An Open-Label, Phase 2 Study to Assess the Safety, Pharmacodynamics, and Efficacy of KRN23 in Children From 1 to 4 Years Old With X-linked Hypophosphatemia (XLH)
Phase: PHASE2
Conditions: X-Linked Hypophosphatemia
Sponsor: Kyowa Kirin, Inc.

 
 
An Open-Label, Phase 2 Study to Assess the Safety, Pharmacodynamics, and Efficacy 
of KRN23 in Children from 1 to 4 Years Old with X-linked Hypophosphatemia (XLH)  
Protocol Number: 
UX023-CL205 
Original Protocol:  
22 October 2015 
Amendment 1:        
28 March 2016 
Amendment 2: 
 
12 June 2017 
 
Investigational Product:   
KRN23 (Recombinant human IgG1 monoclonal 
antibody to fibroblast growth factor 23 [FGF23]) 
Indication: 
X-linked Hypophosphatemia (XLH) 
IND Number: 
76,488 
EudraCT Number 
Not applicable 
Sponsor:   
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA 94949 USA 
Sponsor’s Responsible 
Medical Officer: 
Javier San Martin, MD 
VP, Clinical Sciences 
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA 94949 USA 
 
 
Coordinating Investigator: 
Erik Imel, MD 
Indiana University School of Medicine 
Indianapolis, IN  46202 USA 
 
This study is to be performed in compliance with the protocol, Good Clinical Practices (GCP), 
and applicable regulatory requirements. 
 
Confidentiality Statement:   This document and the information it contains is confidential and proprietary 
and is the property of Ultragenyx Pharmaceutical Inc. (Ultragenyx).  Unauthorized disclosure, reproduction, 
transmission, or use of this document or information is strictly prohibited.  By accepting this document, the 
recipient agrees that the information it contains will not be disclosed without written authorization from 
Ultragenyx, except to the extent required to satisfy Institutional Review Board procedures /Ethics Committee, to 
obtain written informed consent from potential subjects, or as required by law.   
 
PPD

Protocol Number:  UX023-CL205 
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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX023-CL205 Amendment 2 
12 June 2017  
Protocol UX023-CL205 Amendment 1 (dated 28 March 2016) has been modified by 
Amendment 2 to modify the study duration, allow for parent/caregiver administration of 
study drug, and formally incorporate information communicated to investigators via 
memoranda (dated 05 Apr 2016, 30 Sept 2016, 20 Oct 2016, and 13 Dec 2016). The major 
protocol changes that impact study design and conduct are summarized below:  
1. Study Objectives:  The following additional study objective (along with 
corresponding Section 7.5.4 Pharmacokinetic Assessment) has been modified:  
• Pre-dose KRN23 drug concentration levels (PK) 
Rationale: Clarification of language since KRN23 drug concentration levels are being 
assessed at time points corresponding to 1 week post dose in addition to time points 
prior to the first dose or at trough.  
2. Overall Study Design and Plan:  The provision to maintain gender balance has been 
modified: 
To maintain a level of gender balance, no more than 7 70% of subjects of either 
gender will be enrolled. 
Rationale:  The original protocol planned sample size was 10 subjects, therefore 
7 subjects (ie, 70% of the study population) were selected. The change more 
accurately reflects the total enrollment of 13 subjects (9 male; 69%).    
3. Study Duration:  An Extension Period of 96 weeks has been added. 
Rationale:  The Extension Period has been added to the study for continued 
assessment of long-term safety and efficacy of KRN23 in younger children. 
4. Removal of Subjects:  In Section 7.3.3, language has been added to allow orthopedic 
surgery during the Extension Period if recommended by the investigator or consulting 
physician. In addition, subjects who develop hyperparathyroidism may remain on 
study, but use of medication to suppress PTH (eg, Sensipar®, cinacalcet, 
calcimimetics) is not permitted at any time. Subjects should be removed from study if 
treatment for hyperparathyroidism becomes medically necessary.  
Rationale: Given that the study duration was increased, certain conditions or the need 
for medical procedures may develop during the study. The additional provisions 

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allow subjects to remain on study should orthopedic surgery be recommended or mild 
hyperparathyroidism develop. 
5. Treatment:  Section 7.4.1 has been updated to allow for a parent or caregiver to 
administer KRN23 to the subject after proper training by study personnel in 
subcutaneous injection technique and documentation of proficiency. Section 7.4.4 has 
been updated to describe timing of dose adjustments during the Extension Period. 
Sections 7.4.6 and 8.3 have been updated to describe methods for monitoring 
treatment compliance in the home setting via telephone contact and physical 
inventory of empty vials at site visits for study drug accountability.  
Rationale: Allowing subjects’ parents or caregivers to administer KRN23 in the home 
setting will reduce burden on the subjects. Instructions for Use (IFU) have been 
thoughtfully developed with input from XLH patients and will be used to guide 
parents and caregivers through the injection process. The IFU will be provided to 
sites and IRBs for approval prior to the initiation of parent/caregiver administration. 
To avoid potential errors with any dose adjustments, dose changes during the 
Extension Period will be initially implemented at the clinic visits. Site personnel will 
collect information on treatment compliance in the home setting and monitor the 
home administration via telephone contact. 
6. Study Procedures and Assessments: Several changes have been made in 
Section 7.5; a new Schedule of Events table (Table 2.3) was included to describe 
visits and assessments during the Extension Period. 
a) During the Extension Period, clinic visits will occur at approximately 12-week 
intervals (±5 days). Home health or telephone visits will occur every 2 weeks. 
For telephone visits, study sites will schedule biweekly telephone calls with the 
subjects’ parent/caregiver to confirm administration of study drug, and for 
collection of adverse events and concomitant medication information. Site 
personnel will initiate a safety follow-up telephone call 5 weeks (+5 days) after 
the Week 160 visit to determine if the subject is receiving KRN23 therapy under 
commercial use or another mechanism and to collect information on any ongoing 
or new AEs, serious adverse events (SAEs), and concomitant medications for 
subjects not receiving KRN23. The additional safety visit (10 weeks ± 5 days 
after Week 160) will apply to subjects who discontinue treatment early or choose 
not to continue KRN23 therapy as commercial product or through another 
mechanism once the study ends. 
Rationale: Additional clinic visits and telephone calls have been included in the 
Extension Period to monitor long-term safety, compliance, and efficacy at an interval 
deemed appropriate for the age of the population and duration of treatment. 
b) As previously communicated by memorandum (20 Oct 2016), Section 7.5.2 has 
been updated to remove TmP/GFR and TRP as estimates of renal phosphate 

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reabsorption due to the breadth of available data and burden of obtaining urine 
samples in this study population (under 5 years of age). 
c) As previously communicated by memorandum (20 Oct 2016), the Week 22 serum 
calcium assessment has been removed from the Schedule of Events Table 2.1. 
d) As previously communicated by memorandum (05 Apr 2016), Section 7.5.5.2 has 
been updated such that blood pressure will be obtained for subjects aged 3 years 
or above (at study entry or beginning when the subject turns 3 years of age). The 
provision for training on blood pressure measurements at the site initiation visit 
was removed.  
e) As previously communicated by memorandum (13 Dec 2016), Section 7.5.5.4 has 
been updated to indicate that the scope of the genitourinary exam should be 
non-invasive and as per age-appropriate standard of care, at the investigator’s 
discretion based on clinical judgement.  
Rationale: The changes to pharmacodynamic assessments, blood pressure and 
genitourinary examinations provide clarification of study procedures for the 
investigator. 
f) In Section 7.5.5, Electrocardiogram (ECG) has been changed from an ectopic 
mineralization assessment to a general safety assessment. 
Rationale: ECG is performed to evaluate for changes associated with left ventricular 
hypertrophy. Ectopic mineralization is not expected to affect ECG parameters and 
ECG was inadvertently listed in that section in the original protocol.   
g) As described in Section 7.5.5.8, concomitant medications and therapies will be 
reviewed between site visits by telephone call from the study site every 2 weeks 
and recorded in the subject’s CRF.  
Rationale: Inclusion of telephone calls provides a mechanism to track use of 
concomitant medications and therapies at a consistent frequency during the Extension 
Period. 
7. Statistical Analysis and Data Monitoring Committee:  The statistical models for 
efficacy analysis have been updated in Section 7.6.3. A new Section 7.6.4 has been 
inserted to describe the timing of planned analysis for the study. During the Extension 
Period, safety data will be reviewed by the Ultragenyx Study Safety Review Team 
(SSRT) on an ongoing basis (Sections 7.6.5 and 8.5.6 ).  
Rationale:  The analysis is updated to incorporate baseline adjustment and repeated 
measures at multiple time points. Section 7.6.4 clarifies the times during the study 
when safety and efficacy data may be analyzed and more precisely defines the end of 
the study. Sections 7.6.5 and 8.5.6 stipulate the Data Monitoring Committee will 

