, Week 52, safety follow-up visit, and early termination visit. 
ECG assessments are performed in triplicate on Day 1 (pre-dose and post-dose) and on study 
day visits (post-dose only).   
Summaries will be provided over all planned assessments, and repeated with the requirement 
that all post-dose ECG assessments should occur around the expected time of CMax, i.e., 
20-40 minutes post-dose. The mean results of the ECG assessments meeting these criteria 
will be used for summaries and analyses.   
All measures and means of the measures will be included in the listings. 
The following ECG results will be summarized and presented separately by cohort and 
overall by treatment group using format as specified in Table 5.4 at scheduled visits: 
• ECG Mean Heart Rate (beats/min) 
• QT interval (msec) 
• QTcF interval (msec) 
• PR interval (msec) 
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• RR interval (msec) 
• QRS Duration (msec) 
The following endpoints will be summarized at scheduled visits, and across all time points 
(using the highest mean QTc value), and presented by cohort and overall by treatment group 
using format as specified in Table 5.4. 
• Percentage of subjects with QTcF >450 to ≤480ms, >480 to ≤500ms, >500 msec 
The following endpoints will be summarized at scheduled visits, and across all time points, 
and presented by cohort and overall by treatment group using format as specified in Table 5.4 
• Percentage of subjects experiencing at least one instance of a (decrease in mean heart 
rate from pre-dose baseline >25% and a mean heart rate <50 beats/min) post-dose. 
• Percentage of subjects experiencing at least one instance of an (increase in mean heart 
rate from pre-dose baseline >25% and a mean heart rate >100 beats/min) post-dose. 
The following endpoints will be summarized across all time points and presented by cohort 
and overall by treatment group using format as specified in Table 5.4. 
• Percentage of subjects with a QTcF increase of 60ms from pre-dose baseline at any 
time 
• Percentage of subjects with QTcF changes from pre-dose baseline of >30 and 
≤ 60 msec, or >60 msec at any time 
Listings will be provided and ordered by cohort, sentinel/randomized subject, treatment 
group, and visit:  
• All ECG results. 
• All ECG results for subjects with a QTc increase of 60msec from pre-dose baseline. 
15.6 
HPA Axis Assessments  
To address potential effects of vosoritide on activation of the hypothalamic pituitary (HP) 
axis, assessment of salivary cortisol and serum prolactin levels will be analyzed at baseline, 
Week 26, Week 52 and early termination visit.   
This data will be listed.  
15.7 
Child Behavior Checklist (Achenbach, 2000) 
The Child Behavior Checklist (CBCL) 1.5- 5 years questionnaire is captured at Screening, 
Week 26, Week 52, and early termination visit.  
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All summaries will be generated on the Safety Population and include all assessments 
recorded up to 30 days following treatment discontinuation.  Listings will include all reported 
data. 
The CBCL 1.5-5 years old comprise questions addressing symptoms related to mood, 
behavior issues, and sleep disturbance.  It is completed by the parent or primary caregiver.  
The CBCL 1.5-5 years old consists of 100 questions, scored on a three-point Likert scale 
(0=Not True (as far as you know), 1= Somewhat or Sometimes True, 2=Very True or Often 
True). The time frame for item responses is the past 2 months. 
Note: No data is collected from the language scale, as it is supplemental and not required to 
calculate any of the behavior measures. 
The checklist yields scores in the following areas: emotionally reactive, anxious/depressed, 
withdrawn, somatic complaints, sleep problem, attention problems, and aggressive behavior.  
The table in Appendix 25.2 shows how the domains are constructed with regards to the 
individual questions.  The scores for each individual question within a domain are summed to 
give a domain score. 
Each domain score above and total score will be summarized separately by cohort and 
overall by treatment group using format as specified in Table 5.4 at Baseline, Week 26 and 
Week 52 as well as change from baseline at Week 26 and Week 52 (where baseline measures 
exist). 
Domain scores and total score will be listed by cohort, sentinel/randomized subjects, 
treatment group, and subject ID. 
15.8 
Echocardiogram 
Echocardiogram results are only collected at the Screening visit, at safety follow up, and 
early termination visit if the previous assessment was done more than 3 months prior to early 
termination and will be listed by cohort, sentinel/randomized subjects, treatment group, and 
subject ID. 
15.9 
On-Study Procedures, Interventions and Surgeries 
Any procedures, interventions of surgeries that occur on study (post first dose of study 
treatment) will be captured, along with start and stop date. These will be coded using 
MedDRA version 24.1 and will be summarized separately by cohort and overall by treatment 
group using format as specified in Table 5.4, and details provided in a listing. 
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15.10 Hip Monitoring and Rotation 
All hip monitoring clinical assessments, including hip rotation, will be listed by cohort, 
sentinel/randomized subjects, treatment group, subject ID, and assessment date. 
15.11 Body Mass Index and BMI Z-scores 
Weight (kg) and standing height are collected at Screening, Day 1, Day 2, Day 3, Day 8, 
Week 3, Week 6, Week 13, Week 20, Week 26, Week 39, Week 52, and early termination 
visit. 
Standing height are recorded at Screening, Day 1, Week 6, Week 13, Week 26, Week 39, and 
Week 52.  
Body Mass Index (BMI) will be calculated at each visit as: 
Body Mass Index (kg/m2) = 
𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊ℎ𝑡𝑡 (𝑘𝑘𝑘𝑘)
𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻ℎ𝑡𝑡 (𝑚𝑚)2 
In calculation of BMI, in case standing height is not measured and body length is available, a 
derived standing height will be calculated; refer to Section 15.11.   
Only for subjects aged 24 months or older, each measurement of BMI will be converted to an 
age-and sex-appropriate standard deviation score (SDS), also referred to as a Z-score, by 
comparison with reference data available for average stature children from the Centers for 
Disease Control and Prevention (CDC). The derived height mentioned above for BMI is also 
used for BMI in the calculation of BMI Z-score. 
The absolute values at baseline, each 6-month visit, and change from baseline at each 
6-month visits will be summarized and presented separately by cohort and overall by 
treatment group using format as specified in Table 5.4 for both BMI and BMI Z-Score (again 
though, BMI Z-score will only be calculated for subjects aged 24 months or older). 
All assessments will be listed by cohort, sentinel/randomized subjects, treatment group, 
subject ID and visit. 
15.12 Weight Z-Scores 
Weight (kg) is measured at Screening, Day 1, Day 2, Day 3, Day 8, Week 3, Week 6, 
Week 13, Week 20, Week 26, Week 39, Week 52, and early termination visit. 
Each measurement of weight will be converted to an age-and sex-appropriate SDS, also 
referred to as Z-score, by comparison with reference data available for average stature 
children from the CDC. 
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The weight of the subject on Day 1 will be used as the baseline measure, regardless of 
whether this is recorded pre or post-dose. 
The absolute values and change from baseline at scheduled visits will be summarized and 
presented separately by cohort and overall by treatment group using format as specified in 
Table 5.4.  
All assessments will be listed for by cohort, sentinel/randomized subjects, treatment group, 
subject ID, and visit. 
 
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16 
IMAGING SECONDARY ENDPOINT(S)  
Imaging will be performed at screening, Week 52, and early termination visit:   
Dual energy X-ray absorptiometry of whole body and spine 
Anterior-posterior and lateral lumbar spine X-rays 
Anterior-posterior X-rays of lower extremities  
MRI data will be performed at screening, Week 52, and early termination visit to evaluate the 
effect of vosoritide on skull and brain morphology, including face, foramen magnum, 
ventricular, and brain parenchymal dimensions.  
All summaries of imaging data and MRI data will be generated on the FAS and presented by 
cohort and overall by treatment group using the format as specified in Table 5.4. 
16.1 
Lower Limb X-Rays 
For each of the following parameters, the absolute values for both the left and right leg at 
Baseline and Week 52, and change from baseline at Week 52 will be summarized by cohort 
and overall by treatment group using the format as specified in Table 5.4: 
• Left/Right Femur length (cm) 
• Left/Right Fibula length (cm) 
• Left/Right Tibia length (cm)  
• Left/Right Tibia bowing angle (degrees) 
• Left/Right Distance between ankle joint and distal growth plate of fibula (cm) 
• Left/Right Lower Extremity (cm) 
• Ratio of Left/Right Femur length (cm) to Tibia length (cm) 
• Ratio of Left/Right Tibial length (cm) to Fibula length (cm) 
In addition, change from baseline in tibial length (y-axis) at Week 52 will be presented on 
boxplots with a separate box for each leg and treatment group on the x-axis by cohort. 
Similar plots will also be generated for change from baseline in fibula length. 
All assessments will be listed by cohort, treatment group, subject and visit. 
16.2 
Lumbar Spine X-Rays 
Lumbar spine x-rays (AP and lateral views) assessments will be listed by cohort, treatment 
group, subject and visit. 
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16.2.1 Vertebral Height 
Vertebral heights (anterior, medial, and posterior) will be measured for each individual 
vertebra (L1, L2, L3, L4, and L5). 
The following ratios will be calculated for each individual vertebra (L1, L2, L3, L4, and L5) 
and reported to 1 decimal place: 
• Anterior height (cm) to medial height (cm) 
• Anterior height (cm) to posterior height (cm) 
• Medial height (cm) to posterior height (cm) 
For each of the vertebral height and the above ratios, the absolute values at Baseline and 
Week 52, and change from baseline at Week 52 will be summarized and presented by cohort 
and overall by treatment group using the format as specified in Table 5.4. 
16.2.2 Transverse Diameter (Interpedicle Distance) 
The transverse diameter (interpedicle distance) will be measured for each individual vertebra 
(L1, L2, L3, L4, and L5). 
For each transverse diameter vertebra, the absolute values at Baseline, Week 52, and the 
change from baseline at Week 52 will be summarized and presented by cohort and overall by 
treatment group using the format as specified in Table 5.4. 
In addition, change from baseline in transverse diameter (y-axis) for each individual vertebra 
(x-axis) will be presented on a boxplot at Week 52 for each cohort and treatment group. 
16.2.3 Sagittal Width 
The spinal canal width (sagittal width) will be measured for each individual vertebra (L1, L2, 
L3, L4, and L5). 
For each individual vertebra, the absolute values at Baseline, Week 52, and the change from 
baseline Week 52 will be summarized and presented by cohort and overall by treatment 
group using the format as specified in Table 5.4. 
In addition, change from baseline in sagittal width (y-axis) for each individual vertebra 
(x-axis) will be presented on a boxplot at Week 52 for each cohort and treatment group. 
16.2.4 Lumbar Spine Angles 
The following angles will be measures on the lumbar spine x-rays: 
• Sacral tilt (degrees) 
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• Lordosis (inward curve of the spine) (degrees) 
• Kyphosis (convex curvature of the spine) (degrees) 
Each angle will be measured on the spine x-rays and compared to Baseline at Week 52 to 
determine any worsening of sacral tilt, lordosis (inward curve of the spine) or kyphosis 
(convex curvature of the spine). 
The absolute values of the sacral tilt, lordosis and kyphosis angles at Baseline, Week 52, and 
change from baseline at Week 52 will be summarized and presented by cohort and overall by 
treatment group using the format as specified in Table 5.4. 
A worsening in sacral tilt angle compared to baseline will be summarized [n(%)] by cohort 
by treatment group and overall at Week 52 as follows: 
• Percentage of subjects with an increase in sacral tilt angle of ≥5 to < 10 degrees 
• Percentage of subjects with an increase in sacral tilt angle of ≥ 10 degrees 
A worsening in lumbar lordosis compared to baseline will be summarized [n(%)] by cohort 
by treatment group and overall at Week 52 as follows: 
• Percentage of subjects with an increase in lordosis angle of ≥5 to < 10 degrees  
• Percentage of subjects with an increase in lordosis angle of ≥ 10 degrees 
A worsening in kyphosis angle compared to baseline will be summarized [n(%)] by cohort by 
treatment group and overall at Week 52 as follows: 
• Percentage of subjects with an increase in kyphosis angle of ≥5 to < 10 degrees 
• Percentage of subjects with an increase in kyphosis angle of ≥ 10 degrees 
A listing of subjects experiencing a worsening in sacral tilt, kyphosis or lordosis will be 
provided. 
16.3 
Dual Energy X-ray Absorptiometry 
A dual energy x-ray absorptiometry (DXA) scan is performed at Baseline and Week 52, in 
order to collect relevant BMC/BMD data (including Z-scores) for whole body less head, and 
the lumbar spine.   
All DXA data will be summarized separately by cohort and overall by treatment group using 
the format as specified Table 5.4 for each scanner manufacturer (GE - Lunar Prodigy or 
Hologic – Discovery Horizon). Changes over time can only be interpreted if subjects use the 
same scanner consistently throughout the study. Subjects will be summarized according to 
the scanner used for their Baseline assessment. Subjects who have results from more than 
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one scanner type will be excluded from summaries, and their data will be listed only. All data 
will be listed. 
16.3.1 Whole Body Less Head and Lumbar Spine 
The absolute values at Baseline and Week 52, and change from baseline at Week 52 will be 
summarized and presented by cohort and overall by treatment group using the format as 
specified in Table 5.4 for the following measures of bone mineral content (BMC) and bone 
mineral density (BMD): 
• Whole Body Less Head BMC (g) 
• Whole Body Less Head BMD (g/cm2) 
• Whole Body BMC (g) 
• Whole Body BMD (g/cm2) 
• Lumbar Spine BMC (g) 
• Lumbar Spine BMD (g/cm2) 
BMD Z-scores will be provided in the DXA reports, and the absolute values at Baseline and 
Week 52, and change from baseline at Week 52 will be summarized and presented by cohort 
and overall by treatment group using the format as specified in Table 5.4 by scanner for each 
of the following: 
• Whole Body Less Head BMD Z-Score 
• Whole Body BMD Z-Score 
• Lumbar Spine BMD Z-Score 
The absolute values of total body percent fat, android percent fat, and gyenoid percent fat 
will be listed. 
Box plots of whole body less head BMD Z-scores will be provided by cohort by treatment 
group and scanner. 
16.4 
MRI 
For each of the following parameters and ratios, the absolute values and change from 
baseline at Week 52 will be summarized by cohort and overall by treatment group using the 
format as specified in Table 5.4: 
Volume of Face 
Volume of Sinus 
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Volume of Calvarium 
Area of Foramen Magnum 
Area of Spinal Cord at the FM Level  
 
Whole Brain Total Volume   
Ventricles Total Volume  
Ratio of Face volume to Calvarium   
Ratio of Area of Spinal Cord to Foramen Magnum  
Ratio of Face volume to Sinus  
MRI assessments for above variables, evidence of cervicomedullary, and spinal cord 
compression will be listed by cohort, sentinel/randomized subjects, treatment group, subject 
ID and visit. 
 
 
 
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17 
BONE METABOLISM BIOMARKERS 
Bone metabolism biomarkers (both blood and urine) will be collected to assess changes in 
bone metabolism. The safety population will be used for all summaries. 
Serum samples for bone metabolism blood biomarkers (collagen X and bone-specific 
alkaline phosphatase [BSAP]) are collected pre-dose at baseline, Day 8, Week 6, Week 20, 
Week 39, early termination visit. Urine samples for bone metabolism urine biomarkers 
(Cross-linked C-Telopeptide of Collagen Type II [CTX-II]) are collected pre-dose on Day 1, 
Day 2, Day 3, Week 3, Week 13, Week 26, Week 39, Week 52, and early termination visit.  
For BSAP and Collagen X, the absolute values, and change from baseline at scheduled visits 
will be summarized separately by cohort and overall by treatment group using format as 
specified in Table 5.4. 
For CTX-II, the absolute values normalized by creatinine, and change from baseline at 
scheduled visits will be summarized separately by cohort and overall by treatment group 
using format as specified in Table 5.4. 
A box plot of change from baseline in BSAP, Collagen X, CTX-II normalized by urine 
creatinine over time will be provided for pooled sentinel subjects and randomized subjects 
received active treatment.  
Bone metabolism biomarkers will be listed by cohort, sentinel/randomized subjects,  
treatment group, subject ID, and visit. 
 
 
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18 
VOSORITIDE PD ACTIVITY BIOMARKERS 
Samples for vosoritide activity urine biomarkers (cyclic guanosine monophosphate [cGMP] 
and urine chemistry (urine creatinine test) are collected pre-dose and post-dose 
(approximately 2-4 hours after study treatment administration) when possible, on Day 1, 
Day 2, Day 3, Week 3, Week 26, Week 39, Week 52, and early termination visit. Each urine 
collection will be tested for biomarker concentration and urine creatinine concentration for 
normalization.  
The absolute values for pre-dose and post-dose urine cGMP normalized by creatinine at each 
scheduled visit and change from pre-dose to post-dose time points at each scheduled visit 
will be summarized and presented by cohort and overall by treatment group using format as 
specified in Table 5.4.  
When possible, plasma PK samples with sufficient residual volume after completion of PK 
analysis will be used to measure changes in plasma cGMP after dose administration. Plasma 
samples will be collected for PK analysis on Day 1, Week 13, Week 26, Week 39, and 
Week 52. Plasma samples will be collected pre-dose and at 5 (± 2 min), 15 (± 2 min), 
30 (± 5 min), 45 (± 5 min), 60 (± 5 min), 90 (± 5 min), and 120 (± 5 min) minutes post-dose 
on scheduled visits. On Day 1, additional PK samples will be collected at 180 (± 5 min) and 
240 (± 5 min) minutes. 
The absolute values for pre-dose and post-dose plasma cGMP at each scheduled visit and 
change from pre-dose to post-dose time points at each scheduled visit will be summarized 
and presented separately by cohort and overall by treatment group using format as specified 
in Table 5.4.  
A box plot for the maximum change from pre-dose of plasma cGMP and change from pre-
dose of urine cGMP normalized by creatinine by cohort by treatment group by visit will be 
provided. 
Vosoritide activity urine biomarkers will be listed by cohort, sentinel/randomized subjects,  
treatment group and subject ID. 
 