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review safety data through the Treatment Period (Week 64); long-term safety during 
the Extension Period will be reviewed by the Sponsor. 
8. Investigators and Study Administrative Structure:  As previously communicated 
by memorandum (30 Sept 2016), Section 8.2 has been updated to include language 
describing the Coordinating Investigator for the study. The Coordinating Investigator 
is Erik Imel, MD (Indiana University School of Medicine). 
Rationale:   Regulatory guidance requires selection of a Coordinating Investigator for 
a multicenter clinical trial. 
9. Reporting and Follow-up of Adverse Events:  Section 8.5 has been updated to 
define the reporting periods for adverse events as: 
….the time that the subject signs informed consent through the final protocol-defined 
safety follow-up telephone call or safety visit 12 weeks (approximately 5 times the 
elimination half-life) following the last dose of study drug. 
Rationale:  The revised language reflects the revised study design and safety 
follow-up procedures. 
10. In Section 7.5.5.7.2 and the Schedules of Events, the parenthetical explanation of 
anti-KRN23 antibodies has been changed from human anti-human antibodies 
(HAHA) to anti-drug antibodies (ADA). 
Rationale: The change is a clarification. The immunogenicity of KRN23 is evaluated 
by quantifying total anti-drug antibodies (ADA), independent of isotype, in human 
serum. While the study protocol previously used the term “HAHA” for this 
assessment, it has been replaced with the more correct and specific term, ADA. 
 
 
 

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2 SYNOPSIS 
TITLE OF STUDY:  
An Open-Label, Phase 2 Study to Assess the Safety, Pharmacodynamics, and Efficacy of KRN23 in 
Children from 1 to 4 Years Old with X-linked Hypophosphatemia (XLH) 
PROTOCOL NUMBER: 
UX023-CL205 
STUDY SITES: 
Approximately 3 sites in the United States 
PHASE OF DEVELOPMENT: 
Phase 2 
RATIONALE FOR THIS STUDY: 
X-linked hypophosphatemia (XLH) is a disorder of hypophosphatemia, renal phosphate wasting, 
defective bone mineralization, and impaired growth plate or endochondral ossification caused by 
inactivating mutations in the PHEX gene (phosphate-regulating gene with homologies to 
endopeptidases on the X chromosome), and is the most common form of heritable rickets. In the 
absence of functional PHEX, FGF23 production by osteocytes is greatly increased, leading to 
impaired conservation of phosphate by the kidney and consequent hypophosphatemia. FGF23 also 
suppresses 1,25-dihydroxyvitamin D (1,25(OH)2D) production resulting in decreased intestinal 
absorption of calcium and phosphate. The chronic presence of low serum phosphorus levels leads to 
defective bone mineralization and the two major pathologic consequences of the hypophosphatemia, 
rickets and osteomalacia. Rickets and osteomalacia are both disorders of bone mineralization; 
however, rickets is a disease of the growth plates specifically, characterized by deficient 
mineralization as well as by delayed endochondral ossification, leading to reduced growth and 
skeletal deformities. The goal of therapy in children with XLH is to correct or minimize rickets, 
radiographic abnormalities, and skeletal deformities, and to promote maximal growth potential while 
preventing the lifelong bone- and joint-related complications of rickets. Published retrospective data 
suggest that earlier treatment leads to better outcomes for children with XLH (Makitie et al. 2003), 
(Quinlan et al. 2012). 
There is no available medicine that specifically treats the underlying pathophysiology of elevated 
FGF23-induced hypophosphatemia.  The current therapy for pediatric XLH patients consists of 
multiple daily doses of oral phosphate often combined with doses of active vitamin D analogs. 
Dosing is individualized and depends on tolerability of the phosphate dose and the age, size, and 
growth of the child. The goal of therapy with phosphate and vitamin D is to sufficiently supplement 
the body’s pool of phosphate to allow mineralization of bone and improve skeletal outcomes; 
however, because supplementation therapy does not address the mechanism of urinary phosphate 
wasting, increasing phosphate through supplementation also increases renal phosphate throughput 
and urinary phosphate concentrations, thus raising the risk of nephrocalcinosis. 
KRN23 is a recombinant human IgG1 monoclonal antibody that binds to and inhibits the activity of 
FGF23. Phase 1 and Phase 2 studies in adults and children (aged 5-12 years) with XLH have shown 
that KRN23 treatment increases serum phosphorus and 1,25(OH)2D levels and the ratio of renal 
tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR). Initial 
Phase 2 data in children with XLH suggest KRN23 treatment also improves rickets severity with a 

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favorable safety profile. 
Early treatment of children with XLH is associated with better growth and skeletal outcomes. 
In retrospective studies, children beginning treatment before age 1 had consistently higher z scores 
and lower alkaline phosphatase (ALP) levels than children starting treatment later (Makitie et al. 
2003), (Quinlan et al. 2012), suggesting that growth deficits accumulated before treatment may lead 
to permanent height loss. The current study will provide information about the safety profile, dosing, 
and effect of KRN23 on phosphate metabolism in children with XLH (1 to 4 years of age, inclusive) 
and confirmed evidence of rickets. In addition, this study will evaluate whether biweekly dosing of 
KRN23 improves rickets, growth, and lower extremity deformity in young children with XLH. 
OBJECTIVES: 
The primary objectives of the study are to:  
• 
Establish the safety profile of KRN23 for the treatment of XLH in children between 1 and 4 years 
old  
• 
Determine the pharmacodynamic (PD) effects of KRN23 treatment on serum phosphorus and 
other PD markers that reflect the status of phosphate homeostasis in children between 1 and 4 
years old with XLH 
Additional study objectives are to assess the following in children between 1 and 4 years old with 
XLH 
• 
Effects of KRN23 on rickets 
• 
Effects of KRN23 on growth and lower extremity deformity 
• 
KRN23 drug concentration levels (PK) 
STUDY DESIGN AND METHODOLOGY:  
UX023-CL205 is a multicenter, open-label, Phase 2 study in children from 1 to 4 years old with XLH 
who are naïve to therapy or have previously received standard therapy with oral phosphate and active 
vitamin D to assess the safety, PD, and efficacy of KRN23 administered via subcutaneous (SC) 
injections every 2 weeks (Q2W) for a 64-week Treatment Period. Subjects may continue to receive 
KRN23 for up to an additional 96 weeks during the Extension Period. 
The study will enroll approximately 10 pediatric subjects between 1 and 4 years old, inclusive, with 
clinical findings consistent with  XLH including hypophosphatemia and radiographic evidence of 
rickets (at least 5 subjects will have a rickets severity score (RSS) at the knee of ≥1.5 points at 
Screening), and a confirmed PHEX mutation or variant of uncertain significance. To maintain a level 
of gender balance, no more than 70% of subjects of either gender will be enrolled. Subjects will 
discontinue oral phosphate and active vitamin D therapy during Screening and for the duration of the 
study.   
All subjects will receive KRN23 at a starting dose of 0.8 mg/kg Q2W. The dose may be increased to 
1.2 mg/kg at any time during the study if a subject meets the following dose-adjustment criteria: 
1) two consecutive serum phosphorus measurements are below the normal range; 2) serum 
phosphorus has increased by < 0.5 mg/dL from baseline; and 3) the subject has not missed a dose of 
study drug that would account for the decrease in serum phosphorus.   

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At any time during the study, if serum phosphorus increases above the upper limit of normal (ULN) 
for age, the subsequent dose(s) will be withheld and the site will contact the medical monitor before 
dosing resumes. Once other causes of increased serum phosphorus are excluded, KRN23 treatment 
will resume at half the total dose of the last dose received. Serum phosphorus will be followed 
through unscheduled serum phosphorus assessments. A subject will resume dosing at the previous 
full total dose level if they meet the same dose-adjustment criteria listed above.  
NUMBER OF SUBJECTS PLANNED:  
Approximately 10 subjects  
DIAGNOSIS AND CRITERIA FOR INCLUSION AND EXCLUSION:  
Individuals eligible to participate in this study must meet all of the following criteria: 
1) Male or female, aged ≥1 year and < 5 years 
2) PHEX mutation or variant of uncertain significance in either the patient or in a directly 
related family member with appropriate X-linked inheritance 
3) Biochemical findings associated with XLH including:   
a. Serum phosphorus < 3.0 mg/dL (0.97 mmol/L)* 
b. Serum creatinine within age-adjusted normal range*  
4) Radiographic evidence of rickets; at least 5 subjects will be required to have a rickets severity 
score (RSS) at the knee of at least 1.5 points as determined by central read  
5) Willing to provide access to prior medical records for the collection of historical growth, 
biochemical, and radiographic data and disease history  
6) Provide written informed consent by a legally authorized representative after the nature of the 
study has been explained, and prior to any research-related procedures 
7) Must, in the opinion of the investigator, be willing and able to complete all aspects of the 
study, adhere to the study visit schedule, and comply with the assessments 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
1) Unwilling to stop treatment with oral phosphate and/or pharmacologic vitamin D metabolite 
or analog (e.g. calcitriol, alfacalcidol) during the screening period and for the duration of the 
study 
2) Presence of nephrocalcinosis on renal ultrasound grade 4 based on the following scale: 
0 = Normal 
1 = Faint hyperechogenic rim around the medullary pyramids 
2 = More intense echogenic rim with echoes faintly filling the entire pyramid 
3 = Uniformly intense echoes throughout the pyramid 
4 = Stone formation: solitary focus of echoes at the tip of the pyramid 
3) Planned or recommended orthopedic surgery including staples, 8-plates or osteotomy, within 
the clinical trial period 
4) Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted 
normal limits* 

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5) Presence or history of any condition that, in the view of the investigator, places the subject at 
high risk of poor treatment compliance or of not completing the study   
6) Presence of a concurrent disease or condition that would interfere with study participation or 
affect safety  
7) History of recurrent infection or predisposition to infection, or of known immunodeficiency 
8) Use of any investigational product or investigational medical device within 30 days prior to 
screening, or requirement for any investigational agent prior to completion of all scheduled 
study assessments 
* Criteria to be determined based on fasting (min. 4 hours) values collected at Baseline 
INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION:  
KRN23 is a sterile, clear, colorless, and preservative-free solution in single-use 5-mL vials 
containing 1 mL of KRN23 at a concentration of 10 mg/mL or 30 mg/mL. Subjects will receive 
KRN23 at a starting total dose of 0.8 mg/kg. The dose may be increased to 1.2 mg/kg at any time if a 
subject meets the following dose adjustment criteria: 1) two consecutive serum phosphorus 
measurements are below the normal range; 2) serum phosphorus has increased by < 0.5 mg/dL from 
baseline; and 3) the subject has not missed a dose of study drug that would account for the decrease 
in serum phosphorus. At any time during the study, if serum phosphorus increases above the ULN for 
age, the subsequent dose(s) will be withheld and the site will contact the medical monitor before 
dosing resumes. Once other causes of increased serum phosphorus are excluded, KRN23 treatment 
will resume at half the total dose of the last dose received. Serum phosphorus will be followed 
through unscheduled serum phosphorus assessments. A subject will resume dosing at the previous 
full total dose level if they meet the same dose-adjustment criteria listed above.  
KRN23 will be administered via SC injection to the abdomen, upper arms or thighs; the injection site 
will be rotated with each injection. After proper training, a parent or caregiver may administer 
KRN23 to the subject. 
REFERENCE THERAPY(IES), DOSEAND MODE OF ADMINISTRATION:  
This is single-arm, open-label study. All subjects will receive KRN23. No placebo or reference 
therapy will be administered. 
DURATION OF TREATMENT:  
The Treatment Period in this study is 64 weeks. Subjects who complete the Treatment Period may 
continue to receive KRN23 for an additional 96 weeks during the Extension Period. 
CRITERIA FOR EVALUATION: 
Primary Assessments: 
Safety: 
Safety will be evaluated by the incidence, frequency and severity of adverse events (AEs) and serious 
adverse events (SAEs), including clinically significant changes in laboratory test results from 
baseline to scheduled time points (refer to Table 2.1, Table 2.2, and Table 2.3) 
 

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General Safety Variables will include the following: 
• 
Vital signs and weight 
• 
Physical examinations 
• 
Glomerular filtration rate (GFR) 
• 
Chemistry, hematology, and urinalysis, including additional KRN23/XLH biochemical 
parameters of interest (serum calcium, intact parathyroid hormone [iPTH], 25-hydroxyvitamin D 
[25(OH)D], amylase, lipase, and creatinine; and urinary calcium and creatinine) 
• 
Anti-KRN23 antibody testing and dose-limiting toxicities 
• 
Concomitant medications 
• 
Electrocardiogram (ECG) 
Ectopic Mineralization Safety Assessments include: 
• 
Renal ultrasound 
Pharmacodynamics:  
The primary efficacy endpoint is the change from baseline over time in serum phosphorus. 
Additional pharmacodynamics assessments include: 
• 
Change from baseline over time in serum 1,25(OH)2D and urinary phosphorus 
Secondary Assessments: 
• 
Change in rickets at Week 40 as assessed by the Radiograph Global Impression of Change 
(RGI C) global score 
• 
Change in rickets at Week 64 as assessed by RGI-C global score  
• 
Change from baseline in RSS total score at Weeks 40 and 64 
• 
Change in lower extremity skeletal abnormalities, including genu varum and genu valgus, as 
determined by the RGI-C long leg score at Weeks 40 and 64 
• 
Change in recumbent length/standing height from baseline to post-treatment study time points in 
cm, height-for-age z-scores, and percentiles. Historical growth records may be used to evaluate 
change in growth velocity  
• 
Change and percent change from baseline over time in serum alkaline phosphatase (ALP) 
• 
Serum KRN23 concentrations at indicated study time points 
STATISTICAL METHODS:  
A full description of the statistical evaluations will be provided in the Statistical Analysis Plan. 
Safety Analysis: 
All subjects who receive at least one dose of study drug will be included in the safety analysis. 
An independent DMC that includes members with expertise in metabolic bone disease, cardiology, 
and nephrology and the conduct of clinical trials in children will act in an advisory capacity to 

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monitor subject safety on a routine basis through the Treatment Period (Week 64). The DMC will 
meet approximately twice a year. During the Extension Period, safety data will be reviewed by the 
Ultragenyx Study Safety Review Team (SSRT) on an ongoing basis. 
Pharmacodynamics and Efficacy Analysis: 
Descriptive statistics will be used to summarize the data. For continuous variables, the mean, 
standard deviation, median, interquartile range (Q1, Q3), minimum, and maximum will be provided.  
For discrete data, the frequency and percent distributions will be provided. Changes over time and the 
association of the efficacy with the PD variables will be summarized and evaluated. 
Pharmacokinetic Analyses: 
PK parameters will be summarized at each time point. 