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19 
IMMUNOGENICITY ASSESSMENT  
Serum samples for anti-drug antibody (ADA) testing will be drawn pre-dose on Day 1, 
Week 3, Week 13, Week 26, Week 52, and early termination visit.  Blood (serum) samples 
for testing drug-specific IgE will be drawn on Day 1 and in the event of a Grade 3 or 
significant hypersensitivity adverse event, or at the investigator’s discretion.   
ADA testing will include anti-vosoritide total antibody (TAb); TAb cross-reactive with 
endogenous C-type natriuretic peptide (CNP), brain natriuretic peptide (BNP) or atrial 
natriuretic peptide (ANP); and anti-vosoritide neutralizing antibody (NAb). 
NAb testing and TAb testing for cross-reactivity with endogenous CNP, ANP or BNP will be 
performed only on baseline and TAb positive samples. NAb testing will not be performed if 
the corresponding TAb is negative. A listing for each ADA assay will be provided. 
Summary tables will include all safety events up to 30 days following treatment 
discontinuation. Listings will include all reported data. 
The immunogenicity population will be used for all summaries. The data conversion rules for 
immunogenicity analysis are listed below: 
 
 
 
 
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The incidence [n(%)] of TAb titer positive results will be summarized for each scheduled 
visit, and overall (described as ‘Ever Positive’) as follows: 
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑎𝑎 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑛𝑛𝑛𝑛𝑛𝑛−𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑇𝑇𝑇𝑇𝑇𝑇 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟∗100 
The incidence [n(%)] of NAb positive test results, and positive cross-reactivity results for 
ANP, BNP and CNP, will also be calculated based on the number of subjects with a 
non-missing TAb result, and summarized at each scheduled visit and overall. 
The absolute values (numerical values) of TAb titers and NAb titers will be summarized at 
Day 1, Week 3, Week 13, Week 26, and Week 52, and presented separately by cohort and 
overall by treatment group using format as specified in Table 5.4. 
The mean (SD) TAb titer, number of hypersensitivity adverse events (HAEs) excluding 
injection site reactions, and number of subjects experiencing HAE’s will be summarized by 
the highest HAE CTCAE Grade, and presented by TAb status (negative or positive) and 
separately by cohort and overall by treatment group using format as specified in Table 5.4. 
A line graph of the mean TAb titer (+/- SE) will be presented over time for each visit by 
pooled placebo, active for each cohort (pooled for sentinel and randomized subjects), and 
overall. A similar figure will be generated for NAb titers. 
The relationship between immunogenicity (ADA status: negative or positive) and measures 
of safety and efficacy will further be presented graphically by treatment group: 
• Box plot of change from baseline at week 52 in standing height/body length Z-Score 
by TAb status 
• Box plot of change from baseline at week 52 in standing height/body length Z-Score 
by NAb status 
• Box plot of change from baseline at week 52 in standing height/body length by by 
TAb status 
• Box plot of change from baseline at week 52 in standing height/body length by NAb 
status 
• Box plot of number of hypersensitivity adverse events by TAb status 
• Box plot of number of hypersensitivity adverse events (excluding ISRs) by TAb 
status 
• Box plot of number of injection site reaction adverse events by TAb status 
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• Box plot of maximum duration of injection site reaction adverse event by TAb status, 
where injection site hemorrhage, injection site hematoma, injection site bruising, and 
injection site induration will be excluded. 
Should there be a significant relationship between TAb positivity and change from baseline 
at Week 52 in standing height/body length, a scatter plot of change from baseline in standing 
height/body length at Week 52 versus mean TAb titer in TAb positive subjects will be 
presented as a second tier analysis. The Pearson correlation coefficient will be included in the 
figure to describe the association. 
 
In addition, the following listings will be provided:  
• Total antibody titers and neutralizing antibody titers 
• Hypersensitivity adverse events with antibody results 
• Drug-specific IgE, total IgE, C4 and serum tryptase for hypersensitivity reaction 
visits 
• Mean Tab and NAb titers, standing height/body length, standing height/body length 
Z-Scores, and AGV  
• TAb cross reactivity to endogenous natriuretic peptides 
• TAb cross reactivity by subject and cardiac disorder or HLGT ‘fluid and electrolyte 
imbalance’ related adverse event. 
All immunogenicity listings will be ordered by cohort, sentinel/randomized subjects, 
treatment group, 4-digit subject ID (i.e., the subject ID excluding the site number), and visit. 
 
 
 
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20 
PHARMACOKINETICS AND PHARMCODYNAMICS 
Vosoritide concentrations and PK parameters will be summarized descriptively by visit for 
all subjects in the PK population. If supported by the data, impact of demographics and 
immunogenicity on PK parameters and the exposure-response relationship between 
vosoritide exposure and efficacy, biomarker, and safety pharmacodynamic (PD) endpoints of 
interest will be explored. Details on the PK and PK/PD analyses are separately documented 
in the Clinical Pharmacology Analysis Plan. 
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21 
OTHER ANALYSES 
To evaluate the impact of COVID-19 pandemic on the study conduct and results (assumed 
started from 1st January 2020 up until the date of data finalization), the following new outputs 
will be presented separately by cohort and overall by treatment group using format as 
specified in Table 5.4: 
1. For all protocol scheduled visits, number of missed visits, late visits, and clinical site 
visits changed to virtual or home visits due to COVID-19 will be summarized.   
2. COVID-19 has been added to the new MedDRA version 24.1. One AE listing will be 
produced that will include all AEs coded to Preferred Terms containing “COVID-19”. 
Another AE listing will be produced that will be included all AEs due to COVID 
vaccine. 
3. A listing of concomitant medication of COVID vaccine will be provided.  
4. COVID-19 specific protocol deviations will be listed and summarized.  
 
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ANALYSES DIFFERENT FROM PROTOCOL-DEFINED ANALYSES  
Standing height/body length was one of the growth measurements included in the secondary 
efficacy endpoints in the protocol. It is the first key secondary efficacy endpoint in this SAP.   
 
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23 
REFERENCES 
Achenbach, T. M., & Rescorla, L. A. (2000). Manual for the ASEBA Preschool Forms & 
Profiles. Burlington, VT: University of Vermont, Research Center for Children, Youth, & 
Families. 
Bayley Scales of Infant and Toddler Development, Third Edition (Bayley–III) Technical 
Manual 
Health Act CHQ: Infant and Toddler Quality of Life Questionnaire – 97 (itqol-97) © 2013 
Hoover-Fong, JE, Schulze, KJ, McGready, J, Barnes, H et. al. Age-appropriate body mass 
index in children with achondroplasia: interpretation in relation to indexes of height. Am J 
ClinNutr 88[2], 364-371. 2008. 
https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm 
Uniform Data System for Medical Rehabilitation. 2016. The WeeFIM II® Clinical Guide, 
Version 6.4. Buffalo: UDSMR. 
 
 
 
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SUMMARY OF KEY CHANGES TO STUDY SAP  
Version 
Affected Section  
Summary of Revisions 
Number 
Date 
1.1 
17Nov2021 
Section 14.1 
Option OBSMARGINS was added in the PROC 
MIXED procedure. 
1.1 
17Nov2021 
Section 15.1.2 
Definition for Algorithmic Anaphylaxis SMQ 
has been updated. 
1.1 
17Nov2021 
Section 19 
“by cohort” was removed for box plots.  
Box plot for maximum severity of 
hypersensitivity adverse events by TAb status 
was removed. 
Injection site hemorrhage, injection site 
hematoma, injection site bruising, and injection 
site induration will be excluded for the box plot 
of maximum duration of injection site reaction 
adverse event by TAb status. 
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25 
APPENDICES 
25.1 
Summary of Growth Measures Derivations 
Derived Value: 
Measure 
required in 
calculation: 
Age 
Order of Substitution for measure required: 
1 then 2. 
1 
2 
BMI 
Height 
Under 24 
months 
Body Length  
Standing Height  
24 months 
or older 
Standing Height 
Body Length  
AGV 
Height 
Under 24 
months 
Body Length  
Standing Height  
24 months 
or older 
Standing Height 
Body Length  
Standing Height 
Height 
Under 24 
months 
Body Length  
Standing Height  
 24 months 
or older 
Standing Height 
Body Length 
Sitting Height 
Height 
Under 24 
months 
Crown-to-Rump Length 
Sitting Height 
 24 months 
or older 
Sitting Height 
Crown-to-Rump Length 
Height Z-score* 
 
Height 
Under 24 
months 
Body Length 
Standing Height  
24 months 
or older 
Standing Height 
Body Length  
BMI Z-score** 
 
BMI 
Under 24 
months 
 
Will not be calculated 
24 months 
or older 
Standing Height 
Body Length  
Lower Body Length 
Standing Height 
and Sitting 
Height 
Under 24 
months 
Body Length - Crown-
to-Rump Length 
Standing Height - 
Sitting Height 
24 months 
or older 
Standing Height - 
Sitting Height 
Body Length - Crown-
to-Rump Length 
Arm Span to Height 
Ratio 
Height 
Under 24 
months 
Body Length 
Standing Height 
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Derived Value: 
Measure 
required in 
calculation: 
Age 
Order of Substitution for measure required: 
1 then 2. 
1 
2 
24 months 
or older 
Standing Height 
Body Length 
Upper to Lower 
Body Segment 
Ratio 
Upper Body: 
Lower Body 
Under 24 
months 
Crown-to-Rump 
Length:  
(Body Length - Crown- 
to-Rump Length ) 
Sitting Height: 
(Standing Height - 
Sitting Height) 
24 months 
or older 
Sitting Height: 
(Standing Height - 
Sitting Height) 
Crown-to-Rump Length:  
(Body Length - Crown- 
to-Rump Length ) 
*Height Z-scores will be derived using CDC references and macro. 
**BMI Z-score will be calculated in the age appropriate CDC macros, only for subjects aged 24 months or 
older.  
Programming will not supply the BMI value that we derive for our datasets and table summaries to this macro.  
The CDC macro will calculate BMI Z-scores using the Height value supplied as describe above to create the 
Height Z-scores. Therefore, the BMI Z-scores will be consistent with the Height Z-score.  
 
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25.2 
Child Behavior Checklist Domains 
Domain/Subscale 
CBCL 1.5-5 
EMOTIONALLY REACTIVE 
21. Disturbed by change 
46. Twitches 
51. Panics 
79. Shifts between sad-excite 
82. Sudden mood change 
83. Sulks a lot 
92. Upset by new 
97. Whining 
99. Worries 
ANXIOUS/DEPRESSED 
10. Too dependent 
33. Feelings easily hurt 
37. Upset when separated 
43. Looks unhappy 
47. Nervous 
68. Self-conscious 
87. Fearful 
90. Unhappy, sad, depressed 
WITHDRAWN 
2. Acts too young 
4. Avoids eye contact 
23. Doesn’t answer 
62. Refuses active games 
67. Unresponsive to affection 
70. Little affection 
71. Little interest 
98. Withdrawn 
SOMATIC COMPLAINTS 
1. Aches, pains 
7. Can’t stand things out of place 
12. Constipated 
19. Diarrhea 
24. Doesn’t eat well 
39. Headaches 
45. Nausea 
52. Painful bowel movements 
78. Stomachaches 
86. Too concerned with neatness 
93. Vomits 
SLEEP PROBLEMs 
22. Doesn’t want to sleep alone 
38. Trouble sleeping 
48. Nightmares 
64. Resists bed 
74. Sleeps little 
84. Talks, cries in sleep 
94. Wakes often 
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Domain/Subscale 
CBCL 1.5-5 
ATTENTION PROBLEMS 
5. Can’t concentrate 
6. Can’t sit still 
56. Clumsy 
59. Quickly shifts 
95. Wanders away 
 
AGGRESSIVE BEHAVIOR 
8. Can’t stand waiting 
15. Defiant 
16. Demands must be met 
18. Destroys others things 
20. Disobedient 
27. Lacks guilt 
29. Easily frustrated 
35. Gets in fights 
40. Hits others 
42. Hurts unintentionally 
44. Angry moods 
53. Attacks people 
58. Punishment doesn’t change behavior 
66. Screams 
69. Selfish 
81. Stubborn 
85. Temper 
88. Uncooperative 
96. Wants attention 
 
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105 Digital Drive 
Novato, CA 94949 
 
Statistical Analysis Plan 
 
Study 111-206 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled 
Clinical Trial to Evaluate the Safety and Efficacy of 
Vosoritide in Infants and Young Children with 
Achondroplasia, Age 0 to < 60 Months 
 
Version 2: Final CSR 
Date: 02February2022 
The information in this document is considered privileged and confidential by BioMarin 
Pharmaceutical Inc., may not be disclosed to others except to the extent necessary to obtain 
Institutional Review Board approval and informed consent, or as required by Federal and 
State Laws.  Persons to whom this information is disclosed must be informed that this 
information is privileged and confidential and that it should not be further disclosed. 


 
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1 
SAP SYNOPSIS  
TITLES OF STUDY: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial to 
Evaluate the Safety and Efficacy of vosoritide in Infants and Young Children with Achondroplasia, 
Age 0 to < 60 Months. 
PROTOCOL NUMBER: 111-206  
STUDY SITES: Approximately 10-15 clinical centers worldwide 
PHASE OF DEVELOPMENT: Phase 2 
OBJECTIVES:  
The primary objectives of the study are to: 
• 
Evaluate the safety and tolerability of vosoritide in children age 0 to < 60 months with 
Achondroplasia (ACH)  
• 
Evaluate the effect of vosoritide on change from baseline in standing height/body length 
Z-Score 
The secondary objectives of the study are to: 
• 
Evaluate the effect of vosoritide on change from baseline in standing height/body length, 
annualized growth velocity (AGV), and upper: lower segment body ratio throughout the 
52-weeks of the study  
• 
Evaluate the effect of vosoritide on other growth parameters and body proportions 
• 
Evaluate the effect of vosoritide on bone morphology/quality by X-ray and dual X-ray 
absorptiometry (DXA) 
• 
Evaluate the Pharmacokinetics (PK) of vosoritide in children age 0 to < 60 months with 
ACH  
• 
Evaluate hip function 
• 
Evaluate for hip, thigh, or knee pain, or change in gait  
• 
Evaluate the effect of vosoritide on health-related quality of life (HRQoL), developmental 
status, and functional independence using age-specific QoL and functional independence 
questionnaires (Bayley Scales of Infant and Toddler Development, Third edition 
[Bayley-III], Activity of Daily Living and Functional Independence Measure (Wee-FIM), 
Infant Toddler Quality of Life Questionnaire (ITQOL), Child Behavior Checklist (CBCL) 
• 
Evaluate immunogenicity of vosoritide and assess impact on safety, PK, and efficacy 
measures  
• 
Evaluate the effect of vosoritide on bone metabolism and vosoritide pharmacodynamic 
(PD) biomarkers 
• 
Evaluate the effect of vosoritide on sleep apnea 
• 
Evaluate the effect of vosoritide on skull and brain morphology, including foramen 
magnum, ventricular and brain parenchymal dimensions 


 
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• 
Describe the incidence of surgical interventions, including cervical decompression, 
adenotonsillectomy, and tympanostomy 
The exploratory objectives of the study are to: 
• 
Document physical and phenotypic changes with clinical photography (optional) 
• 
Evaluate genomic biomarkers (optional).   
The exploratory objectives of the study are optional and will not be addressed in this SAP.  
STUDY DESIGN AND PLAN: Study 111-206 is a phase 2 randomized, double-blind, placebo-
controlled clinical trial of vosoritide in infants and younger children with a diagnosis of ACH. 
Approximately 70 Subjects will be enrolled into 3 age cohorts: n ≥ 30 total for aged ≥ 24 to 
< 60 months, n ≥ 20 total for aged ≥ 6 to < 24 months, and n ≥ 20 total for aged 0 to < 6 months. 
There will be 3 sentinel subjects for each cohort, and the rest of subjects will be randomized 1:1 to 
treatment or placebo control and stratified by age for Cohorts 1 and 2.  
All subjects who complete the 111-206 study will be eligible to receive vosoritide in the extension 
study 111-208 after the Week 52 visit.  
ANALYSIS POPULATIONS:  
The Full Analysis Set (FAS) is defined according to the intent-to-treat principle and includes all 
enrolled sentinel and randomized subjects with a signed informed consent.  
The Per-Protocol (PP) population is defined as a subset of the FAS population who completed the 
treatment originally allocated (i.e., always received the assigned treatment), with a standing 
height/body length assessment at Week 52 following the protocol window, and with treatment 
compliance of at least 80%. 
The Safety Population is a subset of the FAS who receive at least one dose of vosoritide or placebo 
in this study. 
The PK Population is defined as all sentinel subjects and subjects randomized to vosoritide 
treatment group, who received at least one dose of vosoritide in this study and have at least one 
evaluable PK concentration. 
The Immunogenicity Population is defined as all subjects in the Safety Population who have at 
least one evaluable immunogenicity sample. 
STUDY ENDPOINTS AND ANALYSES:  
Efficacy endpoints and analyses:  
The primary efficacy endpoint is change from baseline in standing height/body-length Z-Score at 
Week 52.  
The key secondary efficacy endpoints include change from baseline at Week 52 in standing 
height/body length, AGV, and upper to lower body ratio. Other secondary efficacy endpoints 
include biomarker samples to evaluate the effect of vosoritide on bone metabolism, vosoritide 
pharmacodynamic biomarkers, growth parameters and body proportions, sleep apnea, skull and 
brain morphology, and clinical outcome assessments (developmental/functional/HRQoL status).  