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Table 2.1: 
Schedule of Events – Screening, Baseline, and Treatment Period Weeks 1-30 
 
Screening/ 
Baseline1 
Treatment Period3 
VISIT TYPE/NUMBER 
SV 
BL 
V12 
HH4 
V2 
HH 
V3 
V4 
HH 
V5 
V6 
HH 
V7 
V8 
HH 
V9 
V10 
HH 
V11 
HH 
V12 
V13 
HH 
V14 
V15 
HH 
V16 
HH 
V17 
HH 
V18 
WEEK 
W -6 
to BL 
W0 
W1 
W2 
W4 
W6 
W8 
W 
10 
W 
12 
W 
14 
W 
15 
W 
16 
W 
18 
W 
20 
W 
22 
W 
24 
W 
26 
W 
28 
W 
30 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History & 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHEX mutation analysis 5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD MEASURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Phosphorus 6 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 
1,25(OH)2 D 6 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
Spot urine 6,7 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
ALP only 6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
EFFICACY MEASURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Growth (recumbent 
length/standing height)  
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Bilateral AP knee X-rays 2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilateral PA hand/wrist2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standing long leg X-Ray2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHARMACOKINETICS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum KRN236  
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 

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Screening/ 
Baseline1 
Treatment Period3 
VISIT TYPE/NUMBER 
SV 
BL 
V12 
HH4 
V2 
HH 
V3 
V4 
HH 
V5 
V6 
HH 
V7 
V8 
HH 
V9 
V10 
HH 
V11 
HH 
V12 
V13 
HH 
V14 
V15 
HH 
V16 
HH 
V17 
HH 
V18 
WEEK 
W -6 
to BL 
W0 
W1 
W2 
W4 
W6 
W8 
W 
10 
W 
12 
W 
14 
W 
15 
W 
16 
W 
18 
W 
20 
W 
22 
W 
24 
W 
26 
W 
28 
W 
30 
SAFETY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 8,9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Physical Examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Renal Ultrasound 2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 2 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Chemistry, Hematology, 
Urinalysis 6,7,10 
X 
X 
  
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
Serum 25(OH)D6 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Serum Calcium 6 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 
Serum Creatinine 6 
X 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
Serum iPTH 6 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
Serum FGF23 6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Anti-KRN23 antibody (ADA) 
6,11 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
DRUG ADMINISTRATION 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
See footnotes after Table 2.3 

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Table 2.2: 
Schedule of Events – Treatment Period Weeks 32 – 64 
 
Treatment Period3 
Visit Type/Number 
V19 
HH 
V20 
HH 
V21 
HH 
V22 
V23 
HH 
V24 
HH 
V25 
HH 
V26 
V27 
HH 
V28 
HH 
V29 
HH 
V30 
V31 
HH 
V32 
HH 
V33 
HH 
V34 
V35 
Week 
W 
32 
W 
34 
W 
36 
W 
38 
W 
40 
W 
42 
W 
44 
W 
46 
W 
48 
W 
50 
W 
52 
W 
54 
W 
56 
W 
58 
W 
60 
W 
62 
W64 
PD MEASURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Phosphorus 6 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
1,25(OH)2 D 6 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Spot urine 6,7 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
ALP only 6 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
EFFICACY MEASURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Growth (length/standing height)  
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Bilateral AP knee X-rays 2 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Bilateral PA hand/wrist         X-
rays 2 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Standing long leg X-ray 2 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
PHARMACOKINETICS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum KRN236 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
SAFETY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 8,9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Physical Examination 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Renal Ultrasound 2 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
ECG 2 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 

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Treatment Period3 
Visit Type/Number 
V19 
HH 
V20 
HH 
V21 
HH 
V22 
V23 
HH 
V24 
HH 
V25 
HH 
V26 
V27 
HH 
V28 
HH 
V29 
HH 
V30 
V31 
HH 
V32 
HH 
V33 
HH 
V34 
V35 
Week 
W 
32 
W 
34 
W 
36 
W 
38 
W 
40 
W 
42 
W 
44 
W 
46 
W 
48 
W 
50 
W 
52 
W 
54 
W 
56 
W 
58 
W 
60 
W 
62 
W64 
Chemistry, Hematology, 
Urinalysis 6,7,10 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Serum 25(OH)D6 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum Calcium 6 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Serum Creatinine 6 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Serum iPTH 6 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum FGF236 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Anti-KRN23 antibody (ADA) 6, 
11 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
DRUG ADMINISTRATION 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

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Table 2.3:   
Schedule of Events – Extension Period (Week 66 – End of Study) 
 
Extension Period3 
 
Visit Type/Number 
HH/ 
TV13 
V41 
V47 
V53 
V59 
V65 
V71 
V77 
V83 
Safety 
Call 15 
Safety Visit 16 
Week/Frequency 
Q2W 
W   76 
W 
88 
W 100 
W 112 
W 
124 
W 136 
W 148 
W  
160/ET14 
W 
165 
W 
170 
PD MEASURES 
 
 
 
 
 
 
 
 
 
 
 
Serum Phosphorus 6 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
1,25(OH)2 D 6 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Spot urine 6,7 
 
 
 
 
X 
 
 
 
X 
 
X 
ALP only 6 
 
 
 
 
X 
 
 
 
X 
 
 
EFFICACY MEASURES 
 
 
 
 
 
 
 
 
 
 
 
Growth (length/standing height)  
 
 
X 
 
X 
 
X 
 
X 
 
 
Bilateral AP knee X-rays 2 
 
 
 
 
X 
 
 
 
X 
 
 
Bilateral PA hand/wrist X-rays 2 
 
 
 
 
X 
 
 
 
X 
 
 
Standing long leg X-ray 2 
 
 
 
 
X 
 
 
 
X 
 
 
PHARMACOKINETICS 
 
 
 
 
 
 
 
 
 
 
 
Serum KRN236 
 
 
 
 
 
 
 
 
X 
 
 
SAFETY 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 8,9 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Weight 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Physical Examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Renal Ultrasound 2 
 
 
 
 
 
 
 
 
X 
 
 

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Extension Period3 
 
Visit Type/Number 
HH/ 
TV13 
V41 
V47 
V53 
V59 
V65 
V71 
V77 
V83 
Safety 
Call 15 
Safety Visit 16 
Week/Frequency 
Q2W 
W   76 
W 
88 
W 100 
W 112 
W 
124 
W 136 
W 148 
W  
160/ET14 
W 
165 
W 
170 
ECG 2 
 
 
 
 
 
 
 
 
X 
 
 
Chemistry, Hematology, Urinalysis 
6,7,10 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Serum 25(OH)D6 
 
 
X 
 
X 
 
X 
 
X 
 
 
Serum Calcium 6 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Serum Creatinine 6 
 
 
X 
 
X 
 
X 
 
X 
 
 
Serum iPTH 6 
 
 
X 
 
X 
 
X 
 
X 
 
 
Serum FGF236 
 
 
 
 
 
 
 
 
X 
 
 
Anti-KRN23 antibody (ADA) 6, 11 
 
 
 
 
 
 
 