 
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In addition to the summary statistics analyses for efficacy endpoints, model-based analysis will be 
conducted for change from baseline at Week 52 in standing height/body length Z-Score, standing 
height/body length, AGV, and upper to lower body ratio for all cohorts overall and/or by cohort, as 
appropriate.  
Safety endpoints and analyses: 
Adverse events (AEs) will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) Version 24.1 and presented by System Organ Class (SOC) and Preferred Term (PT). 
Summaries of AE’s will include all AE’s, serious adverse events (SAEs) and events of interest 
(EOI). 
Clinical laboratory tests will be summarized descriptively. Shift tables tabulating Common 
Terminology Criteria for Adverse Events (CTCAE) severity grade at baseline versus worst post-
baseline grade will be provided.  
Vital signs will be summarized descriptively. Shift tables tabulating shifts from pre-dose (diastolic 
blood pressure (BP) < 40 mmHg, diastolic BP ≥ 40mmHg) to lowest post-injection value (diastolic 
BP ≥40mmHg) will be provided. Additional shift tables will describe similar pre/post injection 
shifts in vital signs.  
X-rays and DXA will be performed on the extremities and spine to evaluate changes in bone 
morphology and quality.  
Anti-vosoritide immunogenicity assessments will be summarized descriptively. Behavioral 
assessments with the CBCL will be summarized descriptively.  
Other analyses:  
Additional analyses will be conducted as appropriate to evaluate the impact of the COVID-19 
pandemic on the study conduct. 
  


 
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TABLE OF CONTENTS 
1 SAP SYNOPSIS ..................................................................................................................2 
2 APPROVAL (SIGNATURE AND DATE) .........................................................................9 
3 LIST OF ABBREVIATIONS ............................................................................................10 
4 INTRODUCTION .............................................................................................................12 
4.1 Objectives of Study ...................................................................................................12 
4.2 Study Design .............................................................................................................13 
4.3 Study Populations .....................................................................................................15 
4.4 Study Dosage and Administration ............................................................................15 
4.5 Sample Size Determination .......................................................................................15 
4.6 Blinding and Randomization Methods .....................................................................15 
4.6.1 
Blinding Method ..........................................................................................15 
4.6.2 
Randomization Method ...............................................................................15 
4.7 Interim Analysis ........................................................................................................16 
5 GENERAL ANALYSIS CONSIDERATIONS ................................................................17 
5.1 Analysis Populations .................................................................................................19 
5.1.1 
Full Analysis Set .........................................................................................19 
5.1.2 
Per-Protocol .................................................................................................19 
5.1.3 
Safety ...........................................................................................................19 
5.1.4 
PK ................................................................................................................19 
5.1.5 
Immunogenicity ...........................................................................................20 
5.2 Pooling of Data from Sites with Small Enrollment ..................................................20 
5.3 Study Day Derivation ................................................................................................20 
5.4 Visit Windows for Analysis ......................................................................................20 
5.5 Handling of Dropouts and Missing Data ..................................................................22 
5.5.1 
Partial Dates ................................................................................................22 
6 SUBJECT DISPOSITION .................................................................................................24 
7 DISCONTINUATION AND COMPLETION ..................................................................25 
8 PROTOCOL EXEMPTIONS AND DEVIATIONS .........................................................26 
9 DEMOGRAPHICS AND BASELINE CHARACTERISTICS.........................................27 


 
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10 MEDICAL HISTORY .......................................................................................................29 
11 PRIOR AND CONCOMITANT MEDICATIONS ...........................................................30 
12 COMPLIANCE..................................................................................................................31 
13 EXTENT OF EXPOSURE TO STUDY TREATMENT ..................................................32 
14 EFFICACY EVALUATIONS ...........................................................................................33 
14.1 General Approaches for Analyzing Growth Parameters ...........................................33 
14.2 Primary Efficacy Endpoint ........................................................................................35 
14.2.1 Primary Analyses ........................................................................................35 
14.2.2 Sensitivity Analyses ....................................................................................36 
14.3 Secondary Efficacy Endpoint(s) ...............................................................................36 
14.3.1 Standing Height/Body Length .....................................................................36 
14.3.2 Annualized Growth Velocity .......................................................................37 
14.3.3 Upper to Lower Body Segment Ratio .........................................................38 
14.3.4 Body Proportion Ratios ...............................................................................38 
14.3.5 Other Growth Measures ..............................................................................39 
14.4 Health-Related Quality of Life .................................................................................39 
14.4.1 Bayley-III ....................................................................................................40 
14.4.2 Infant and Toddler Quality of Life Questionnaire (itqol-97, 2013) 
(ITQOL) ......................................................................................................42 
14.4.3 Function Independence Measure (WeeFIM) (Wee-FIM II Version 
6.4) ..............................................................................................................43 
14.5 Sleep Study Scores ....................................................................................................44 
15 SAFETY EVALUATIONS ...............................................................................................45 
15.1 Adverse Events .........................................................................................................45 
15.1.1 Treatment-Emergent Adverse Events .........................................................45 
15.1.2 Events of Interest .........................................................................................47 
15.1.3 Injection Site Reaction Symptoms ..............................................................49 
15.2 Clinical Laboratory Tests ..........................................................................................49 
15.3 Vital Signs .................................................................................................................51 
15.4 Biological Parental Standing Height .........................................................................52 


 
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15.5 Electrocardiogram .....................................................................................................52 
15.6 HPA Axis Assessments .............................................................................................53 
15.7 Child Behavior Checklist (Achenbach, 2000) ..........................................................53 
15.8 Echocardiogram ........................................................................................................54 
15.9 On-Study Procedures, Interventions and Surgeries ..................................................54 
15.10 Hip Monitoring and Rotation ....................................................................................55 
15.11 Body Mass Index and BMI Z-scores ........................................................................55 
15.12 Weight Z-Scores .......................................................................................................55 
16 IMAGING SECONDARY ENDPOINT(S) ......................................................................57 
16.1 Lower Limb X-Rays .................................................................................................57 
16.2 Lumbar Spine X-Rays ...............................................................................................57 
16.2.1 Vertebral Height ..........................................................................................58 
16.2.2 Transverse Diameter (Interpedicle Distance) ..............................................58 
16.2.3 Sagittal Width ..............................................................................................58 
16.2.4 Lumbar Spine Angles ..................................................................................58 
16.3 Dual Energy X-ray Absorptiometry ..........................................................................59 
16.3.1 Whole Body Less Head and Lumbar Spine ................................................60 
16.4 MRI ...........................................................................................................................60 
17 BONE METABOLISM BIOMARKERS ..........................................................................62 
18 VOSORITIDE PD ACTIVITY BIOMARKERS ..............................................................63 
19 IMMUNOGENICITY ASSESSMENT .............................................................................64 
20 PHARMACOKINETICS AND PHARMCODYNAMICS ...............................................68 
21 OTHER ANALYSES ........................................................................................................69 
22 ANALYSES DIFFERENT FROM PROTOCOL-DEFINED ANALYSES .....................70 
23 REFERENCES ..................................................................................................................71 
24 SUMMARY OF KEY CHANGES TO STUDY SAP .......................................................72 
25 APPENDICES ...................................................................................................................74 
25.1 Summary of Growth Measures Derivations ..............................................................74 
25.2 Child Behavior Checklist Domains ...........................................................................76 
 


 
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LIST OF TABLES  
Table 5.1:  Format for Efficacy Summary Analyses for Cohort 1 ...........................................17 
Table 5.2:  Format for Efficacy Summary Analyses for Cohort 2 ...........................................17 
Table 5.3:  Format for Efficacy Summary Analyses for Cohort 3 ...........................................17 
Table 5.4:  Format for Safety Summary Analyses for Cohort 1* ............................................18 
Table 5.4.1:  Visit Windows for Observed Assessments in BMN 111-901 and 
BMN 111-206 ................................................................................................21 
Table 5.4.2:  Visit Windows for Observed Assessments in 111-206 ......................................22 
Table 15.3.1:  Vital Sign Post-dose Assessment Frequency ....................................................51 
 
LIST OF FIGURES  
Figure 4.2.1:  Study Design .....................................................................................................14 
 


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2 
APPROVAL (SIGNATURE AND DATE) 
Statistical Science 
DD MON YYYY 
Data Analytical Science 
DD MON YYYY 
Clinical Science Lead 
DD MON YYYY 
Pharmacovigilance Lead 
DD MON YYYY 
Head of Statistical Science 
DD MON YYYY 
Head of Clinical Science 
DD MON YYYY 
(Signatures and dates are in the last page of this SAP)


 
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3 
LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
µg/kg 
microgram/kilogram 
ACH 
achondroplasia 
ADA 
anti-drug antibody 
AE 
adverse event 
AGV 
annualized growth velocity 
ANCOVA 
Analysis of covariance 
ANP 
atrial natriuretic peptide 
ATC 
Anatomical Therapeutic Chemical 
BMC 
bone mineral content 
BMD 
bone mineral density 
BMI 
body mass index 
BMN 
BioMarin 
BNP 
brain natriuretic peptide 
BP 
blood pressure 
BSAP 
bone-specific alkaline phosphatase 
CBCL 
Child Behavior Checklist 
CDC 
Centers for Disease Control and Prevention 
CM 
concomitant medication 
CRF 
case report form 
cGMP 
cyclic guanosine monophosphate 
CNP 
C-type natriuretic peptide 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events (v4.03) 
CTX-II 
C-terminal telopeptide of cross-linked collagen type II 
DBL 
database lock 
DMC 
data monitoring committee 
DXA 
dual x-ray absorptiometry 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
JNDA 
Japan New Drug Application 


 
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HPA 
hypothalamic pituitary adrenal 
HRQoL 
health-related quality of life 
ISR 
injection site reaction 
ITQoL 
Infant Toddler Quality of Life Questionnaire 
IXRS 
interactive web or voice response system 
MAA 
Marketing Authorization Application 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAb 
neutralizing antibody 
NCI 
National Cancer Institute 
NDA 
New Drug Application 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PP 
per protocol 
PT 
preferred term 
QTc-F 
Fridericia’s corrected QT interval 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
Subcutaneous 
SCFE 
slipped capital femoral epiphysis 
SD 
standard deviation 
SDS 
standard deviation score 
SE 
standard error 
SMQ 
Standardized MedDRA query 
SOC 
system organ class 
Tab 
total anti-drug antibody 
TEAE 
treatment-emergent adverse event 
TLGs 
tables, listings, and graphs 
WeeFIM 
Activity of Daily Living and Functional Independence Measure 
WHO 
World Health Organization 


 
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4 
INTRODUCTION  
Study 111-206 (original protocol effective date: 06 December 2017) is a Phase 2 randomized, 
double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of vosoritide 
in infants and young children with ACH, aged 0 to < 60 months.  
This SAP is based on Amendment 2 of Study 111-206 (date: 08 February 2019). It describes 
the analyses and evaluations that will be provided for the final clinical study report (CSR). 
The final Version 2.0 of the SAP incorporates feedback from the Food and Drug 
Administration (FDA) received on Version 1.1 of the SAP (date: 17 November 2021), which 
was received on 19 January 2022. Any additional changes are provided in the table in Section 
24. 
Where there are major differences between the protocol-defined analyses, and the SAP-
defined analyses, these will be identified in the SAP. The SAP-defined analyses prevail. 
4.1 
Objectives of Study  
The primary objectives of study are to: 
• Evaluate the safety and tolerability of vosoritide in children age 0 to < 60 months 
with ACH 
• Evaluate the effect of vosoritide on change from baseline in standing height/body 
length Z-Score (height Z-Score may be used interchangeable) 
The secondary objectives of study are to: 
• Evaluate the effect of vosoritide on change from baseline in standing height/body 
length, AGV, and upper: lower body segment ratio throughout the 52 weeks of the 
study 
• Evaluate the effect of vosoritide on other growth parameters and body proportions 
• Evaluate the effect of vosoritide on bone morphology/quality by x-ray and DXA 
• Evaluate the PK of vosoritide in children age 0 to < 60 months with ACH 
• Evaluate hip function 
• Evaluate for hip, thigh, or knee pain, or change in gait 
• Evaluate the effect of vosoritide on HRQoL, developmental status, and/functional 
independence using age-specific QoL and functional independence 
questionnaires/QOL status (Bayley-III), Wee-FIM, ITQOL, and CBCL 
• Evaluate immunogenicity of vosoritide and assess impact on safety, PK, and efficacy 
measures 


 
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• Evaluate the effect of vosoritide on bone metabolism and vosoritide PD biomarkers 
• Evaluate the effect of vosoritide on sleep apnea 
• Evaluate the effect of vosoritide on skull and brain morphology, including foramen 
magnum, ventricular and brain parenchymal dimensions 
• Describe the incidence of surgical interventions, including cervical decompression, 
adenotonsillectomy, and tympanostomy 
The exploratory objectives are to: 
• Documental physical and phenotypic changes with clinical photography (optional) 
• Evaluate genomic biomarkers (optional) 
The exploratory objectives of the study are optional and will not be addressed in this SAP. 
4.2 
Study Design  
Study 111-206 is a phase 2 stratified randomized, double-blind, placebo-controlled clinical 
trial of vosoritide in infants and younger children with a diagnosis of ACH. 
Subjects aged ≥ 6 months to < 60 months old who have documented ACH confirmed by 
genetic testing; at least a 6-month period of pretreatment growth assessment in Study 
111-901 immediately before study entry; and who meet the study eligibility criteria, will 
participate. Eligible subjects ranging from 0 months to < 3 months old may enroll directly 
into 111-206 and have a minimum of 3 months of pre-treatment observation prior to 
commencing treatment with investigational product or may enroll in 111-901 for a minimum 
of 3 months of pretreatment growth assessment immediately before roll-over to 111-206. 
Approximately 70 subjects will be enrolled at approximately 10-15 clinical centers 
worldwide. 
Subjects will be enrolled into 3 age cohorts based on age at study screening starting with the 
eldest population. Within Cohorts 1 and 2, subjects will be stratified by age: 
• Cohort 1 – children aged ≥ 24 to < 60 months (n ≥ 30 total: 3 sentinel subjects who 
receive vosoritide, and at least 27 additional subjects randomized 1:1 to treatment or 
placebo control), stratified by age (≥ 24 months to < 36 months and ≥ 36 months to 
< 60 months) 
• Cohort 2 – children aged ≥ 6 to < 24 months (n ≥ 20 total: 3 sentinel subjects who 
receive vosoritide, and at least 17 additional subjects randomized 1:1 to treatment or 
placebo control), stratified by age (≥ 6 months to < 15 months and ≥ 15 months to 
< 24 months) 


 
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• Cohort 3 – children aged 0 to < 6 months (n ≥ 20 total: 3 sentinel subjects who 
receive vosoritide, and at least 17 additional subjects randomized 1:1 to treatment or 
placebo control). Treatment begins at ≥ 3 months to < 6 months after 3 months of 
observation.  
Sentinel subjects from each cohort will be enrolled, treated with vosoritide, and studied for 
short-term safety and PK data. After the sentinel data are evaluated within a cohort additional 
recruited subjects will be randomized to receive vosoritide or placebo subcutaneous daily 
(1:1 ratio) for 52 weeks.  
As subjects age on study, they will be administered the dose determined to be appropriate for 
their current age as follows: 
All sentinel and randomized subjects in Cohort 1 received 15 μg/kg dose. Sentinel subjects in 
Cohort 2 initially received 15 μg/kg dose and the dose was escalated to 30 μg/kg while they 
remained < 24 months of age following review of PK data as per protocol. All randomized 
subjects in Cohort 2 will receive 30 μg/kg dose while they remained < 24 months of age. 
All sentinel and randomized subjects in Cohort 3 received 30 μg/kg dose while they 
remained < 24 months of age. The dose for all sentinel and randomized subjects in Cohorts 2 
and 3 will be adjusted to 15 µg/kg/day after they turn 24 months old. 
The 111-206 study design is presented in Figure 4.2.1. All subjects who complete the 
111-206 study will be eligible to receive vosoritide in the extension study 111-208 after the 
Week 52 visit. 
Figure 4.2.1:  Study Design  
 


 
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4.3 
Study Populations  
Subjects aged 0 to < 60 months old, with documented ACH confirmed by genetic testing, and 
who meet the study eligibility criteria will participate.  
For additional criteria for selection of study population, please refer to inclusion and 
exclusion criteria for the protocol. 
4.4 
Study Dosage and Administration  
In Study 111-206, sentinel subjects in Cohort 1 will receive an initial daily dose of 15 μg/kg. 
All available safety and PK data will be reviewed after 3 sentinel subjects reach Day 8. If the 
criteria for dose adjustment are met, the 3 sentinel subjects will be started on the new 
adjusted dose at their next scheduled visit and the remainder of the subjects in the age cohort 
will also be enrolled starting at the new adjusted dose. The 3 sentinel subjects for the second 
and third cohorts will be evaluated similarly to the sentinel subjects in the first cohort for 
potential dose adjustment. Additional sentinels may be added to any cohort if needed for 
additional safety and/or PK assessment.  
4.5 
Sample Size Determination  
Approximately 70 subjects aged 0 to < 60 months at study entry will participate in 111-206. 
No formal sample size calculations were performed. The number of subjects is considered 
appropriate to evaluate the safety and efficacy of vosoritide in the target population. 
4.6 
Blinding and Randomization Methods  
4.6.1 Blinding Method  
This is a placebo-controlled, double-blind study.  Blinding is strictly maintained during the 
study and a study specific masking plan describes how potentially unblinding data are 
handled during the lifetime of the study. The study will remain blinded until after all data has 
been entered, and the final database has been locked. 
4.6.2 Randomization Method  
The centralized randomization with stratification is managed by an external vendor, using 
IXRS technology.   
Subjects will be enrolled into 3 age cohorts based on age at study screening starting with the 
eldest population. In each cohort, eligible subjects will be randomized in a 1:1 ratio to 
vosoritide or placebo after 3 sentinel subjects are treated. Cohorts 1 and 2 will be stratified by 
age. Subjects are randomized separately within each cohort in Japan.  


 
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4.7 
Interim Analysis  
No formal interim futility/efficacy analyses are planned. Two informal interim analyses 
including data from both Studies 111-206 and 111-208 were performed for selected domains: 
one for New Drug Application (NDA) to Food and Drug Administration (FDA) and 
marketing authorization applications (MAA) to European Medicines Agency (EMA), dated 
18December 2019, and another for Japan New Drug Application (JNDA), dated 
11November 2020. For these analyses, subjects remained blinded and no efficacy data was 
analyzed for the randomized subjects nor post baseline listings except for serious adverse 
events. 
In addition to safety and PK monitoring by BioMarin Personnel, an independent data 
monitoring committee (DMC) will act in an advisory capacity to BioMarin to monitor 
subject safety and PK of subjects who participate in the study. A DMC review will occur to 
evaluate all available safety and PK data after the sentinel subjects complete 12 weeks of 
dosing, and DMC will make recommendations for stopping or continuing the study, and 
endorse dose adjustments if needed, based on pre-specified criteria. DMC data review 
meetings occur approximately every 6 months during the course of the study. 
 


 
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5 
GENERAL ANALYSIS CONSIDERATIONS  
The analyses described in this final SAP are based on Amendment 2 of the protocol 
(date: 08 February 2019). 
Individual subject data that is reflected in data summaries will be provided in listings. Unless 
otherwise specified, all listings will be by cohort, by sentinel/randomized subjects, by 
treatment group, and ordered by subject number, where subject number includes the site 
number.  
Unless otherwise specified, summary tables for efficacy variables will use format in 
Table 5.1, Table 5.2, and Table 5.3 for Cohorts 1, 2, and 3, respectively.  Summary tables for 
safety variables will be separated by cohort and overall by treatment group using format in 
Table 5.4.  
Table 5.1:  Format for Efficacy Summary Analyses for Cohort 1  
Sentinel 
Randomized 
All Vosoritide Treated* 
Vosoritide 
Placebo 
≥ 24 to 
< 36 
months 
≥ 36 to 
< 60 months 
Over
all 
≥ 24 to < 
36 
months 
≥ 36 to 
< 60 months 
Over
all 
≥ 24 to < 
36 
months 
≥ 36 to 
< 60 months 
Over
all 
*All vosoritide treated includes sentinel subjects and randomized subjects who received vosoritide. 
 
Table 5.2:  Format for Efficacy Summary Analyses for Cohort 2  
Sentinel 
Randomized 
All Vosoritide Treated* 
Vosoritide 
Placebo 
≥ 6 to 
< 15 
months 
≥ 15 to 
< 24 months 
Over
all 
≥ 6 to < 
15 
months 
≥ 15 to 
< 24 months 
Over
all 
≥ 6 to < 
15 
months 
≥ 15 to 
< 24 months 
Over
all 
*All vosoritide treated includes sentinel subjects and randomized subjects who received vosoritide. 
 
Table 5.3:  Format for Efficacy Summary Analyses for Cohort 3  
Sentinel 
Randomized 
All Vosoritide Treated* 
Vosoritide 
Placebo 
*All vosoritide treated includes sentinel subjects and randomized subjects who received vosoritide. 


 
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Table 5.4:  Format for Safety Summary Analyses for Cohort 1*  
Sentinel 
Randomized 
All Vosoritide Treated** 
Vosoritide 
Placebo 
* Cohort 2, Cohort 3, and Overall will have the same format as Cohort 1. 
**All vosoritide treated includes sentinel subjects and randomized subjects who received vosoritide. 
 
Baseline growth measures (other than AGV, baseline AGV is defined in Section 14.3.2) and 
baseline weight are those assessed on Day 1 of dosing, regardless of timing relative to 
dosing. (Note: If no assessments are available, then the baseline assessment will be the last 
non-missing assessment prior to Day 1).  Baseline assessments are the last non-missing 
on-study assessments prior to administration of study treatment. Change from baseline is 
calculated as: (post-baseline value – baseline value); Percent change from baseline is 
calculated as: ([post-baseline value – baseline value]/baseline value) x100. 
The screening visit will not be presented in descriptive summaries over time.  When the 
analysis windows have been applied (see Section 5.4), data collected at the screening visit 
may be included in the baseline assessment.  All assessments will be listed, but only those 
assessments assigned to visits according to the windows applied (see Section 5.4) will be 
summarized in tables or graphically.  Exceptions to this are summaries of the worst 
post-baseline laboratory data in shift tables where all assessments are considered. 
Unless otherwise specified, summary statistics n, mean, standard deviation (SD), median, 
25th and 75th percentile, minimum, and maximum will be provided for numerical variables. 
The mean, 25th percentile, median, 75th percentile, and estimates of precision (e.g. SD, 
confidence interval) will be displayed to one more decimal place than the collected data. 
Minimum and maximum values will be presented to the same decimal places as the collected 
data. The number of decimal places to which endpoints are reported follow the project 
programming standards. 
Number and percentage will be provided for categorical variables. When summarizing 
categorical data, for mutually exclusive categories, the sum of the individual categories, 
including a separate “Missing” category, should equal 100%.  Unless otherwise specified, if 
categories have no data, then they will not be displayed.  
All statistical analyses will be performed using SAS® version 9.4 or a later release (SAS 
Institute, North Carolina, USA) and results be presented in the form of tables, listings, and 
graphs (TLGs). All statistical analyses, including dataset creation and output generation, will 


 
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be performed by Biostatistics and Statistical Programming personnel of BioMarin’s 
Biometrics department. 
5.1 
Analysis Populations  
5.1.1 Full Analysis Set  
The Full Analysis Set (FAS) is defined according to the intent-to-treat principle and includes 
all enrolled sentinel and randomized subjects with a signed informed consent. The FAS will 
be the main analysis population for summaries and/or analyses described in the SAP, 
including but not limited to summaries and/or analyses of demographics, baseline 
characteristics, dispositions, and all efficacy endpoints.   
All listings, excluding screen failures, will be produced on the FAS. 
5.1.2 Per-Protocol  
The Per-Protocol (PP) population is defined as a subset of the FAS population who 
completed the treatment originally allocated (i.e., always received the assigned treatment 
(vosoritide or placebo)), with a standing height/body length assessment at Week 52 following 
protocol window, and with treatment compliance of at least 80%. 
The PP population will be used for sensitivity analysis of the primary and key secondary 
efficacy endpoints only. 
5.1.3 Safety  
The Safety Population is a subset of the FAS who receive at least one dose of vosoritide or 
placebo in the study. The Safety Population will be used to present the safety summaries by 
actual treatment received. Subjects randomized to one treatment group, who only receive the 
study treatment for the other treatment group, will be analyzed in the arm of the study 
treatment they received. 
The Safety Population will be used to present the safety data.   
5.1.4 PK  
The PK Population is defined as all sentinel subjects and subjects randomized to vosoritide 
treatment group, who received at least one dose of vosoritide in this study and have at least 
one evaluable PK concentration. 


 
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5.1.5 Immunogenicity  
The Immunogenicity Population is defined as all subjects in the Safety Population who have 
at least one evaluable immunogenicity sample. Subjects randomized to one treatment group, 
who only receive the study treatment for the other treatment group, will be analyzed in the 
arm of the study treatment they received. 
5.2 
Pooling of Data from Sites with Small Enrollment  
Not applicable, as there are no analyses by site.  
5.3 
Study Day Derivation  
Study day in 111-206 will be determined by subtracting the initial study treatment start date 
from a visit date plus 1 if the visit date occurs on or after the initial study treatment start date. 
Otherwise, the study day will be the visit date minus the initial study treatment start date. 
Therefore, Study Day 1 will occur on the initial study treatment start date. i.e. 
• Study Day 1 = Day of first dose of study treatment. 
• If Visit Date < Study Treatment Start Date, then Study Day = Visit Date - Study 
Treatment Start Date 
• If Visit Date >= Study Treatment Start Date, then Study Day = Visit Date - Study 
Treatment Start Date +1 
5.4 
Visit Windows for Analysis  
An assessment for a subject will be classified according to the study day of the assessment 
where it falls within a window.   
Observational data in 111-901 for subjects who enrolled in 111-206 and are included in the 
corresponding analysis population will be used in efficacy summary tables and figures. 
For Cohort 3 subjects, data from the observational period in 111-901 or 111-206 will be 
included. The analysis visits and windows for observational assessments in 111-901 and 
111-206 are defined in Table 5.4.1. Unless otherwise specified, only the derived visits listed 
in the table will be included in summary tables and figures. 


 
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Table 5.4.1:  Visit Windows for Observed Assessments in BMN 111-901 and 
BMN 111-206  
Derived Visit 
Target Daya 
Analysis Windowa 
3 Months Prior in 111-206 or 111-901 for Cohort 3 subjects* 
-91 
target day +/- 42 days 
 6 Months Prior in 111-901* 
-182 
target day +/- 42 days 
a Target days and analysis windows are relative to the 111-206 Day 1 date defined in Section 5.3 above. 
* In the event a subject does not have an assessment in the 3 months prior or 6 months prior window then the 
closest assessment to the target date will be considered. If the two closest assessments to the target day are 
equidistant from the target day, the latest assessment will be used.  
 
For each subject and growth measure in study 111-901, the record closest to the target day 
within the analysis window will be retained for inclusion in summary tables. 
Spaghetti plots of standing height/body length Z-Score will include measures every 6 months 
recorded and including the “6 months prior”, “3 months prior” for subjects in Cohort 3 from 
Study 111-901 or 111-206. This will allow for all subjects with height assessments 3 months 
prior to Day 1 to have at least one assessment included.  
The analysis windows for assessments in 111-206 are defined in Table 5.4.2. The analysis 
windows are designated to be consecutive for scheduled visits to accommodate delayed visits 
due to impact of COVID-19. The upper bound of each visit window will be target day plus 
half of the difference between the current target day and the next target day, and the lower 
bounds of the window will be the upper bound of the previous window plus 1 except for 
Day 1, Day 2, Day 3, and Week 52. Lower bound, upper bound, and target date are the same 
for Day 1, Day 2, and Day 3. The upper bound of Week 52 will be target day plus 42 days. If 
there are two or more assessments within a designated window, the assessment that is closest 
to the target day will be used for analyses.  If the two closest assessments to the target day are 
equidistant from the target day, the assessments taken on a scheduled visit per case report 
form (CRF) page will be used; if both are scheduled visits but not on the same day, the latest 
assessments will be used; if both are on the same day, the average of the assessments will be 
used.  Unless otherwise specified, all analyses are based on derived visits. 


 
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Table 5.4.2:  Visit Windows for Observed Assessments in 111-206  
Derived Visit 
Target Daya 
Analysis Windowa 
Baseline 
 
The last assessment prior to the first dose of study treatment unless 
otherwise specified. 
Day 1 
Day 1 
Day 1 
Day 2 
Day 2 
Day 2 
Day 3 
Day 3 
Day 3 
Day 8 
Day 8 
Day 4 - 15 
Week 3 
Day 22 
Day 16 - 33  
Week 6 
Day 43 
Day 34 - 68  
Week 13 
Day 92 
Day 69 -117  
Week 20 
Day 141 
Day 118 - 162  
Week 26 
Day 183 
Day 163 - 229  
Week 39 
Day 274 
Day 230 - 320  
Week 52 
Day 365 
Day 321 - 407  
a Target days and analysis windows are relative to Day 1 date defined in Section 5.3.  
 
5.5 
Handling of Dropouts and Missing Data  
For descriptive summaries, missing data will not be imputed. For model-based analyses, an 
imputation will be conducted for endpoints missed at Week 52. Detailed imputation rules are 
described in Section 14.1.  
Other than for partial/missing dates described below, there will be no imputation for safety 
data. 
5.5.1 Partial Dates  
Where start and stop dates for medications or adverse events are incomplete, imputation rules 
will be applied.  
In the event that the start date of a medication/AE is partial, the following imputation rules 
will be applied: 
• If only day is missing, then the start date will be imputed as the first day of the month. 
If month and year are the same as the month and year of first dose of study treatment, 
then the start date will be imputed as the first dose date in the study in which the AE 
occurred.  


 
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• If only year is non-missing, then the start date will be imputed as the first day of the 
year. If year is the same as the year of first dose of study treatment, then the start date 
will be imputed as the first dose date in the study in which the AE occurred. 
In the event that the stop date of a medication/AE is partial, the following imputation rules 
will be applied: 
• If only day is missing, then the end date will be imputed as the last day of the month.  
• If only year is non-missing, then the end date will be imputed as the last day of the 
year. If the imputed date is beyond the study completed or discontinued date of the 
study in which the AE occurred, the imputed date will be replaced with the study 
completed or discontinued date. 


 
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6 
SUBJECT DISPOSITION  
Disposition will be presented based on the FAS. The number of subjects 
enrolled/randomized, the number of subjects who received study treatment, the number of 
subjects who completed study treatment, and the number of subjects who completed the 
study will be reported separately by cohort and overall by treatment group using format as 
specified in Table 5.4.  
Disposition data will be listed for both the sentinels and randomized subjects by cohort and 
treatment group, and will indicate the investigator site. In addition, a listing will be provided 
for those subjects who were screen failures, along with the reason for screen failure. 


 
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7 
DISCONTINUATION AND COMPLETION  
For subjects who prematurely discontinued from the study, the primary reason for 
discontinuation will be summarized. A similar summary will be provided for subjects who 
discontinued study treatment. 
The number of subjects who completed study treatment and the number of subjects who 
completed the study will be summarized by cohort and overall by treatment group using 
format as specified in Table 5.4. All summaries will be based on the FAS. 
Listing will be provided on the FAS. 
 


 
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8 
PROTOCOL EXEMPTIONS AND DEVIATIONS  
The number and percentage of subjects with any protocol deviation, any major protocol 
deviation, and any minor protocol deviation will be presented separately by cohort and 
overall by treatment group using format as specified in Table 5.4, according to the categories 
described in the study specific protocol deviation plan. Reasons for major/minor deviations 
will be summarized. Subjects who received the wrong treatment will be identified after data 
base lock and considered as a Major Protocol Deviation. 
All summaries will be based on the FAS. 
All protocol deviations will be listed for sentinel and randomized subjects by cohort. 
sentinel/randomized subjects, treatment group, and subject ID. A separate listing of all major 
deviations which have been classified as a “Dosing Irregularity” will also be provided. 
In addition, a summary and listing of COVID-19 specific protocol deviations will be 
provided.   


 
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9 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS  
Demographic and baseline characteristics will be summarized for the FAS, and presented for 
by cohort by treatment group with the format as specified in Table 5.1, Table 5.2, and 
Table 5.3 for Cohorts 1, 2, and 3, respectively and Table 5.4 for Overall. Rules on standing 
height/body length and sitting height/crown to rump length are provided in Section 14.1. 
Demographics will be summarized as: 
• Age at Screening (months with 1 decimal place) 
• Age at Day 1 (months with 1 decimal place) 
• Sex (Male, Female) 
• Race (American Indian or Alaska Native, Asian [Japanese/Other], Black or African 
American, Native Hawaiian or Pacific Islander, White, Multiple, Not Provided Due to 
Patient Privacy Rules) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
Baseline characteristics will be summarized as: 
• Weight (kg) and Weight Z-Score 
• Body Mass Index (BMI) (kg/m2), and also BMI Z-Score for subjects aged 24 months 
or older  
Baseline growth measures will be summarized as: 
• Height Z-Score (Refer to Section 14.2.1)  
• AGV (cm/yr)  
• Standing Height/Body Length (cm)  
• Sitting Height/Crown to Rump(cm)  
• Lower Body Length (cm) = Standing Height - Sitting Height  
• Head Circumference (cm) 
• Upper Arm Length (cm) 
• Lower Arm (Forearm) Length (cm) 
• Arm Span (cm) 
• Upper Leg Length (Thigh) (cm) 
• Knee to Foot Height (cm) 


 
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• Tibial Length (cm) 
• Upper to Lower Body Segment Ratio 
• Arm Span to Standing Height Ratio  
• Upper Arm Length to Lower Arm (Forearm) Length Ratio 
• Upper Leg Length to Tibial Length Ratio 
A listing of each sentinel and randomized subject’s demographic/baseline data will be 
provided. 


 
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10 
MEDICAL HISTORY  
Medical history will be solicited from each subject, including all major illnesses, diagnoses, 
and surgeries that the subject has ever had; any prior or existing medical conditions that 
might interfere with study participation or safety; and evaluation for knee, thigh, hip or groin 
pain, or change in gait/activity.  
All medical history terms will be coded in accordance with MedDRA Version 24.1 that each 
term is assigned a SOC and PT.   
A list of PTs considered to be ACH-related will be reviewed prior to the data cut. A listing 
for the complete list of final terms will be generated, retained in the study file, and 
documented in the CSR.  
All recorded medical history will be summarized on the FAS by SOC and by PT by cohort 
and overall by treatment group using format as specified in Table 5.4, ordered by descending 
order of frequency of SOC in the overall population. In addition, achondroplasia-related 
medical history will be listed and summarized separately by SOC and PT in a similar 
manner. 
The number of subjects with abnormal physical exam results at screening will be 
summarized and listed. 
A listing of each subject’s medical history will be provided, plus a listing of each subject’s 
achondroplasia-related medical history. 


 
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11 
PRIOR AND CONCOMITANT MEDICATIONS  
Prior and concomitant medications will be summarized for the FAS.  For analysis purposes, 
the following definitions will be used to determine prior and concomitant medications for the 
entire study period: 
• Prior medications: Any medications taken and ended prior to the initial study 
treatment administration date will be considered prior medications. 
• Concomitant medications: Any medications taken on or after the initial study 
treatment administration date up to 30 days after discontinuation of study treatment 
will be considered concomitant medications and included in summary tables. This 
also includes medications initially taken prior to the initial study treatment 
administration date but continued or ended on or after the initial study treatment 
administration date. 
Concomitant medications will be summarized separately by cohort and overall by treatment 
group using format as specified in Table 5.4, and a separate summary will be provided which 
includes only those concomitant medications that were initiated on study.  
All medications will be coded using the latest version available within BioMarin of the 
World Health Organization Drug (WHO Drug) dictionary (Version September 2021).  Prior 
and concomitant medication use will be separately summarized by Anatomical Therapeutic 
Chemical (ATC) medication class (Level 2) and preferred name (i.e., generic medication 
name). If a medication doesn’t have ATC level 2, they are grouped as “ATC Level 2 
classification unavailable”. A subject reporting the same medication more than once will be 
counted once when calculating the number and percentage of subjects who received that 
medication. A listing of prior and concomitant medications will be provided. In addition, a 
listing for COVID vaccine will be provided.  
 