 
X 
 
 
DRUG ADMINISTRATION 12 
Q2 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
FOOTNOTES FOR Table 2.1, Table 2.2, AND Table 2.3: 
1 
The baseline visit may occur up to approximately 6 weeks after Screening in those subjects without a previously documented PHEX mutation to allow for 
PHEX mutation results to be determined 
2 
All Screening/Baseline assessments and inclusion/exclusion criteria based on local lab results must be satisfied prior to randomization and dosing. Renal 
ultrasound, ECG, and x-rays may be performed within ± 3 days of clinic visit to accommodate scheduling availability.   
3 
Subjects will return to the clinic for site visits at approximately 4-week intervals from Baseline to Week 24 and at 8-week intervals from Week 24 to 
Week 64.  The visit window is ± 3 days. During the Extension Period, clinic visits will occur at 12-week intervals (± 5 days).  
4 
Home health (HH) visits may also be conducted at the clinic depending on proximity of the subject to the investigational site and local availability of home 
health care resources. The visit window is ± 3 days. 
5 
PHEX mutation analysis will be performed for all subjects. Potential subjects with prior confirmation of a PHEX mutation or variant of uncertain 
significance in either self or a family member with appropriate X-linked inheritance who meet other eligibility requirements may enroll before screening 
PHEX mutation results are returned. 

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6 
Blood and urine to be collected after a minimum fasting time of 4 hours and prior to drug administration (if applicable). Record fasting duration on CRF. 
Subjects who live more than 45 minutes from the site may stay overnight on the night before the site visit to facilitate fasting sample collection. At Baseline, 
local lab values will be used to confirm eligibility. Baseline samples will also be sent to the central lab for data analysis.  Serum phosphorus may be 
collected as an unscheduled lab if necessary 
7 
Spot urine collections for urinary calcium, phosphorus, and creatinine 
8 
At site visits, vital sign measurements consist of seated systolic/diastolic blood pressure (BP) measured in millimeters of mercury (mm Hg), heart rate (HR; 
beats per minute), respiration rate (breaths per minute), and temperature in degrees Celsius (°C).  Blood pressure will only be obtained for subjects age 3 
years or above (at study entry or beginning when a subject turns 3 years of age). Obtain HR, respiration rate, and temperature at the beginning of each visit 
before any additional assessments are completed. At the Screening Visit  BP should be measured 3 times, 30 seconds apart at the beginning of each visit; 3 
additional BP measurements, 30 seconds apart, should be obtained at the end of the study visit after all procedures have been performed. At baseline and 
post-baseline visits, 3 BP measurements 30 seconds apart, should be obtained at the beginning of the study visit.  
9 
At HH visits, vital sign measurements consist of HR (beats per minute) and temperature in degrees Celsius (°C).  Obtain at the beginning of each visit before 
any additional assessments are completed. 
10 
Serum chemistry panels may include PD parameters (i.e., serum phosphorus and ALP), and safety parameters of interest (i.e., calcium) to avoid duplication 
of testing. Urinalysis will be conducted if possible based on urine volume collected. 
11 
If the development of anti-KRN23 antibodies is suspected in a given subject, samples may be obtained at additional time points on a case-by-case basis, if 
warranted. 
12 
During the Extension Period, study drug may be administered by a subject’s parent or caregiver without healthcare provider supervision after proper training 
and documentation of competency in subcutaneous injection technique. In these cases study drug administration will be confirmed by telephone visit (TV). 
13 
In addition to the specific visits noted, during the Extension Period additional HH or telephone visits (TV) will occur at Q2 week intervals (± 5 days and no 
fewer than 8 days apart) (ie, beginning at Week 66). In the case of TV, study drug administration will be confirmed; concomitant medications and AEs and 
SAEs will also be recorded. 
14 
Radiography (x-rays) of the wrists and knees will not be performed at the early termination (ET) visit if conducted within 3 months of termination. Standing 
long leg radiographs will not be performed at the ET visit if conducted within 6 months of termination. 
15 
To be completed for those subjects who complete Week 160 and do not continue on KRN23 treatment immediately through commercial use or through 
another mechanism. Site personnel will initiate a safety follow-up telephone call 5 weeks (+ 5 days) after the Week 160 visit to collect information on 
whether KRN23 has been started through another mechanism and, if not, any ongoing or new AEs, SAEs, or concomitant medications. 
16 
An additional safety visit will take place 10 weeks ± 5 days after the Week 160/ET visit for those subjects who discontinue treatment, or do not continue on 
KRN23 through commercial use or another mechanism. This safety visit will not occur for subjects who complete the Week 160 visit and are documented to 
be continuing on KRN23 through commercial use or another mechanism. Every reasonable effort should be made to have required subjects return to the 
clinic for the final safety visit; however, subjects who are unable to return to the clinic, the final safety visit will be conducted via telephone call. 

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3 TABLE OF CONTENTS 
1 TITLE PAGE .......................................................................................................................1 
2 SYNOPSIS ...........................................................................................................................6 
3 TABLE OF CONTENTS ...................................................................................................19 
4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................23 
5 INTRODUCTION .............................................................................................................26 
5.1 Overview of XLH .....................................................................................................27 
5.2 Brief Overview of KRN23 Development .................................................................28 
5.2.1 
Brief Description of KRN23 .......................................................................28 
5.2.1.1 
Mechanism of Action in XLH .....................................................28 
5.2.2 
Nonclinical Studies ......................................................................................29 
5.2.3 
Clinical Studies ............................................................................................30 
5.3 Summary of Overall Risks and Potential Benefits ....................................................31 
5.4 Study Rationale .........................................................................................................32 
6 STUDY OBJECTIVES ......................................................................................................34 
7 INVESTIGATIONAL PLAN ............................................................................................35 
7.1 Overall Study Design and Plan .................................................................................35 
7.2 Discussion of Study Design, Including Choice of Control Group ............................36 
7.3 Selection of Study Population ...................................................................................36 
7.3.1 
Inclusion Criteria .........................................................................................37 
7.3.2 
Exclusion Criteria ........................................................................................37 
7.3.3 
Removal of Subjects from Therapy or Assessment ....................................38 
7.3.3.1 
Stopping Rules .............................................................................39 
7.4 Treatment ..................................................................................................................39 
7.4.1 
Investigational Product ................................................................................40 
7.4.2 
Reference Therapy ......................................................................................40 
7.4.3 
Method of Assigning Subjects to Treatment Groups ..................................40 

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7.4.4 
Selection of Doses .......................................................................................40 
7.4.5 
Prior and Concomitant Therapy ..................................................................41 
7.4.5.1 
Prohibited Medications ................................................................41 
7.4.5.2 
Permitted Medications .................................................................42 
7.4.6 
Treatment Compliance ................................................................................42 
7.5 Study Procedures and Assessments ..........................................................................43 
7.5.1 
Schedule of Events ......................................................................................43 
7.5.2 
Pharmacodynamic Assessments ..................................................................44 
7.5.2.1 
Serum Phosphorus .......................................................................44 
7.5.2.2 
Additional Pharmacodynamic Markers .......................................44 
7.5.2.3 
Serum Alkaline Phosphatase........................................................45 
7.5.3 
Clinical Efficacy Measures .........................................................................45 
7.5.3.1 
Radiographs .................................................................................45 
7.5.3.2 
Growth .........................................................................................46 
7.5.4 
Pharmacokinetic Assessment ......................................................................46 
7.5.5 
Safety Measurements ..................................................................................46 
7.5.5.1 
Medical History ...........................................................................46 
7.5.5.2 
Vital Signs ....................................................................................47 
7.5.5.3 
Weight ..........................................................................................48 
7.5.5.4 
Physical Examination...................................................................48 
7.5.5.5 
Renal Ultrasound and Glomerular Filtration Rate .......................48 
7.5.5.6 
Electrocardiogram ........................................................................48 
7.5.5.7 
Clinical Laboratory Tests for Safety ............................................49 
7.5.5.8 
Concomitant Medications/Therapies ...........................................51 
7.5.5.9 
Dose Limiting Toxicity ................................................................51 
7.5.5.10 
Adverse Events ............................................................................52 
7.5.6 
Appropriateness of Measurements ..............................................................52 
7.6 Statistical Methods and Determination of Sample Size ............................................53 