 


 
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12 
COMPLIANCE  
Treatment compliance will be calculated based on the study treatment preparation and study 
treatment administration records captured in the eCRF, and summarized separately by cohort 
and overall by treatment group using format as specified in Table 5.4 for the safety 
population.  
For each subject it considers all data up to the last recorded dose. For each column, results 
will be separated for 15 µg/kg, 30 µg/kg, and overall.   
For each daily injection, the amount of study treatment taken will be calculated based on the 
number of units in the syringe pre-injection, minus the number of units remaining in the 
syringe post-injection. For the cases that the number of units in the syringe pre-injection is 
not captured in the eCRF, if response to “Was study drug administrated?” is “Yes”, then it 
will be assumed to be the same as the planned dose; if response to “Was study drug 
administrated?” is “No”, then it will be assumed to be missing and these records will not be 
included in the compliance calculation.  
The total amount of study treatment taken will be calculated based on the amount of study 
treatment taken (units) in the corresponding treatment duration.  
The total amount of study treatment planned is determined based on the duration of treatment 
and the planned dose per day. 
Percentage compliance for each subject will be derived from the total amount of study 
treatment intake divided by the planned study treatment intake, and multiplied by 100: 
Treatment Compliance (%) = 
𝑇𝑜𝑡𝑎𝑙 𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑆𝑡𝑢𝑑𝑦 𝐷𝑟𝑢𝑔 𝑇𝑎𝑘𝑒𝑛 (𝑢𝑛𝑖𝑡𝑠)
𝑇𝑜𝑡𝑎𝑙 𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑆𝑡𝑢𝑑𝑦 𝐷𝑟𝑢𝑔 𝑃𝑙𝑎𝑛𝑛𝑒𝑑 (𝑢𝑛𝑖𝑡𝑠) x 100 
Treatment compliance will be calculated and summarized separately by cohort and overall by 
treatment group using format as specified in Table 5.4. For each column, results will be 
separated for 15 µg/kg, 30 µg/kg, and overall.   
• Compliance with protocol-specified treatment regimen (%) 
• Compliance with protocol-specified treatment regimen (≥50%, ≥60%, ≥70%, ≥80%, 
≥90%, ≥100%, >=110%, >=120%) 
Listings will be provided for compliance.  


 
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13 
EXTENT OF EXPOSURE TO STUDY TREATMENT  
Dosing information is recorded by subjects in the paper diary and also by the site on visit 
days.  In the case of duplicate records with the same date, if the investigator confirms the 
date, then investigator reported dosing data will be used.  All summaries will be produced 
based on the safety population, and presented separately by cohort and overall by treatment 
group using format as specified in Table 5.4. For each column, results will be separated for 
15 µg/kg, 30 µg/kg, and overall.   
Descriptive statistics will be provided for the following variables:  
• Duration of treatment (days) 
= Date of last dose – Date of first dose + 1 
• Total number of doses administered 
= Number of doses administered between date of Day 1 and date of last dose 
• Total number of doses missed 
= Number of doses missed between date of Day 1 and date of last dose 
• Total amount of weight adjusted dose administered (µg/kg) by planned dose  
• Average weight-adjusted daily dose administered (µg/kg/day) by planned dose  
The frequency and percent of subjects will be provided for the following variables, where 
missed doses are counted between the date of first dose (Day 1) and date of last dose: 
• Number of subjects who missed at least one dose 
• Number of subjects who missed more than one dose 
• Number of subjects who missed more than 5 consecutive doses 
• Number of subjects who missed more than 10 consecutive doses 
The frequency and percent of events will be provided overall for the following variable: 
• The total number of missed doses and reason for each missed dose (Site Error, 
Parent/Caregiver Error, Home Health Error, Adverse Event, Other, Missing) will be 
provided.   
A listing of each subject’s extent of exposure by planned dose 15 µg/kg and 30 µg/kg will 
also be provided.  


 
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14 
EFFICACY EVALUATIONS  
14.1 
General Approaches for Analyzing Growth Parameters  
All growth parameters assessed by anthropometric measurements are measured at Baseline, 
Day 1, Week 6, Week 13, Week 26, Week 39, Week 52, and early termination visit.  
Growth parameters are measured 3 times for each assessment. It is the mean of these 3 
assessments that are considered for the summaries and analyses. In the event that all 3 are not 
available, the mean of the 2, or the individual assessment is taken. All measures and means 
of the measures will be included in the listings. 
The general rule when summarizing height (standing and sitting) is that standing 
height/sitting height will be used if subjects ≥ 24 months, body length/crown to rump will be 
used if subjects < 24 months. For subjects with both sets of measurements available, like to 
like will be used based on their measurements available for their age at baseline.  
Thus, in general, for subjects in Cohort 1 standing height and sitting height will be 
summarized. For subjects in Cohorts 2 and 3 body length and crown to rump will be 
summarized.  If body length is not measured and standing height is available, standing height 
will be used. If both sets of measures are available, like to like will be used based on their 
measurements available for their age at baseline.  
These rules will impact the following growth endpoints: standing height/body length 
Z-Score, standing height/body length, AGV, sitting height/crown to rump, lower body length, 
arm span to height ratio, upper to lower body segment ratio, BMI, and BMI Z-Score. 
BMI Z-Score will only be derived for subjects aged 24 months or older. 
Body length and crown to rump will not be summarized separately but integrated within the 
summaries for standing height and sitting height. Body length and crown to rump are 
however provided separately in a listing. 
Appendix 25.1 provides details of the derivations used for each endpoint. 
All efficacy endpoints will be assessed using the FAS.  
Visit windows are applied for all assessments (see Section 5.4) and are used to summarize 
the growth measures by visit. 
All parameter assessments are considered for inclusion in analyses.  


 
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With the exception of AGV (see Section 14.3.2), summary tables for all growth measures 
including standing height/body length Z-Score, standing height/body length, upper to lower 
body segment ratio, body proportion ratios, other growth measures (see Section 14.3.5), 
BMI, BMI Z-Scores, and weight Z-Scores will include assessments at baseline, Week 26 and 
Week 52 from Study 111-206, and 6 months prior in Study 111-901. For subjects in Cohort 3 
assessments at 3 months prior to baseline in Studies 111-206 or 111-901 will be included.  
Each table will include summaries of the absolute observed measures and its change from 
baseline at each of these time points. The tables will summarize data separately by cohort by 
treatment group using format as specified in Table 5.1, Table 5.2, and Table 5.3 for Cohorts 
1, 2, and 3, respectively. 
ANCOVA models will be conducted for change from baseline at Week 52 in standing 
height/body length Z-Score, standing height/body length, AGV, and upper to lower body 
ratio for all cohorts overall and/or by cohort, as appropriate. Unless otherwise specified, all 
models will include the following baseline covariates: randomization age stratum, age at 
baseline, baseline AGV, and sex. Analyses of standing height/body length Z-Score, standing 
height/body length, and upper to lower body ratio will include their baseline as additional 
covariate.  
For the model-based analyses, if the required assessment at Week 52 is missing but there are 
assessments before and after Week 52, a linear interpolation using the measurements closest 
to the before and after Week 52 will be used, otherwise those with no assessment after Week 
52, multiple imputation by using placebo data from subjects in the same cohort (PROC MI) 
will be used to impute the missing values for standing height/body length and upper to lower 
body segment ratio at Week 52.  
In addition to the primary analyses conducted on FAS, sensitivity analyses will also be 
conducted and are described in Section 14.2. 
Results of the statistical analyses will be provided in separate tables, including the least-
squares (LS) mean change from baseline at Week 52 for each treatment group, the treatment 
difference in LS means (calculated as vosoritide - Placebo), the 95% confidence interval (CI) 
for the treatment difference, and corresponding 2-sided p-value. 
Listings for standing height/body length and standing height/body length z-score will include 
all assessments (i.e., all measures and means of the measures) and spaghetti plots for height 
and height Z-Score will include assessments every 6 months and will be ordered by cohort, 


 
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sentinel/randomized subject, treatment, subject ID and visit date including 111-901 and 
111-206. 
14.2 
Primary Efficacy Endpoint  
The primary efficacy endpoint is change from baseline in standing height/body length Z-
Score at Week 52.  
Each measurement of derived standing height/body length will be converted to an age-and 
sex-appropriate standard deviation score (SDS), also referred to as a Z-Score, by comparison 
with reference data available for average stature children from the CDC. Note no data 
conversions are applied between body length and standing height as recommended for 
average stature.  
Standing height/body length Z-Scores will be derived using CDC references and macro 
(CDC, 2019). 
14.2.1 Primary Analyses  
The standing height/body length Z-Score at 6 Months Prior to baseline, 3 Months Prior to 
baseline for Cohort 3, baseline, Week 26 and Week 52, and it’s change from baseline at 
Week 26 and Week 52 will be summarized and presented separately by cohort by treatment 
group using format as specified in Table 5.1, Table 5.2, and Table 5.3 for Cohorts 1, 2, and 3, 
respectively.  
Height Z-Scores derived for all visits from 111-901 and 111-206 will be included in data 
listings. 
A line plot of individual standing height/body length Z-Score will be presented at baseline 
and Week 52 for each subject by cohort by stratified age stratum. A line plot of the mean (+/-
SD) standing height/body length Z-Score will be presented by cohort at 6 Months Prior (3-
month prior for Subjects in Cohort 3), Baseline, Week 26 and Week 52.  
For the model-based ANCOVA analyses, estimand formulation is as follows: 
• Population: All randomized subjects in FAS overall and/or by cohort as appropriate 
• Variable: Change from baseline in standing height/body length Z-Score at Week 52 
• Intercurrent event: Regardless of whether or not switching to rescue medication had 
occurred or subjects had discontinued from the treatment. See Section 14.1 for 
handling of missing data 
• Population-level summary: Lsmean difference and 95%CI between the treatment 
groups based on ANCOVA models defined in Section 14.1 


 
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ANCOVA model will include the fixed-effects of treatment (active arm vs. placebo arm) and 
baseline covariates, where baseline covariates include randomization age stratum, age at 
baseline, sex, baseline AGV, and baseline height Z-Score. The following SAS Proc Mixed 
with option OBSMARGINS for lsmeans will be used to perform the analysis on all 
randomized subjects in FAS overall and/or by cohort by each imputed dataset:  
PROC MIXED;  
CLASS Treatment Sex Age_stratum;  
MODEL Change from baseline in height Z-Score at Week 52 = Treatment 
Age_baseline Sex Age_stratum AGV_baseline Height Z-Score_baseline;  
LSMEANS Treatment / DIFF CL OM;  
ESTIMATE 'Active - Placebo' Treatment 1 -1/CL; 
RUN;  
For the models that will include the data from the multiple imputation a “by imputation 
statement will be included” and then  PROC MIANALYZE will be used to combine the 
estimates from each of the mixed models.  
These analyses will be repeated by also including sentinel subjects from the corresponding 
cohort. 
14.2.2 Sensitivity Analyses  
The following sensitivity analyses will be conducted on the primary efficacy endpoint: 
(1) Model-based analyses on the subjects in the PP population  
(2) Model-based analyses on the subjects with no missing data at Week 52  
14.3 
Secondary Efficacy Endpoint(s)  
14.3.1 Standing Height/Body Length  
Rules for standing height/body length is described in Section 14.1.  
The standing height/body length and its change from baseline will be summarized and 
presented separately by cohort by treatment group using the format as specified in Table 5.1, 
Table 5.2, and Table 5.3 for Cohorts 1, 2, and 3, respectively.   
Standing height/body length will be analyzed using the same methods and estimand 
formulation as the primary efficacy endpoint analysis and sensitivity analyses. An analysis of 
change from baseline in standing height/body length at Week 52 will be performed using an 


 
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ANCOVA model that includes the fixed-effects of treatment (active arm vs. placebo arm) 
and baseline covariates, where baseline covariates include randomization age stratum, age at 
baseline, sex, baseline AGV, and baseline standing height/body length.  
Standing height/body length for all visits will be included in data listings including data from 
111-901 and 111-206. 
Spaghetti plots of standing height/body length at every 6 months assessments including 
height assessments collected in the 111-901 study (3-month prior for Subjects in Cohort 3) 
will be provided for each subject separately by cohort. This plot will include age-sex specific 
reference ranges for average stature children (from CDC, 2019) and age-sex specific 
reference ranges for short stature children (Hoover-Fong, 2021). 
For these plots if body length is used for Cohort 1, it will be indicated in the plot. Likewise, if 
standing height is used for Cohort 2, it will be indicated in the plot.  
A line plot of the mean (+/-SD) standing height/body length will be presented by cohort at 6 
Months Prior (3-month prior for Subjects in Cohort 3), Baseline, Week 26 and Week 52.  
14.3.2 Annualized Growth Velocity  
For a given interval [Date1, Date2], the AGV is defined as follows: 
AGV (cm/yr) = (Derived Standing Height at Date 2-Derived Standing Height at Date 
1)/(Interval Length (Days)) x 365.25 
where the interval length in days is calculated as Date2 - Date1.  
AGV (cm/yr) will be calculated at baseline, Week 26, and Week 52. AGV at baseline will be 
calculated by using height measurements in Study 111-901 6 months prior to Day 1 of Study 
111-206 for subjects in Cohorts 1 and 2, and using height measures in Study 111-901 or 111-
206 3 months prior to Day 1 of Study 111-206 for subjects in Cohort 3. AGV at other time 
points will be calculated cumulatively from Day 1 of 111-206 and every 6 months interval.  
The absolute values for cumulative AGV and 6-month AGV and their change from baseline 
will be summarized and presented separately by cohort by treatment group using the format 
specified in Table 5.1, Table 5.2, and Table 5.3 for Cohorts 1, 2, and 3, respectively.  
Cumulative AGV will be analyzed using the same methods and estimand formulation as the 
primary efficacy endpoint analysis and sensitivity analyses. An analysis of change from 
baseline in cumulative AGV at Week 52 will be performed using an ANCOVA that includes 
the fixed-effects of treatment (active arm vs. placebo arm) and baseline covariates, where 


 
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baseline covariates include randomization age stratum, age at baseline, sex, and baseline 
AGV.  
A box and whisker plot will be provided for AGV (cm/yr) over time by cohort and treatment 
group. A line plot of individual cumulative AGV will be presented at baseline and Week 52 
for each subject by cohort by stratified age stratum.  
Listings for the cumulative AGV and 6 months AGV will include all calculated AGV. 
14.3.3 Upper to Lower Body Segment Ratio  
The upper to lower body segment ratio will be calculated at each visit as follows: 
Upper to Lower Body Segment Ratio = 
𝐷𝑒𝑟𝑖𝑣𝑒𝑑 𝑆𝑖𝑡𝑡𝑖𝑛𝑔 ℎ𝑒𝑖𝑔ℎ𝑡(𝑐𝑚)
𝐷𝑒𝑟𝑖𝑣𝑒𝑑 𝑆𝑡𝑎𝑛𝑑𝑖𝑛𝑔 ℎ𝑒𝑖𝑔ℎ𝑡(𝑐𝑚)−𝑑𝑒𝑟𝑖𝑣𝑒𝑑 𝑆𝑖𝑡𝑡𝑖𝑛𝑔 ℎ𝑒𝑖𝑔ℎ𝑡(𝑐𝑚). 
The ratio of derived sitting height and derived standing height will also be calculated.  
The upper to lower body segment ratio, the sitting to standing height ratio, and their change 
from baseline will be summarized and presented separately by cohort by treatment group 
using the format as specified in Table 5.1, Table 5.2, and Table 5.3 for Cohorts 1, 2, and 3, 
respectively.   
Upper to lower body segment ratio will be analyzed using the same methods and estimand 
formulation as the primary efficacy endpoint analysis and sensitivity analyses, an analysis of 
change from baseline in the upper to lower body segment ratio at Week 52 will be performed 
using an ANCOVA model that includes the fixed-effects of treatment (active arm vs. placebo 
arm) and baseline covariates, where baseline covariates include randomization age stratum, 
age at baseline, sex, baseline AGV, and baseline upper to lower body segment ratio.  
Upper to lower body segment ratio and sitting to standing height ratio derived for all visits 
will be included in data listings including data from 111-901 and 111-206. 
A line plot of individual upper to lower body segment ratio will be presented at baseline and 
Week 52 for each subject by cohort by stratified age stratum. A line plot of the mean (+/-SD) 
upper to lower body segment ratio will be presented by cohort at 6 Months Prior (3-month 
prior for Subjects in Cohort 3), Baseline, Week 26 and Week 52.  
14.3.4 Body Proportion Ratios  
Body proportion ratios include:  
• Upper Arm Length to Lower Arm (Forearm) Length Ratio 
• Upper Leg Length (Thigh) to Knee to Heel Length Ratio 


 
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• Upper Leg Length (Thigh) to Tibial Length Ratio 
• Arm Span to Standing Height Ratio 
The absolute values and its change from baseline will be summarized and presented 
separately by cohort by treatment group using the format as specified in Table 5.1, Table 5.2, 
and Table 5.3 for Cohorts 1, 2, and 3, respectively.   
All assessments will be listed. 
14.3.5 Other Growth Measures  
Other growth measures include:  
• Sitting Height (cm)/Crown to Rump (cm) 
• Upper Leg Length (Thigh) (cm) 
• Lower Leg Length: Knee to Foot (cm) 
• Lower Leg Length: Tibia Length (cm) 
• Head Circumference (cm) 
• Upper Arm Length (cm) 
• Lower Arm (Forearm) Length (cm) 
• Arm Span (cm) 
In addition, derived standing height and derived sitting height will be calculated as specified 
in Section 14.1, and a measure of lower body length will be calculated as follows: 
• Lower Body Length (cm) = Derived Standing height – Derived Sitting height 
Baseline growth measures are those assessed on Day 1, regardless of timing relative to 
dosing. All summaries and analyses will be based on the FAS. 
For each of the above growth measures (including lower body length), the absolute values 
and its change from baseline will be summarized and presented by cohort by treatment group 
using the format as specified in Table 5.1, Table 5.2, and Table 5.3 for Cohorts 1, 2, and 3, 
respectively.   
All assessments will be listed by subject and visit. 
14.4 
Health-Related Quality of Life  
The Health-Related Quality of Life (HRQoL) questionnaires and functional independence 
questionnaires are captured at Baseline, Week 26, Week 52.  All summaries will be 
generated on the FAS. 