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7.6.1 
Determination of Sample Size .....................................................................53 
7.6.2 
Analysis Populations ...................................................................................53 
7.6.2.1 
Efficacy Analysis Set ...................................................................53 
7.6.2.2 
Safety Analysis Set ......................................................................53 
7.6.2.3 
Pharmacokinetic and Pharmacodynamic Analysis Set ................53 
7.6.3 
General Principles .......................................................................................54 
7.6.3.1 
Subject Accountability .................................................................54 
7.6.3.2 
Demographics and Baseline Characteristics ................................54 
7.6.3.3 
Pharmacodynamic Analyses ........................................................54 
7.6.3.4 
Clinical Efficacy Analysis ...........................................................54 
7.6.3.5 
Pharmacokinetics Analyses .........................................................55 
7.6.3.6 
Safety Analyses ............................................................................55 
7.6.4 
Timing of Analysis ......................................................................................55 
7.6.5 
Data Monitoring Committee .......................................................................56 
8 STUDY CONDUCT ..........................................................................................................56 
8.1 Ethics .........................................................................................................................56 
8.1.1 
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) ............................................................................................................56 
8.1.2 
Ethical Conduct of Study ............................................................................56 
8.1.3 
Subject Information and Consent ................................................................57 
8.2 Investigators and Study Administrative Structure ....................................................57 
8.3 Investigational Product Accountability .....................................................................58 
8.4 Data Handling and Record Keeping .........................................................................58 
8.4.1 
Case Report Forms and Source Documents ................................................58 
8.4.2 
Data Quality Assurance ...............................................................................58 
8.4.3 
Record Retention .........................................................................................59 
8.5 Reporting and Follow-up of Adverse Events ............................................................59 
8.5.1 
Definition of Adverse Events ......................................................................59 

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8.5.2 
Severity of Adverse Events .........................................................................60 
8.5.3 
Relationship of Adverse Events to Study Drug ...........................................61 
8.5.4 
Adverse Event Reporting ............................................................................62 
8.5.4.1 
General .........................................................................................62 
8.5.4.2 
Serious Adverse Events, Serious Adverse Drug Reactions, 
and Requirements for Immediate Reporting ................................62 
8.5.5 
Communication Plan ...................................................................................62 
8.5.5.1 
Serious Adverse Drug Reaction Reporting ..................................62 
8.5.5.2 
Urgent Safety Matters and Non-SUSAR Reporting ....................63 
8.5.6 
Review of Safety Data .................................................................................63 
8.5.7 
Safety Contact Information .........................................................................64 
8.6 Financing and Insurance ...........................................................................................64 
8.7 Publication Policy .....................................................................................................64 
9 REFERENCES ..................................................................................................................65 
10 SIGNATURE PAGE .........................................................................................................68 
 
List of Tables 
Table 2.1: 
Schedule of Events – Screening, Baseline, and Treatment 
Period Weeks 1-30 ...............................................................................12 
Table 2.2: 
Schedule of Events – Treatment Period Weeks 32 – 64 ......................14 
Table 2.3:   
Schedule of Events – Extension Period (Week 66 – End of 
Study) ...................................................................................................16 
Table 7.5.5.7.1: 
Clinical Laboratory Assessments .........................................................50 
 

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4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
1,25(OH)2D 
1,25-dihydroxyvitamin D 
25(OH)D 
25-hydroxyvitamin D 
ADA 
Anti-drug antibody 
AE 
Adverse Event 
ALP 
ANCOVA 
Alkaline phosphatase 
Analysis of Covariance 
AP 
Anteroposterior 
CFR 
Code of Federal Regulations 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
DLT 
Dose limiting toxicity 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECLA 
Electrochemiluminescent assay 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
FGF23 
Fibroblast growth factor 23 
GCP 
Good Clinical Practice 
GEE 
Generalized estimating equation 
GFR 
Glomerular filtration rate 
HIPAA 
Health Insurance Portability and Accountability Act 
Hyp 
Hypophosphatemic  
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
ICH E6 
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical 
Practice E6 
IND 
Investigational New Drug (application) 
IP 
Investigational Product 

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IRB 
Institutional Review Board 
iPTH 
Intact parathyroid hormone 
IV 
Intravenous 
KHK 
Kyowa Hakko Kirin Pharma, Inc. 
LVH 
Left ventricular hypertrophy 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
No adverse effect level 
PA 
Posteroanterior 
PD 
Pharmacodynamic(s) 
PHEX 
Phosphate regulating gene with homology to endopeptidases located on 
the X chromosome 
PK 
Pharmacokinetic(s) 
PT 
Preferred term 
Q2W 
Biweekly, once every two weeks 
Q4W 
Monthly, once every four weeks 
REB 
Research Ethics Board 
RGI-C 
Radiographic Global Impression of Change 
RSS 
Rickets severity score 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SDV 
Source data verification 
SSRT 
Ultragenyx Study Safety Review Team 
SUSAR 
Suspected unexpected serious adverse reactions 
TmP/GFR 
Ratio of renal tubular maximum reabsorption rate of phosphate to 
glomerular filtration rate 
ULN 
Upper limit of normal 
US 
United States 
XLH 
X-linked hypophosphatemia 
 

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Definition of Terms 
Investigational Product is defined as, “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 E6: Guideline for Good Clinical Practice).  
The terms “Investigational Product” and “study drug” may be used interchangeably in the 
protocol. 

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5 INTRODUCTION 
X-linked hypophosphatemia (XLH) is a disorder of hypophosphatemia, renal phosphate 
wasting, defective bone mineralization, and impaired growth plate or endochondral 
ossification caused by inactivating mutations in the PHEX gene (phosphate-regulating gene 
with homologies to endopeptidases on the X chromosome), and is the most common form of 
heritable rickets. In the absence of functional PHEX, release of fibroblast growth factor 23 
(FGF23) by osteocytes is greatly increased, leading to impaired conservation of phosphate by 
the kidney and consequent hypophosphatemia. FGF23 also suppresses 1,25-
dihydroxyvitamin D (1,25(OH)2D) production resulting in decreased intestinal absorption of 
calcium and phosphate.  
Chronic hypophosphatemia leads to rickets in children and osteomalacia in adults, the 
two major pathologic features of XLH. Rickets and osteomalacia are both disorders of bone 
mineralization; however, rickets is a disease of the growth plates specifically, characterized 
by deficient mineralization as well as by delayed endochondral ossification, leading to 
reduced growth and skeletal deformities (Shore et al. 2013). Osteomalacia occurs in both 
children and adults wherein low levels of phosphorus prevent normal mineralization of 
osteoid, resulting in low bone turnover and poor quality bone (Shore et al. 2013). The goal of 
therapy in children with XLH is to correct or minimize rickets, radiographic abnormalities, 
and skeletal deformities, and to promote maximal growth potential while preventing the 
lifelong bone- and joint-related complications of rickets. Published data suggest that earlier 
treatment may lead to better long-term outcomes. In retrospective studies, children beginning 
treatment before age 1 had consistently higher z scores and lower alkaline phosphatase 
(ALP) levels than children starting treatment later (Makitie et al. 2003), (Quinlan et al. 2012).  
There is no available medicine that specifically treats the underlying pathophysiology of 
elevated FGF23-induced hypophosphatemia in XLH. The current therapy for pediatric XLH 
patients consists of multiple daily doses of oral phosphate often combined with doses of 
active vitamin D analogs. Dosing is individualized and depends on tolerability of the 
phosphate dose and the age, size, and growth of the child. Doses may be further adjusted 
based on the efficacy response to treatment or evidence of secondary complications 
(Carpenter et al. 2011).  The goal of therapy with oral phosphate and active vitamin D is to 
sufficiently supplement the body’s pool of phosphate to allow mineralization of bone and 
improve skeletal outcomes; however, because supplementation therapy does not address the 
mechanism of urinary phosphate wasting, increasing phosphate through supplementation also 
increases renal phosphate throughput and urinary phosphate concentrations, thus raising the 
risk of nephrocalcinosis. Therefore, an opportunity exists for more targeted treatment of XLH 
by blocking the action of aberrantly elevated FGF23 to normalize serum phosphorus and 
prevent long-term consequences of chronic hypophosphatemia. 
Proof-of-concept studies in a relevant murine model support the use of an anti-FGF23 
monoclonal antibody (mAb) as a treatment for XLH. Experiments in both juvenile and adult 
hypophosphatemic mice provided evidence that treatment with an anti-FGF23 mAb 
normalized or ameliorated many of the characteristic abnormalities associated with XLH 

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(Aono et al. 2009), (Aono et al. 2011). KRN23 is a fully human IgG1 mAb that binds to and 
inhibits FGF23. The Sponsor and development partner, Kyowa Hakko Kirin Co. Ltd. (KHK) 
are investigating KRN23 as a potential therapeutic candidate for the treatment of XLH, a 
disease distinguished by high levels of serum FGF23. 
KHK has conducted a series of nonclinical pharmacology, pharmacokinetic (PK), and 
toxicology studies supporting the investigation of KRN23 in adults and children. 
Three clinical studies have been completed in adult patients with XLH: a single dose Phase 1 
safety and tolerability study of KRN23, a repeat dose Phase 1/2 dose escalation study, and an 
associated treatment extension study. An additional open-label, long-term extension study in 
adults is ongoing. A Phase 2 study (UX023-CL201) in pediatric XLH patients aged 5 to 
12 years receiving KRN23 at multiple doses up to 2.0 mg/kg every 2 weeks (Q2W) or every 
4 weeks (Q4W) is ongoing and no new safety concerns have been identified.  
This Phase 2 study will be conducted in children with XLH, aged 1 to 4 years, inclusive, to 
provide information about the safety profile, dosing, and effect of KRN23 on phosphate 
metabolism in children under 5 years old. In addition, this study will evaluate whether Q2W 
dosing of KRN23 improves rickets, growth, and lower extremity deformity in young children 
with XLH. 
5.1 
Overview of XLH 
XLH is a rare, genetic disorder that is serious, chronically debilitating, and represents an 
unmet medical need. This genetic deficiency is estimated to occur in about 1:20,000 live 
births (Burnett et al. 1964), (Imel et al. 2005), (Beck-Nielsen et al. 2009). XLH is the most 
common inherited form of rickets and the most common inherited defect in renal tubular 
phosphate transport. XLH is transmitted as an X-linked dominant disorder (Dixon et al. 
1998). Mutations resulting in the loss of function of PHEX form the genetic basis for XLH 
(Carpenter et al. 2011). More than 300 different PHEX gene mutations have been identified 
in patients with XLH (PHEXdb); however, few definitive correlations have been observed 
between specific mutations and phenotypic severity. 
Patients with XLH have hypophosphatemia due to excessive FGF23 levels (Jonsson et al. 
2003), (Yamazaki et al. 2002); however, the precise mechanism by which PHEX disruption 
results in elevated FGF23 is complex and not fully understood (Carpenter et al. 2011), (Rowe 
2012). FGF23 plays an important role as a specific regulator of serum phosphorus; its major 
function is to reduce serum phosphorus levels by inhibiting renal proximal tubular phosphate 
reabsorption (Fukumoto 2008), (Razzaque et al. 2007). FGF23 also decreases serum 
1,25(OH)2D levels by inhibiting 1-alpha-hydroxylase activity in the kidney, thereby 
decreasing intestinal absorption of phosphate and calcium. Both actions by FGF23 on the 
tubular reabsorption and intestinal absorption via vitamin D metabolism lead to a decrease in 
serum phosphorus levels. 
Patients with XLH often present during childhood with rickets due to hypophosphatemia and 
frequently develop skeletal abnormalities (e.g., bowed legs), impaired growth, and short adult 
stature (Tenenhouse et al. 2001). As young patients age and progress into adulthood, the 

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symptom pattern evolves due to decreased phosphate requirements for bone growth. 
Adult XLH patients suffer from bone pain and osteomalacia, increased risk of bone fractures, 
joint abnormalities and joint pain, enthesopathy, and osteoarthritis (Carpenter et al. 2011). 
There is a great deal of variability in the manifestations of XLH. In more severe disease, 
hypophosphatemia leads to decreased mineralization of newly formed bone and rickets. 
Surgical correction of limb deformities is often required (Santos et al. 2013), (Zivicnjak et al. 
2011). 
The current therapy for pediatric XLH patients consists of multiple daily doses of oral 
phosphate often combined with doses of active vitamin D metabolites (e.g., calcitriol and 
alfacalcidol). No consensus exists regarding treatment of adult patients with XLH (Linglart et 
al. 2014). The use of oral phosphate and vitamin D may be initiated for the treatment of 
osteomalacia, bone/joint pain, and pseudofractures in symptomatic patients, although 
evidence of efficacy in adults is limited (Sullivan et al. 1992). Treatment with oral phosphate 
and active vitamin D requires frequent and continued monitoring of patients. Serum and 
urine mineral metabolite levels and imaging studies are required to assess toxicity and 
secondary complications, including nephrocalcinosis, hypercalciuria, and 
hyperparathyroidism (Carpenter et al. 2011). 
5.2 
Brief Overview of KRN23 Development 
A brief overview of existing information on KRN23 is provided below; a comprehensive 
review of the data is contained in the Investigator’s Brochure (IB) provided by Ultragenyx 
Pharmaceutical Inc. (Ultragenyx), which should be reviewed prior to initiating the study. 
5.2.1 
Brief Description of KRN23 
KRN23 is a recombinant human IgG1 mAb that binds to an0064 inhibits the activity of 
FGF23. KRN23 is expressed in Chinese hamster ovary dihydrofolate reductase-deficient 
cells. The secreted KRN23 antibody is recovered from the culture medium and purified using 
a series of chromatographic and filtration steps. Based on the amino acid sequence, the 
predicted molecular mass of KRN23 is approximately 140 kilodaltons (kDa). Nonclinical 
studies demonstrated KRN23 possesses high binding affinity to the N-terminal domain of 
FGF23. KRN23 binds to FGF23 from humans, cynomolgus monkeys and rabbits, but not to 
other species tested. 
5.2.1.1 
Mechanism of Action in XLH 
Patients with XLH have hypophosphatemia due to excessive serum FGF23 levels. FGF23 
reduces serum phosphorus levels by two distinct mechanisms of action (Fukumoto 2008), 
(Razzaque et al. 2007), (Yamazaki et al. 2008). The primary mechanism is to inhibit 
phosphate reabsorption in the proximal tubule of the kidney. The secondary mechanism is to 
decrease phosphate absorption by the small intestine through the inhibition of 1,25(OH)2D 
production in the kidney. 