 
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Each table will include summaries of the absolute measures at each of these time points and 
change from baseline at every 26 weeks. The tables will be summarized separately by cohort 
by treatment group using the format as specified in Table 5.1, Table 5.2, and Table 5.3 for 
Cohorts 1, 2, and 3, respectively.  
The statistical summaries will include the number of subjects with assessable data, mean, SD, 
median, 25th and 75th percentile, minimum and maximum. Subjects will not be included in a 
summary table if there is no baseline assessment available.  
Separate summary tables will be provided for the total summary scores and the individual 
domains (scales). Individual questions (items) are not included in the summary tables. 
Age-defined versions within the same questionnaire will be summarized together. If subjects 
progress during the course of the study from one age-defined questionnaire to the next age-
defined questionnaire the results will be summarized together and the baseline assessment 
from the child’s first questionnaire is referred to when summarizing change from baseline. 
If a questionnaire for the wrong age group was filled, outcomes will not be included in the 
summary table but will be included in the listings.  
Self-reports and parent-reports will be summarized separately but together in the bat charts. 
All subject data listings will include total scores, and domain (scale) scores. 
14.4.1 Bayley-III  
The Bayley-III is a performance-based outcome assessment for use in children from 1 to 
42 months.  
Scales include Cognitive scale, Language (Receptive Communication and Expressive 
Communication subscales) scale, and Motor (Gross and Fine Motor subscales) scales. 
In addition to its use for subjects ranging from 1 to 42 months old, the Bayley-III assessment 
will be administered to those entering the study between 42 and 60 months old and for the 
remainder of the duration of this study, as this assessment can capture ongoing 
developmental issues associated with ACH. Bayley-III is waived for subjects < 1 month old. 
Scales/Subscales: 
• Cognitive 
• Language 
o Receptive Communication  
o Expressive Communication  


 
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• Motor 
o Fine Motor  
o Gross Motor   
Each (sub)scale yields a total raw score which is then standardized according to the subject’s 
chronological age (scaled scores). 
Scoring 
Number of items depends on which set is given in each domain. The number of questions 
administered depends in part on the child’s age and on their developmental level. 
The total raw scores for the Cognitive Scale and the Receptive Communication, Expressive 
Communication, Fine Motor, and Gross Motor subscale are the sums of the number of points 
earned for a (sub)scale. 
The raw scores cannot be accurately compared to each other as each subscale has a different 
number of items resulting in a different range of possible scores. Therefore, the comparisons 
are best based on derived scores: age-based scaled scores or composite scores8. 
Scaled scores represent a child’s performance on a (sub)scale relative to the same age peers. 
They are derived from the total raw scores on each of the subscale and are scaled to a metric 
with a range of 1 to 19, a mean of 10 and a SD of 3. 
Composite scores are scaled to a metric with a mean of 100 and a SD of 15, and range from 
40–160. 
For the Language and Motor Scale, composite scores are derived from the sums of 
age-corrected scaled scores. For each composite, the distribution of the sum of scaled scores 
is used to derive corresponding percentiles which are converted to composite scores with a 
mean of 100 and a standard deviation of 15. 
For the Cognitive subdomain the scaled score to composite equivalent is a linear conversion 
from one scale (mean=10, SD=3) to another (mean=100, SD=15).  
For the scaled scores and composite scores, the absolute values will be summarized 
separately by cohort by treatment group using the format as specified in Table 5.1, Table 5.2, 
and Table 5.3 for Cohorts 1, 2, and 3, respectively. 
The 3 composite scores (Cognitive, Language and Motor) will be displayed by cohort and 
treatment group in a bar chart. 


 
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14.4.2 Infant and Toddler Quality of Life Questionnaire (itqol-97, 2013) (ITQOL)  
The Infant Toddler Quality of Life questionnaire (ITQOL) is an observer-reported outcome 
tool developed for use in children from 2 months to 5 years old that attempts to capture 
physical, mental and social well-being. The ITQOL adopts the World Health Organization’s 
definition of health as a state of complete physical, mental and social well-being, and not 
merely the absence of disease. The ITQOL also assesses the quality of the parents/guardians’ 
life. The 97-item full-length version (ITQOL) will be used for this study. ITQOL is waived 
for subjects < 2 months old. 
Domains 
The following domains are part of the ITQoL: 
• Overall Health (1item) 
• Physical abilities (10 items) 
• Growth and development (10 items) 
• Pain (3 items) 
• Temperament and mood (18 items) 
• Behavior (12 items) 
• Global behavior (1 items) 
• Getting on with others (15 items) 
• Global health perceptions (11 items) 
• Change in health (1 item) 
• Parental impact emotional (7 items) 
• Parental impact time (7 items) 
• Family cohesion (1 item) 
For the ITQOL, the exact number of items that can be missing differs depending on which 
section is being scored, though the general rule is that a section can be scored if at least half 
the responses in that section were completed. 
Summary scores for the 13 domains (overall score) will be summarized separately by cohort 
by treatment group using the format as specified in Table 5.1, Table 5.2, and Table 5.3 for 
Cohorts 1, 2, and 3, respectively. 


 
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The summary scores for Overall Health, Physical Abilities and Growth and Development 
will be displayed separately for the sentinel and randomized subjects by cohort and treatment 
group in a bar chart. 
14.4.3 Function Independence Measure (WeeFIM) (Wee-FIM II Version 6.4)  
The WeeFIM (Functional Independence Measure for children) instrument is a functional 
independence assessment tool that measures functional performance across three domains 
(self-care, mobility and cognition) from the caregiver’s perspective. 
Performance of a child on each of the individual items within the WeeFIM is assigned to one 
of seven levels on an ordinal scale that represent the function from complete and modified 
independence (levels 7 and 6) without a helping person to modified and complete 
dependence (levels 5 to 1) with a helping person. 
If individual items (questions) within a domain are missing, the item result is imputed to 1, 
per guidance in The WeeFIM Clinical Guide v 6.49. 
If all items for a domain score are missing the domain score is considered missing. 
If a domain score is missing, the Total score is missing. 
For each of the following domains and the total score, the absolute values at each scheduled 
visit, and change from baseline at each scheduled visit, will be summarized separately by 
cohort by treatment group using the format as specified in Table 5.1, Table 5.2, and Table 5.3 
for Cohorts 1, 2, and 3, respectively: 
• Self-care Score (min score=8, max score=56) 
• Mobility Score (min score=5, max score =35) 
• Cognition Score (min score=5, max score=35) 
• Total WeeFIM rating (min=18, max=126) 
Domain and total scores will be listed by cohort, sentinel/randomized subjects, treatment 
group, and subject number. 
Note: Although each domain will be summarized so that all aspects of this validated scale are 
reported, the cognition aspect of the WeeFIM (cognition subtotal score) is considered not to 
be of concern for subjects with achondroplasia. 
The three domains and Total WeeFIM score will also be displayed by visit in a bar chart and 
presented separately for the sentinel and randomized subjects by cohort and treatment group. 


 
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14.5 
Sleep Study Scores  
A sleep study will be performed in a limited number of qualified sleep centers. A 
sleep-testing device will be used to assess the presence and severity of sleep-disordered 
breathing by measurement of blood oxygen saturation, pulse rate, and airflow during 
overnight monitoring. Assessment of episodes of sleep apnea will include, but may not be 
limited to, the number of episodes of apnea and hypopnea per hour (Apnea/Hypopnea Index).  
Sleep study data is collected at Screening, Week 52, and early termination visit. 
Following episodes of sleep apnea variables will be summarized separately by cohort by 
treatment group using the format as specified in Table 5.1, Table 5.2, and Table 5.3 for 
Cohorts 1, 2, and 3, respectively. 
• Number of episodes of apnea per hour (Apnea Index).   
• Number of episodes of hypopnea per hour (Hypopnea Index).  
• Number of episodes of obstructive apnea hypopneas per hour (Apnea Hypopnea 
Index) 
• Number of episodes of obstructive apneas per hour (Obstructive Apnea Index) 
• Number of episodes of central apneas per hour (Central Apneas Index) 
• Number of desaturations per hour ≥ 3%  
Listing of the above episode of sleep apnea variables will be provided.  
 


 
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15 
SAFETY EVALUATIONS  
The safety population will be used for all safety summaries.  
Summary tables assessing safety parameters at planned visits over time will include all safety 
events up to 30 days following treatment discontinuation. These summary tables will be 
presented separately by cohort and overall by treatment group using format as specified in 
Table 5.4. Listings will include all reported data.  
Safety will be assessed by examining the incidence, frequency, severity (determined using 
the CTCAE version 4.03), and relationship to study treatment of all TEAEs reported during 
the study period. In addition, changes from baseline in clinical laboratory results and vital 
signs will be assessed. 
15.1 
Adverse Events  
Adverse events (AEs) will be coded in accordance with MedDRA Version 24.1 and 
performed prior to DBL. Coding of the severity of AEs is performed by the investigators 
using national cancer institute (NCI) CTCAE version 4.03, where events are coded from 
CTCAE Grade 1 to Grade 5.  
Only TEAEs defined as any adverse event that newly appeared, increased in frequency, or 
worsened in severity following initiation of study treatment administration are reported by 
the investigators and consequently are included in the summary tables. 
In the event that the start date of an AE is incomplete or missing, conservative imputation 
rules are applied so that where there is uncertainty, the event is considered treatment 
emergent. Similarly, the AE end dates are imputed in a conservative manner to a maximum 
length. 
15.1.1 Treatment-Emergent Adverse Events  
Treatment-emergent adverse events (TEAEs) will be summarized separately by cohort and 
overall by treatment group using format as specified in Table 5.4. In summaries by SOC 
and/or PT, subjects with more than one AE of the same SOC or PT will be counted once 
within that SOC/PT. For those AEs that occurred more than once during the study, AEs by 
severity will be summarized by the maximum CTCAE grade and by all CTCAE grades. The 
tables are ordered by the descending frequency of SOC or PT of overall in the table.   
The following summary tables will be provided: 


 
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• Overview of the incidence of TEAEs  
• Overview of exposure-adjusted event rates of TEAEs  
• Incidence and exposure-adjusted event rates of TEAEs by SOC, PT, and CTCAE 
grade  
• Incidence of TEAEs by SOC, PT and highest CTCAE grade 
• Incidence of and exposure-adjusted event rates TEAEs by PT  
• Incidence of TEAEs by SOC 
• Incidence of and exposure-adjusted event rates treatment related TEAEs by SOC, PT 
and CTCAE grade 
• Incidence of and exposure-adjusted event rates TEAEs with CTCAE Grade >= 3 by 
SOC, PT and CTCAE grade  
• Incidence of serious adverse events (SAEs) by SOC and PT 
• Incidence of non-serious adverse events by SOC and PT 
• Incidence of TEAEs leading to study or study treatment discontinuation by PT 
• Incidence of TEAEs leading to study treatment interruption by PT 
• Incidence of TEAEs leading to study treatment dose reduction by PT 
• Incidence of achondroplasia related TEAEs by SOC and PT* 
* Achondroplasia-related TEAEs will be identified using the PTs identified for 
achondroplasia-related medical history (see Section 10). In addition, all AEs will be reviewed 
prior to DBL and the list updated as required. 
For exposure-adjusted event rates of TEAEs, exposure will be derived to up to the last dose 
reported in the study database.  
Listings: 
In addition to the above tables, the following listings will be provided and ordered by subject 
and AE start date: 
• All TEAEs 
• TEAEs with CTCAE Grade ≥ 3 
• Achondroplasia-related TEAEs 
• SAEs 
• Deaths 


 
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• TEAEs leading to study or study treatment discontinuation 
• TEAEs leading to study treatment interruption or dose reduction 
• TEAEs of confirmed/suspected COVID-19 
• TEAEs occurring within 14 days following COVID-19 Vaccine 
15.1.2 Events of Interest  
Events of interest (EOI) will be summarized by PT separately by cohort and overall by 
treatment group using format as specified in Table 5.4. For those AEs that occurred more 
than once during the study, the maximum severity will be used to summarize the AEs by 
severity. 
The following are identified as events of interest: 
Injection site reactions (ISR) 
• TEAEs with a MedDRA High Level Term (HLT) of “Injection site reaction”. 
Hypotension 
• TEAEs with PT: Blood pressure ambulatory decreased, Blood pressure decreased, 
Blood pressure diastolic decreased, Blood pressure orthostatic decreased, Blood 
pressure systolic decreased, Blood pressure systolic inspiratory decreased, Diastolic 
hypotension, Hypotension, Orthostatic hypotension. 
Heart rate change 
• TEAEs with a PT: Atrial tachycardia, Postural orthostatic tachycardia syndrome, 
Rebound tachycardia, Sinus tachycardia, Supraventricular tachycardia, Tachycardia, 
Tachycardia paroxysmal, Ventricular tachycardia, Bradycardia. 
Hypersensitivity SMQ 
• TEAEs with a PT included in the MedDRA hypersensitivity SMQ 
Algorithmic Anaphylaxis SMQ (with sponsor-defined time restrictions) 
• TEAEs with a PT included in the MedDRA anaphylactic reaction SMQ, with an 
additional time restriction: a narrow scope PT within 48 hours of a dose, or two broad 
scope PTs from different classes where both PTs are within 48 hours of the same 
dose. 
Fractures 
• TEAEs with a PT containing the term “fracture” and also PTs of Bone fragmentation, 
Bone fissure, Scapulothoracic dissociation and Flail chest 


 
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Slipped Capital Femoral Epiphysis (SCFE) 
• TEAEs with a PT: Epiphyseal disorder, Epiphyseal injury 
Avascular necrosis and osteonecrosis 
• TEAEs with a PT: Osteonecrosis, Osteonecrosis of jaw, Osteonecrosis of external 
auditory canal, Necrosis ischaemic 
Events of interest will be summarized as follows: 
• Incidence and exposure-adjusted event rates of ISR events by PT 
• Incidence and exposure-adjusted event rates of hypotension by PT 
• Incidence and exposure-adjusted event rates of heart rate change events by PT 
• Incidence and exposure-adjusted event rates of hypersensitivity (SMQ) 
• Profile of ISRs 
• Profile of hypotension 
• Profile of heart rate change events 
Profile summaries include: highest CTCAE grade, number of events per subject, time from 
first dose to first event onset, duration of events (days), action taken with study treatment, 
outcome of events. 
Listings: 
In addition to the above tables the following EOI listings are also provided: 
• TEAEs of injection site reaction 
• TEAEs of hypotension 
• TEAEs of documented symptomatic hypotension 
• TEAEs of heart rate change events 
• TEAEs of hypersensitivity (SMQ) 
• TEAEs of algorithmic anaphylaxis (SMQ) with sponsor-defined time restrictions 
• TEAEs of fractures 
• TEAEs of SCFE 
• TEAEs of avascular necrosis and osteonecrosis 


 
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15.1.3 Injection Site Reaction Symptoms  
Injection site reactions (ISRs) associated with single symptoms are recorded on the AE page 
(as a single symptom). ISRs with multiple symptoms are recorded as an AE of “Injection Site 
Reaction” on the AE page and the associated individual symptoms are recorded on the ISR 
symptom page. 
In order to describe all ISR symptoms recorded, summaries will be based on the data 
collected on the ISR Symptoms page and also those single symptoms recorded as an adverse 
event. 
Incidence and exposure-adjusted event rates of ISR Symptoms will be summarized by PT 
and separately by cohort and overall by treatment group using format as specified in 
Table 5.4.   
ISR Symptoms will be listed. 
15.2 
Clinical Laboratory Tests  
Clinical laboratory tests (hematology, chemistry, and urinalysis) are performed at Screening, 
and pre-dose at Day 1, Day 8, Week 3, Week 6, Week 20, Week 39, Week 52 and early 
termination visit.  
All summary tables will include laboratory assessments from baseline up to 30 days post 
treatment discontinuation. Results will be reported separately as hematology, chemistry, 
urinalysis, and “other laboratory tests”.  
Laboratory tests will be graded as low/normal/high based on laboratory normal ranges.  In 
addition, for laboratory tests with CTC grading available, all non-missing numeric results 
will be used to determine CTC grade programmatically, based on CTCAE v4.03.  
 For the following parameters, the distinction is made between significantly low/high results: 
• Glucose (Hypoglycemia/Hyperglycemia) 
• Hemaglobin (Anemia/Hemaglobin increased) 
• Lymphocytes (Lymphocyte count decreased/Lymphocyte count increased) 
• Potassium (Hypokalemia/Hyperkalemia) 
• Sodium (Hyponatremia/Hypernatremia) 
• Calcium (Hypocalcemia/Hypercalcemia) 


 
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The absolute values for pre-dose laboratory results at each scheduled visit, change from 
baseline in pre-dose laboratory results, and percent change from baseline in pre-dose 
laboratory results at each scheduled visit will be summarized and presented separately by 
cohort and overall by treatment group using format as specified in Table 5.4.   
Shift tables from baseline to worst post-baseline value (including scheduled and unscheduled 
visits) based on the CTC grading (Normal – Grade 5) will be generated for each Lab 
parameter where CTCAE grading is available, excluding parameters where CTCAE Grade 
does not rely on quantitative results alone (e.g. potassium and uric acid).  Percentages are 
based on the number of subjects with each Baseline CTCAE grade (Normal, Grade 1, Grade 
2, Grade 3, Grade 4, Grade 5, Missing, Overall). Shift tables will be produced separately by 
cohort and overall by treatment group using format as specified in Table 5.4. 
For laboratory tests where grades are not defined by CTCAE, or where CTCAE grading does 
not rely on quantitative results alone (e.g. potassium and uric acid), shift tables will be 
generated using the low/normal/high classification to compare to baseline to the worst post-
baseline value.   
Line plots of the mean results (+/- SD) for the pre-dose windowed absolute values including 
all scheduled visits will be provided for the following parameters by treatment group by 
cohort. Data from the sentinel subjects and randomized subjects received active treatment 
within each cohort will be pooled: 
• Hematology: erythrocytes, hematocrit, hemoglobin, leukocytes, neutrophils, platelets, 
WBC and RBC count. 
• Chemistry: alanine aminotransferase, albumin, alkaline phosphatase, aspartate 
aminotransferase, bicarbonate, bilirubin, blood urea nitrogen, calcium chloride, 
creatinine, direct bilirubin, glucose, lactate dehydrogenase, phosphate, potassium, 
protein, sodium, thyrotropin, vitamin D. 
Listings: 
In addition to the above tables, the following listings will be provided and will contain CTC 
grade and laboratory reference ranges: 
• Hematology results 
• Chemistry results 
• Urinalysis results 
• Urine chemistry results 
• Other laboratory test results 


 
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• Laboratory results with CTCAE Grade ≥ 3 
Listings will include all reported data and will be ordered by cohort, sentinel/randomized 
subject, subject ID, and assessment date. 
15.3 
Vital Signs  
Vital Signs (heart rate, systolic/diastolic blood pressure, respiratory rate, and body 
temperature) are assessed at Screening, Day 1, Day 2, Day 3, Day 8, Week 3, Week 6, 
Week 13, Week 20, Week 26, Week 39, Week 52, safety follow-up visit, and early 
termination visit. 
All summary tables will include vital signs recorded from baseline up to 30 days post 
treatment discontinuation.  
The vital signs that are collected pre-dose and post-dose. Vital sign assessment frequency is 
shown below.  
Table 15.3.1:  Vital Sign Post-dose Assessment Frequency  
 
 
The absolute values for pre-dose vital signs at each scheduled visit, and change from baseline 
in pre-dose vital signs at each scheduled visit will be summarized and presented separately 
by cohort and overall by treatment group using format as specified in Table 5.4.    
Line plots will be generated, which present the mean pre-dose and post-dose absolute values 
(+/-SD) for each visit by treatment group by cohort. Data from the sentinel subjects and 
randomized subjects received active treatment within each cohort will be pooled. 
The percentage of subjects experiencing at least one instance of a decrease of 20% in 
diastolic blood pressure from pre-dose to same-day post dose will be summarized by visit 
and for overall (each subject meeting criteria at any time in the study will be counted only 
once) for both sentinel subjects and randomized subjects. 
Shift tables (Diastolic BP <40mmHg, Diastolic BP ≥40mmHg) from pre-dose to lowest 
same-day post-dose value category (Diastolic BP <40mmHg, Diastolic BP ≥40mmHg) will 


 
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be generated by visit and for overall (each subject meeting criteria at any time in the study 
will be counted only once) for both sentinel subjects and randomized subjects. 
Shift tables (Diastolic BP <30mmHg, Diastolic BP ≥30mmHg) from pre-dose to same-day 
lowest post-dose value category (Diastolic BP <30mmHg, Diastolic BP ≥30mmHg) will be 
generated by visit and for overall (each subject meeting criteria at any time in the study will 
be counted only once) for both sentinel subjects and randomized subjects. 
Shift tables (Systolic BP < (70mmHg plus 2 x Age), Systolic BP ≥ (70mmHg plus 2 x Age)) 
from pre-dose to lowest same-day post-dose value category ((Systolic BP < (70mmHg plus 
2 x Age), Systolic BP ≥ (70mmHg plus 2 x Age)) will be generated by visit and for overall 
(each subject meeting criteria at any time in the study will be counted only once).  Subject’s 
age used in this calculation is the integer value. 
A listing of vital sign data will also be provided. 
15.4 
Biological Parental Standing Height  
If available standing height of the subject’s biological parents will be listed.  
15.5 
Electrocardiogram  
Electrocardiogram (ECG) data are recorded at Screening, Day 1, Day 8, Week 6, Week 13, 
Week 20, Week 26, Week 39, Week 52, safety follow-up visit, and early termination visit. 
ECG assessments are performed in triplicate on Day 1 (pre-dose and post-dose) and on study 
day visits (post-dose only).   
Summaries will be provided over all planned assessments, and repeated with the requirement 
that all post-dose ECG assessments should occur around the expected time of CMax, i.e., 
20-40 minutes post-dose. The mean results of the ECG assessments meeting these criteria 
will be used for summaries and analyses.   
All measures and means of the measures will be included in the listings. 
The following ECG results will be summarized and presented separately by cohort and 
overall by treatment group using format as specified in Table 5.4 at scheduled visits: 
• ECG Mean Heart Rate (beats/min) 
• QT interval (msec) 
• QTcF interval (msec) 
• PR interval (msec) 


 
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• RR interval (msec) 
• QRS Duration (msec) 
The following endpoints will be summarized at scheduled visits, and across all time points 
(using the highest mean QTc value), and presented by cohort and overall by treatment group 
using format as specified in Table 5.4. 
• Percentage of subjects with QTcF >450 to ≤480ms, >480 to ≤500ms, >500 msec 
The following endpoints will be summarized at scheduled visits, and across all time points, 
and presented by cohort and overall by treatment group using format as specified in Table 5.4 
• Percentage of subjects experiencing at least one instance of a (decrease in mean heart 
rate from pre-dose baseline >25% and a mean heart rate <50 beats/min) post-dose. 
• Percentage of subjects experiencing at least one instance of an (increase in mean heart 
rate from pre-dose baseline >25% and a mean heart rate >100 beats/min) post-dose. 
The following endpoints will be summarized across all time points and presented by cohort 
and overall by treatment group using format as specified in Table 5.4. 
• Percentage of subjects with a QTcF increase of 60ms from pre-dose baseline at any 
time 
• Percentage of subjects with QTcF changes from pre-dose baseline of >30 and 
≤ 60 msec, or >60 msec at any time 
Listings will be provided and ordered by cohort, sentinel/randomized subject, treatment 
group, and visit:  
• All ECG results. 
• All ECG results for subjects with a QTc increase of 60msec from pre-dose baseline. 
15.6 
HPA Axis Assessments  
To address potential effects of vosoritide on activation of the hypothalamic pituitary (HP) 
axis, assessment of salivary cortisol and serum prolactin levels will be analyzed at baseline, 
Week 26, Week 52 and early termination visit.   
This data will be listed.  
15.7 
Child Behavior Checklist (Achenbach, 2000)  
The Child Behavior Checklist (CBCL) 1.5- 5 years questionnaire is captured at Screening, 
Week 26, Week 52, and early termination visit.  


 
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All summaries will be generated on the Safety Population and include all assessments 
recorded up to 30 days following treatment discontinuation.  Listings will include all reported 
data. 
The CBCL 1.5-5 years old comprise questions addressing symptoms related to mood, 
behavior issues, and sleep disturbance.  It is completed by the parent or primary caregiver.  
The CBCL 1.5-5 years old consists of 100 questions, scored on a three-point Likert scale 
(0=Not True (as far as you know), 1= Somewhat or Sometimes True, 2=Very True or Often 
True). The time frame for item responses is the past 2 months. 
Note: No data is collected from the language scale, as it is supplemental and not required to 
calculate any of the behavior measures. 
The checklist yields scores in the following areas: emotionally reactive, anxious/depressed, 
withdrawn, somatic complaints, sleep problem, attention problems, and aggressive behavior.  
The table in Appendix 25.2 shows how the domains are constructed with regards to the 
individual questions.  The scores for each individual question within a domain are summed to 
give a domain score. 
Each domain score above and total score will be summarized separately by cohort and 
overall by treatment group using format as specified in Table 5.4 at Baseline, Week 26 and 
Week 52 as well as change from baseline at Week 26 and Week 52 (where baseline measures 
exist). 
Domain scores and total score will be listed by cohort, sentinel/randomized subjects, 
treatment group, and subject ID. 
15.8 
Echocardiogram  
Echocardiogram results are only collected at the Screening visit, at safety follow up, and 
early termination visit if the previous assessment was done more than 3 months prior to early 
termination and will be listed by cohort, sentinel/randomized subjects, treatment group, and 
subject ID. 
15.9 
On-Study Procedures, Interventions and Surgeries  
Any procedures, interventions of surgeries that occur on study (post first dose of study 
treatment) will be captured, along with start and stop date. These will be coded using 
MedDRA version 24.1 and will be summarized separately by cohort and overall by treatment 
group using format as specified in Table 5.4, and details provided in a listing. 


 
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15.10 Hip Monitoring and Rotation  
All hip monitoring clinical assessments, including hip rotation, will be listed by cohort, 
sentinel/randomized subjects, treatment group, subject ID, and assessment date. 
15.11 Body Mass Index and BMI Z-scores  
Weight (kg) and standing height are collected at Screening, Day 1, Day 2, Day 3, Day 8, 
Week 3, Week 6, Week 13, Week 20, Week 26, Week 39, Week 52, and early termination 
visit. 
Standing height are recorded at Screening, Day 1, Week 6, Week 13, Week 26, Week 39, and 
Week 52.  
Body Mass Index (BMI) will be calculated at each visit as: 
Body Mass Index (kg/m2) = 
𝑊𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)
𝐻𝑒𝑖𝑔ℎ𝑡 (𝑚)2 
In calculation of BMI, in case standing height is not measured and body length is available, a 
derived standing height will be calculated; refer to Section Error! Reference source not 
found..   
Only for subjects aged 24 months or older, each measurement of BMI will be converted to an 
age-and sex-appropriate standard deviation score (SDS), also referred to as a Z-score, by 
comparison with reference data available for average stature children from the Centers for 
Disease Control and Prevention (CDC). The derived height mentioned above for BMI is also 
used for BMI in the calculation of BMI Z-score. 
The absolute values at baseline, each 6-month visit, and change from baseline at each 
6-month visits will be summarized and presented separately by cohort and overall by 
treatment group using format as specified in Table 5.4 for both BMI and BMI Z-Score (again 
though, BMI Z-score will only be calculated for subjects aged 24 months or older). 
All assessments will be listed by cohort, sentinel/randomized subjects, treatment group, 
subject ID and visit. 
15.12 Weight Z-Scores  
Weight (kg) is measured at Screening, Day 1, Day 2, Day 3, Day 8, Week 3, Week 6, 
Week 13, Week 20, Week 26, Week 39, Week 52, and early termination visit. 


 
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Each measurement of weight will be converted to an age-and sex-appropriate SDS, also 
referred to as Z-score, by comparison with reference data available for average stature 
children from the CDC. 
The weight of the subject on Day 1 will be used as the baseline measure, regardless of 
whether this is recorded pre or post-dose. 
The absolute values and change from baseline at scheduled visits will be summarized and 
presented separately by cohort and overall by treatment group using format as specified in 
Table 5.4.  
All assessments will be listed for by cohort, sentinel/randomized subjects, treatment group, 
subject ID, and visit. 
 


 
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16 
IMAGING SECONDARY ENDPOINT(S)  
Imaging will be performed at screening, Week 52, and early termination visit:   
Dual energy X-ray absorptiometry of whole body and spine 
Anterior-posterior and lateral lumbar spine X-rays 
Anterior-posterior X-rays of lower extremities  
MRI data will be performed at screening, Week 52, and early termination visit to evaluate the 
effect of vosoritide on skull and brain morphology, including face, foramen magnum, 
ventricular, and brain parenchymal dimensions.  
All summaries of imaging data and MRI data will be generated on the FAS and presented by 
cohort and overall by treatment group using the format as specified in Table 5.4. 
16.1 
Lower Limb X-Rays  
For each of the following parameters, the absolute values for both the left and right leg at 
Baseline and Week 52, and change from baseline at Week 52 will be summarized by cohort 
and overall by treatment group using the format as specified in Table 5.4: 
• Left/Right Femur length (cm) 
• Left/Right Fibula length (cm) 
• Left/Right Tibia length (cm)  
• Left/Right Tibia bowing angle (degrees) 
• Left/Right Distance between ankle joint and distal growth plate of fibula (cm) 
• Left/Right Lower Extremity (cm) 
• Ratio of Left/Right Femur length (cm) to Tibia length (cm) 
• Ratio of Left/Right Tibial length (cm) to Fibula length (cm) 
In addition, change from baseline in tibial length (y-axis) at Week 52 will be presented on 
boxplots with a separate box for each leg and treatment group on the x-axis by cohort. 
Similar plots will also be generated for change from baseline in fibula length. 
All assessments will be listed by cohort, treatment group, subject and visit. 
16.2 
Lumbar Spine X-Rays  
Lumbar spine x-rays (AP and lateral views) assessments will be listed by cohort, treatment 
group, subject and visit. 


 
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16.2.1 Vertebral Height  
Vertebral heights (anterior, medial, and posterior) will be measured for each individual 
vertebra (L1, L2, L3, L4, and L5). 
The following ratios will be calculated for each individual vertebra (L1, L2, L3, L4, and L5) 
and reported to 1 decimal place: 
• Anterior height (cm) to medial height (cm) 
• Anterior height (cm) to posterior height (cm) 
• Medial height (cm) to posterior height (cm) 
For each of the vertebral height and the above ratios, the absolute values at Baseline and 
Week 52, and change from baseline at Week 52 will be summarized and presented by cohort 
and overall by treatment group using the format as specified in Table 5.4. 
16.2.2 Transverse Diameter (Interpedicle Distance)  
The transverse diameter (interpedicle distance) will be measured for each individual vertebra 
(L1, L2, L3, L4, and L5). 
For each transverse diameter vertebra, the absolute values at Baseline, Week 52, and the 
change from baseline at Week 52 will be summarized and presented by cohort and overall by 
treatment group using the format as specified in Table 5.4. 
In addition, change from baseline in transverse diameter (y-axis) for each individual vertebra 
(x-axis) will be presented on a boxplot at Week 52 for each cohort and treatment group. 
16.2.3 Sagittal Width  
The spinal canal width (sagittal width) will be measured for each individual vertebra (L1, L2, 
L3, L4, and L5). 
For each individual vertebra, the absolute values at Baseline, Week 52, and the change from 
baseline Week 52 will be summarized and presented by cohort and overall by treatment 
group using the format as specified in Table 5.4. 
In addition, change from baseline in sagittal width (y-axis) for each individual vertebra 
(x-axis) will be presented on a boxplot at Week 52 for each cohort and treatment group. 
16.2.4 Lumbar Spine Angles  
The following angles will be measures on the lumbar spine x-rays: 
• Sacral tilt (degrees) 


 
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• Lordosis (inward curve of the spine) (degrees) 
• Kyphosis (convex curvature of the spine) (degrees) 
Each angle will be measured on the spine x-rays and compared to Baseline at Week 52 to 
determine any worsening of sacral tilt, lordosis (inward curve of the spine) or kyphosis 
(convex curvature of the spine). 
The absolute values of the sacral tilt, lordosis and kyphosis angles at Baseline, Week 52, and 
change from baseline at Week 52 will be summarized and presented by cohort and overall by 
treatment group using the format as specified in Table 5.4. 
A worsening in sacral tilt angle compared to baseline will be summarized [n(%)] by cohort 
by treatment group and overall at Week 52 as follows: 
• Percentage of subjects with an increase in sacral tilt angle of ≥5 to < 10 degrees 
• Percentage of subjects with an increase in sacral tilt angle of ≥ 10 degrees 
A worsening in lumbar lordosis compared to baseline will be summarized [n(%)] by cohort 
by treatment group and overall at Week 52 as follows: 
• Percentage of subjects with an increase in lordosis angle of ≥5 to < 10 degrees  
• Percentage of subjects with an increase in lordosis angle of ≥ 10 degrees 
A worsening in kyphosis angle compared to baseline will be summarized [n(%)] by cohort by 
treatment group and overall at Week 52 as follows: 
• Percentage of subjects with an increase in kyphosis angle of ≥5 to < 10 degrees 
• Percentage of subjects with an increase in kyphosis angle of ≥ 10 degrees 
A listing of subjects experiencing a worsening in sacral tilt, kyphosis or lordosis will be 
provided. 
16.3 
Dual Energy X-ray Absorptiometry  
A dual energy x-ray absorptiometry (DXA) scan is performed at Baseline and Week 52, in 
order to collect relevant BMC/BMD data (including Z-scores) for whole body less head, and 
the lumbar spine.   
All DXA data will be summarized separately by cohort and overall by treatment group using 
the format as specified Table 5.4 for each scanner manufacturer (GE - Lunar Prodigy or 
Hologic – Discovery Horizon). Changes over time can only be interpreted if subjects use the 
same scanner consistently throughout the study. Subjects will be summarized according to 
the scanner used for their Baseline assessment. Subjects who have results from more than 


 
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one scanner type will be excluded from summaries, and their data will be listed only. All data 
will be listed. 
16.3.1 Whole Body Less Head and Lumbar Spine  
The absolute values at Baseline and Week 52, and change from baseline at Week 52 will be 
summarized and presented by cohort and overall by treatment group using the format as 
specified in Table 5.4 for the following measures of bone mineral content (BMC) and bone 
mineral density (BMD): 
• Whole Body Less Head BMC (g) 
• Whole Body Less Head BMD (g/cm2) 
• Whole Body BMC (g) 
• Whole Body BMD (g/cm2) 
• Lumbar Spine BMC (g) 
• Lumbar Spine BMD (g/cm2) 
BMD Z-scores will be provided in the DXA reports, and the absolute values at Baseline and 
Week 52, and change from baseline at Week 52 will be summarized and presented by cohort 
and overall by treatment group using the format as specified in Table 5.4 by scanner for each 
of the following: 
• Whole Body Less Head BMD Z-Score 
• Whole Body BMD Z-Score 
• Lumbar Spine BMD Z-Score 
The absolute values of total body percent fat, android percent fat, and gyenoid percent fat 
will be listed. 
Box plots of whole body less head BMD Z-Scores will be provided by cohort by treatment 
group and scanner. 
16.4 
MRI  
For each of the following parameters and ratios, the absolute values, change from baseline 
and percent change from baseline at Week 52 will be summarized by cohort and overall by 
treatment group using the format as specified in Table 5.4: 
Volume of Face 
Volume of Sinus 


 
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Volume of Calvarium 
Area of Foramen Magnum 
Area of Spinal Cord at the FM Level  
 
Whole Brain Total Volume   
Ventricles Total Volume  
Ratio of Face volume to Calvarium   
Ratio of Area of Spinal Cord to Foramen Magnum  
Ratio of Face volume to Sinus  
MRI assessments for above variables, evidence of cervicomedullary, and spinal cord 
compression will be listed by cohort, sentinel/randomized subjects, treatment group, subject 
ID and visit. 
 
 
 


 
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17 
BONE METABOLISM BIOMARKERS  
Bone metabolism biomarkers (both blood and urine) will be collected to assess changes in 
bone metabolism. The safety population will be used for all summaries. 
Serum samples for bone metabolism blood biomarkers (collagen X and bone-specific 
alkaline phosphatase [BSAP]) are collected pre-dose at baseline, Day 8, Week 6, Week 20, 
Week 39, early termination visit. Urine samples for bone metabolism urine biomarkers 
(Cross-linked C-Telopeptide of Collagen Type II [CTX-II]) are collected pre-dose on Day 1, 
Day 2, Day 3, Week 3, Week 13, Week 26, Week 39, Week 52, and early termination visit.  
For BSAP and Collagen X, the absolute values, and change from baseline at scheduled visits 
will be summarized separately by cohort and overall by treatment group using format as 
specified in Table 5.4. 
For CTX-II, the absolute values normalized by creatinine, and change from baseline at 
scheduled visits will be summarized separately by cohort and overall by treatment group 
using format as specified in Table 5.4. 
A box plot of change from baseline in BSAP, Collagen X, CTX-II normalized by urine 
creatinine over time will be provided for pooled sentinel subjects and randomized subjects 
received active treatment.  
Bone metabolism biomarkers will be listed by cohort, sentinel/randomized subjects,  
treatment group, subject ID, and visit. 
 
 


 
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18 
VOSORITIDE PD ACTIVITY BIOMARKERS  
Samples for vosoritide activity urine biomarkers (cyclic guanosine monophosphate [cGMP] 
and urine chemistry (urine creatinine test) are collected pre-dose and post-dose 
(approximately 2-4 hours after study treatment administration) when possible, on Day 1, 
Day 2, Day 3, Week 3, Week 26, Week 39, Week 52, and early termination visit. Each urine 
collection will be tested for biomarker concentration and urine creatinine concentration for 
normalization.  
The absolute values for pre-dose and post-dose urine cGMP normalized by creatinine at each 
scheduled visit and change from pre-dose to post-dose time points at each scheduled visit 
will be summarized and presented by cohort and overall by treatment group using format as 
specified in Table 5.4.  
When possible, plasma PK samples with sufficient residual volume after completion of PK 
analysis will be used to measure changes in plasma cGMP after dose administration. Plasma 
samples will be collected for PK analysis on Day 1, Week 13, Week 26, Week 39, and 
Week 52. Plasma samples will be collected pre-dose and at 5 (± 2 min), 15 (± 2 min), 
30 (± 5 min), 45 (± 5 min), 60 (± 5 min), 90 (± 5 min), and 120 (± 5 min) minutes post-dose 
on scheduled visits. On Day 1, additional PK samples will be collected at 180 (± 5 min) and 
240 (± 5 min) minutes. 
The absolute values for pre-dose and post-dose plasma cGMP at each scheduled visit and 
change from pre-dose to post-dose time points at each scheduled visit will be summarized 
and presented separately by cohort and overall by treatment group using format as specified 
in Table 5.4.  
A box plot for the maximum change from pre-dose of plasma cGMP and change from pre-
dose of urine cGMP normalized by creatinine by cohort by treatment group by visit will be 
provided. 
Vosoritide activity urine biomarkers will be listed by cohort, sentinel/randomized subjects,  
treatment group and subject ID. 
 


 
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19 
IMMUNOGENICITY ASSESSMENT  
Serum samples for anti-drug antibody (ADA) testing will be drawn pre-dose on Day 1, 
Week 3, Week 13, Week 26, Week 52, and early termination visit.  Blood (serum) samples 
for testing drug-specific IgE will be drawn on Day 1 and in the event of a Grade 3 or 
significant hypersensitivity adverse event, or at the investigator’s discretion.   
ADA testing will include anti-vosoritide total antibody (TAb); TAb cross-reactive with 
endogenous C-type natriuretic peptide (CNP), brain natriuretic peptide (BNP) or atrial 
natriuretic peptide (ANP); and anti-vosoritide neutralizing antibody (NAb). 
NAb testing and TAb testing for cross-reactivity with endogenous CNP, ANP or BNP will be 
performed only on baseline and TAb positive samples. NAb testing will not be performed if 
the corresponding TAb is negative. A listing for each ADA assay will be provided. 
Summary tables will include all safety events up to 30 days following treatment 
discontinuation. Listings will include all reported data. 
The immunogenicity population will be used for all summaries. The data conversion rules for 
immunogenicity analysis are listed below: 
 
 
 
 


 
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The incidence [n(%)] of TAb titer positive results will be summarized for each scheduled 
visit, and overall (described as ‘Ever Positive’) as follows: 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠 𝑤𝑖𝑡ℎ 𝑎 𝑝𝑜𝑠𝑖𝑡𝑖𝑣𝑒 𝑡𝑒𝑠𝑡 𝑟𝑒𝑠𝑢𝑙𝑡
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠 𝑤𝑖𝑡ℎ 𝑛𝑜𝑛−𝑚𝑖𝑠𝑠𝑖𝑛𝑔 𝑇𝐴𝑏 𝑟𝑒𝑠𝑢𝑙𝑡∗100 
The incidence [n(%)] of NAb positive test results, and positive cross-reactivity results for 
ANP, BNP and CNP, will also be calculated based on the number of subjects with a 
non-missing TAb result, and summarized at each scheduled visit and overall. 
The absolute values (numerical values) of TAb titers and NAb titers will be summarized at 
Day 1, Week 3, Week 13, Week 26, and Week 52, and presented separately by cohort and 
overall by treatment group using format as specified in Table 5.4. 
The mean (SD) TAb titer, number of hypersensitivity adverse events (HAEs) excluding 
injection site reactions, and number of subjects experiencing HAE’s will be summarized by 
the highest HAE CTCAE Grade, and presented by TAb status (negative or positive) and 
separately by cohort and overall by treatment group using format as specified in Table 5.4. 
A line graph of the mean TAb titer (+/- SE) will be presented over time for each visit by 
pooled placebo, active for each cohort (pooled for sentinel and randomized subjects), and 
overall. A similar figure will be generated for NAb titers. 
The relationship between immunogenicity (ADA status: negative or positive) and measures 
of safety and efficacy will further be presented graphically by treatment group: 
• Box plot of change from baseline at week 52 in standing height/body length Z-Score 
by TAb status 
• Box plot of change from baseline at week 52 in standing height/body length Z-Score 
by NAb status 
• Box plot of change from baseline at week 52 in standing height/body length by by 
TAb status 
• Box plot of change from baseline at week 52 in standing height/body length by NAb 
status 
• Box plot of number of hypersensitivity adverse events by TAb status 
• Box plot of number of hypersensitivity adverse events (excluding ISRs) by TAb 
status 
• Box plot of number of injection site reaction adverse events by TAb status 


 
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• Box plot of maximum duration of injection site reaction adverse event by TAb status, 
where injection site hemorrhage, injection site hematoma, injection site bruising, and 
injection site induration will be excluded. 
Should there be a significant relationship between TAb positivity and change from baseline 
at Week 52 in standing height/body length, a scatter plot of change from baseline in standing 
height/body length at Week 52 versus mean TAb titer in TAb positive subjects will be 
presented as a second tier analysis. The Pearson correlation coefficient will be included in the 
figure to describe the association. 
 
In addition, the following listings will be provided:  
• Total antibody titers and neutralizing antibody titers 
• Hypersensitivity adverse events with antibody results 
• Drug-specific IgE, total IgE, C4 and serum tryptase for hypersensitivity reaction 
visits 
• Mean Tab and NAb titers, standing height/body length, standing height/body length 
Z-Scores, and AGV  
• TAb cross reactivity to endogenous natriuretic peptides 
• TAb cross reactivity by subject and cardiac disorder or HLGT ‘fluid and electrolyte 
imbalance’ related adverse event. 
All immunogenicity listings will be ordered by cohort, sentinel/randomized subjects, 
treatment group, 4-digit subject ID (i.e., the subject ID excluding the site number), and visit. 
 
 
 


 
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20 
PHARMACOKINETICS AND PHARMCODYNAMICS  
Vosoritide concentrations and PK parameters will be summarized descriptively by visit for 
all subjects in the PK population. If supported by the data, impact of demographics and 
immunogenicity on PK parameters and the exposure-response relationship between 
vosoritide exposure and efficacy, biomarker, and safety pharmacodynamic (PD) endpoints of 
interest will be explored. Details on the PK and PK/PD analyses are separately documented 
in the Clinical Pharmacology Analysis Plan. 


 
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21 
OTHER ANALYSES  
To evaluate the impact of COVID-19 pandemic on the study conduct and results (assumed 
started from 1st January 2020 up until the date of data finalization), the following new outputs 
will be presented separately by cohort and overall by treatment group using format as 
specified in Table 5.4: 
1. For all protocol scheduled visits, number of missed visits, late visits, and clinical site 
visits changed to virtual or home visits due to COVID-19 will be summarized.   
2. COVID-19 has been added to the new MedDRA version 24.1. One AE listing will be 
produced that will include all AEs coded to Preferred Terms containing “COVID-19”. 
Another AE listing will be produced that will be included all AEs occurring within 
14 days following COVID vaccine. 
3. A listing of concomitant medication of COVID vaccine will be provided.  
4. COVID-19 specific protocol deviations will be listed and summarized.  
 


 
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22 
ANALYSES DIFFERENT FROM PROTOCOL-DEFINED ANALYSES  
Standing height/body length was one of the growth measurements included in the secondary 
efficacy endpoints in the protocol. It is the first key secondary efficacy endpoint in this SAP.   
 


 
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23 
REFERENCES  
Achenbach, T. M., & Rescorla, L. A. (2000). Manual for the ASEBA Preschool Forms & 
Profiles. Burlington, VT: University of Vermont, Research Center for Children, Youth, & 
Families. 
Bayley Scales of Infant and Toddler Development, Third Edition (Bayley–III) Technical 
Manual 
Health Act CHQ: Infant and Toddler Quality of Life Questionnaire – 97 (itqol-97) © 2013 
Hoover-Fong, JE, Schulze, KJ, Alade, AY, J, Bober, MB et. al. Growth in achondroplasia 
including stature, weight, weight-for-height and head circumference from CLARITY: 
achondroplasia natural history study – a multi-center retrospective cohort study of 
achondroplasia in the US. Orphanet Journal of Rare Diseases 16:522, 1-19. 2021. 
https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm 
Uniform Data System for Medical Rehabilitation. 2016. The WeeFIM II® Clinical Guide, 
Version 6.4. Buffalo: UDSMR. 
 
 
 


 
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24 
SUMMARY OF KEY CHANGES TO STUDY SAP  
Version 
Affected Section  
Summary of Revisions 
Number 
Date 
1.1 
 
17Nov2021 
 
Section 14.1 
Option OBSMARGINS was added in the 
PROC MIXED procedure. 
Section 15.1.2 
Definition for Algorithmic Anaphylaxis 
SMQ has been updated. 
Section 19 
“by cohort” was removed for box plots.  
Box plot for maximum severity of 
hypersensitivity adverse events by TAb status 
was removed. 
Injection site hemorrhage, injection site 
hematoma, injection site bruising, and 
injection site induration will be excluded for 
the box plot of maximum duration of 
injection site reaction adverse event by TAb 
status. 
2.0 
02Feb2022 
Section 14.1 
Per feedback from FDA, multiple imputation 
was added as imputation method if 
assessment at Week 52 is missing and there 
is no assessment after Week 52. 
Section 14.2.1 
Per feedback from FDA, it was made clear 
that the primary analysis will be performed 
on randomized subjects only. “by 
_imputation_” was added in the PROC 
MIXED procedure to analyze the multiple 
imputed data, “PROC MIANALYZE” was 
added to summarize results from multiple 
imputation.  
Section 14.2.1 & Section 14.3 
Age stratum was added as a covariate in the 
ANCOVA model since subjects were 
randomized by age stratum 
Section 14.2.1 
Spaghetti plots for standing height/body 
length Z-Score were replaced by individual 
line plots and line plots of mean +/- SD. 
Section 14.3.1 
Line plots of mean +/- SD for standing 
height/body length were added. 
Section 14.3.2 
Individual line plots of cumulative AGV 
were added. 
Section 14.3.3 
Individual line plots and line plots of mean 
+/- SD for upper to lower body segment ratio 
were added. 


 
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Version 
Affected Section  
Summary of Revisions 
Number 
Date 
Section 14.4.6 
Variables for sleep study scores were updated 
to be clear and consistent with the data 
collected. 
Section 15.3 
By visit was added for the tables of change in 
blood pressures. 
Section 16.4 
Percent change from baseline was added for 
summary of MRI. 
Section 23 
Reference of achondroplasia data was 
updated. 


 
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25 
APPENDICES  
25.1 
Summary of Growth Measures Derivations  
Derived Value: 
Measure 
required in 
calculation: 
Age 
Order of Substitution for measure required: 
1 then 2. 
1 
2 
BMI 
Height 
Under 24 
months 
Body Length  
Standing Height  
24 months 
or older 
Standing Height 
Body Length  
AGV 
Height 
Under 24 
months 
Body Length  
Standing Height  
24 months 
or older 
Standing Height 
Body Length  
Standing Height 
Height 
Under 24 
months 
Body Length  
Standing Height  
 24 months 
or older 
Standing Height 
Body Length 
Sitting Height 
Height 
Under 24 
months 
Crown-to-Rump Length 
Sitting Height 
 24 months 
or older 
Sitting Height 
Crown-to-Rump Length 
Height Z-Score* 
 
Height 
Under 24 
months 
Body Length 
Standing Height  
24 months 
or older 
Standing Height 
Body Length  
BMI Z-Score** 
 
BMI 
Under 24 
months 
 
Will not be calculated 
24 months 
or older 
Standing Height 
Body Length  
Lower Body Length 
Standing Height 
and Sitting 
Height 
Under 24 
months 
Body Length - Crown-
to-Rump Length 
Standing Height - 
Sitting Height 
24 months 
or older 
Standing Height - 
Sitting Height 
Body Length - Crown-
to-Rump Length 
Arm Span to Height 
Ratio 
Height 
Under 24 
months 
Body Length 
Standing Height 


 
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Derived Value: 
Measure 
required in 
calculation: 
Age 
Order of Substitution for measure required: 
1 then 2. 
1 
2 
24 months 
or older 
Standing Height 
Body Length 
Upper to Lower 
Body Segment 
Ratio 
Upper Body: 
Lower Body 
Under 24 
months 
Crown-to-Rump 
Length:  
(Body Length - Crown- 
to-Rump Length ) 
Sitting Height: 
(Standing Height - 
Sitting Height) 
24 months 
or older 
Sitting Height: 
(Standing Height - 
Sitting Height) 
Crown-to-Rump Length:  
(Body Length - Crown- 
to-Rump Length ) 
*Height Z-Scores will be derived using CDC references and macro. 
**BMI Z-Score will be calculated in the age appropriate CDC macros, only for subjects aged 24 months or 
older.  
Programming will not supply the BMI value that we derive for our datasets and table summaries to this macro.  
The CDC macro will calculate BMI Z-Scores using the Height value supplied as describe above to create the 
Height Z-Scores. Therefore, the BMI Z-Scores will be consistent with the Height Z-Score.  
 


 
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25.2 
Child Behavior Checklist Domains  
Domain/Subscale 
CBCL 1.5-5 
EMOTIONALLY REACTIVE 
21. Disturbed by change 
46. Twitches 
51. Panics 
79. Shifts between sad-excite 
82. Sudden mood change 
83. Sulks a lot 
92. Upset by new 
97. Whining 
99. Worries 
ANXIOUS/DEPRESSED 
10. Too dependent 
33. Feelings easily hurt 
37. Upset when separated 
43. Looks unhappy 
47. Nervous 
68. Self-conscious 
87. Fearful 
90. Unhappy, sad, depressed 
WITHDRAWN 
2. Acts too young 
4. Avoids eye contact 
23. Doesn’t answer 
62. Refuses active games 
67. Unresponsive to affection 
70. Little affection 
71. Little interest 
98. Withdrawn 
SOMATIC COMPLAINTS 
1. Aches, pains 
7. Can’t stand things out of place 
12. Constipated 
19. Diarrhea 
24. Doesn’t eat well 
39. Headaches 
45. Nausea 
52. Painful bowel movements 
78. Stomachaches 
86. Too concerned with neatness 
93. Vomits 
SLEEP PROBLEMs 
22. Doesn’t want to sleep alone 
38. Trouble sleeping 
48. Nightmares 
64. Resists bed 
74. Sleeps little 
84. Talks, cries in sleep 
94. Wakes often 


 
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Domain/Subscale 
CBCL 1.5-5 
ATTENTION PROBLEMS 
5. Can’t concentrate 
6. Can’t sit still 
56. Clumsy 
59. Quickly shifts 
95. Wanders away 
 
AGGRESSIVE BEHAVIOR 
8. Can’t stand waiting 
15. Defiant 
16. Demands must be met 
18. Destroys others things 
20. Disobedient 
27. Lacks guilt 
29. Easily frustrated 
35. Gets in fights 
40. Hits others 
42. Hurts unintentionally 
44. Angry moods 
53. Attacks people 
58. Punishment doesn’t change behavior 
66. Screams 
69. Selfish 
81. Stubborn 
85. Temper 
88. Uncooperative 
96. Wants attention 
 


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