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KRN23 has the potential to block or reduce FGF23 action and improve phosphate 
homeostasis in XLH patients. KRN23 binds the amino-terminal domain of FGF23 that 
interacts with the FGF-binding portion of the combination FGFR1/Klotho receptor, 
preventing FGF23 from binding to and signaling from its receptor. Both intact and 
fragmented FGF23 polypeptides are immunoprecipitated with KRN23 (Yamazaki et al. 
2008). By inhibiting FGF23, KRN23 restores tubular reabsorption of phosphate (TmP/GFR) 
from the kidney and increases the production of 1,25(OH)2D that also enhances intestinal 
absorption of phosphate. It is expected that by directly inhibiting excess FGF23, the 
underlying cause of XLH, and thereby improving phosphate homeostasis and healing rickets, 
KRN23 has the potential to significantly alter the natural history of the disease.  
5.2.2 
Nonclinical Studies 
The hypophosphatemic (Hyp) mouse is a murine homologue of XLH with a deletion in the 
3ꞌ region of the PHEX gene (Liu et al. 2007), (Perwad et al. 2005). In addition to 
hypophosphatemia, rickets, and associated developmental abnormalities, these animals 
display elevated serum FGF23 levels and increased expression of FGF23 in the bone. 
Since KRN23 does not bind murine FGF23, the pharmacological effects of murine 
anti-FGF23 mAbs were examined in juvenile and adult Hyp mice (Aono et al. 2009), (Aono 
et al. 2011). In juvenile Hyp mice, anti-FGF23 treatment corrected hypophosphatemia and 
ameliorated the rachitic bone phenotypes (Aono et al. 2009). In adult Hyp mice, anti-FGF23 
treatment increased serum phosphate and 1,25(OH)2D levels, and increased grip strength and 
spontaneous movement (Aono et al. 2011). These studies provide proof-of-concept that 
treatment with antibodies targeting FGF23 may reverse or ameliorate characteristic 
abnormalities associated with XLH. 
KRN23 binds to human, rabbit, and monkey FGF23 with comparable affinities. In a study 
conducted under Good Laboratory Practice (GLP) conditions, KRN23 cross-reactivity was 
evaluated against a full panel of human, rabbit (32 tissues), and cynomolgus monkey 
(33 tissues) tissues by immunohistochemistry. No specific KRN23 staining was observed 
suggesting untoward direct-effects of KRN23 are not expected in any tissues of normal 
humans, rabbits, or cynomolgus monkeys.  
A series of nonclinical pharmacology, PK, and toxicity studies have been conducted in 
rabbits and cynomolgus monkeys to support the use of KRN23 in adults and children. 
Findings of potential clinical significance and relevance to this protocol are summarized 
below; additional information is provided in the IB. 
• The no adverse effect level (NOAEL) in a 40-week toxicity study in adult cynomolgus 
monkeys was 0.03 mg/kg KRN23 for males and 0.3 mg/kg KRN23 for females. 
The NOAEL in a 40-week toxicity study in juvenile cynomolgus monkeys and a 
single-dose study in rabbits was 0.3 mg/kg KRN23. 
• Soft tissue and organ mineralization was a consistent finding associated with prolonged 
and excessive serum phosphate levels including the kidney where nephrocalcinosis was 

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observed at the highest dose tested and reversibility of mineralization could not be 
established. 
• The most prominent pharmacologic actions of KRN23 were dose-dependent changes in 
serum inorganic phosphorus and 1,25(OH)2D in rabbits and juvenile, adult and pregnant 
cynomolgus monkeys. 
• No gross or histopathological abnormalities were observed at the intravenous (IV) 
infusion sites or subcutaneous (SC) injection sites in the 40-week repeat dose toxicity 
studies in adult and juvenile cynomolgus monkeys.  
• KRN23 demonstrated consistent and predictable PK behavior in both rabbits and 
cynomolgus monkeys based on the results of single and repeat dose studies where 
exposure was by either the IV or SC route. 
The NOAEL was the same in juvenile and adult monkeys suggesting no difference in 
sensitivity to the adverse effects of KRN23. The results from single- and repeat-dose 
toxicology studies in rabbits and juvenile, adult and pregnant cynomolgus monkeys suggest 
the primary toxicological effects of KRN23 are associated with prolonged and excessive 
antagonism of the normal regulatory actions of FGF23 on renal tubular phosphate 
reabsorption and vitamin D metabolism. 
5.2.3 
Clinical Studies 
Multiple clinical studies of FGF23 in adults or children with XLH are completed or ongoing. 
Four clinical studies have been conducted in adult patients with XLH: a single dose Phase 1 
safety and tolerability study of KRN23 (KRN23-US-02), a single dose Phase 1 safety and 
tolerability study in Japan and Korea (KRN23-001), a repeat dose Phase 1/2 dose escalation 
study (KRN23-INT-001), and an associated treatment extension study (KRN23 INT-002). 
An additional open-label long-term extension study (UX023-CL203) in adults, a 
double-blind, placebo-controlled, Phase 3 study (UX023-CL303), and an open-label, paired 
bone biopsy Phase 3 study to evaluate changes in osteomalacia at the tissue level with 
KRN23 treatment are ongoing. Details of study parameters and PK, PD, clinical efficacy, and 
safety results are provided in the IB. A Phase 2 study evaluating dose, PD, efficacy, and 
safety is also ongoing in pediatric XLH patients (UX023-CL201) aged 5 to 12 years. 
Data from clinical studies to date are consistent with the proposed mechanism of action: that 
KRN23 blocks FGF23 action, leading to a sustained increase in serum phosphorus levels due 
to increased TmP/GFR and increased intestinal absorption caused by increased 1,25(OH)2D. 
Single and repeat-dose clinical studies indicate SC administration of KRN23 consistently 
increased and sustained serum phosphorus levels and TmP/GFR, without a major impact on 
urine calcium levels or vitamin D metabolism (Carpenter et al. 2014), (Imel et al. 2015). 
Data from the extension study in adults suggest KRN23 could provide sustained increases in 
serum phosphorus levels sufficiently such that improvements in bone physiology, structure, 
and function would be expected (Imel et al. 2015).  
Repeated doses of KRN23 up to 1.0 mg/kg were well tolerated by adult XLH subjects 
throughout the Phase 1/2 dose escalation study and associated treatment extension study 

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(Imel et al. 2015). No deaths or life threatening treatment emergent adverse events (AEs) 
have been reported. In the extension study, serious adverse events (SAEs) reported for 
3 subjects were unlikely to be or were not study drug related: breast cancer, hypertensive 
crisis, and cervical spinal stenosis. Throughout the long-term extension study, 
treatment-related AEs were reported for 14 subjects (63.6%) treated with KRN23 and 
included injection site reaction (5 subjects, 22.7%), arthralgia (3 subjects, 13.6%), restless 
legs syndrome (2 subjects, 9.1%), and injection site pain (2 subjects, 9.1%). No discernible 
clinically significant trends of lab abnormalities suggestive of a treatment-related adverse 
effect were noted. Overall, no immunogenicity or patterns of dose-limiting toxicity have been 
associated with KRN23 treatment. 
Similar to the adult studies, interim analyses from the Phase 2 pediatric study 
(UX023-CL201) showed KRN23 treatment up to 2 mg/kg Q2W or Q4W increased serum 
phosphorus levels, TmP/GFR, and 1,25(OH)2D levels. Interim results also show KRN23 
improved rickets, with a mean reduction in rickets severity score (RSS) from Baseline to 
Week 40. Consistency in the rickets results was observed using the Radiographic Global 
Impression of Change (RGI-C) scoring method. Overall, the dose-response and 
pharmacodynamic (PD) results observed in the pediatric study were consistent with the adult 
XLH data generated to date. None of the subjects had serum phosphorus levels above the 
normal range in either dosing group. Most treatment-related AEs were mild, most commonly 
a transient injection site reaction (39%). One child experienced a serious AE and was 
hospitalized for fever/muscle pain that improved and continues in the trial. No clinically 
meaningful changes occurred in serum or urine calcium, serum iPTH, or renal ultrasound.  
5.3 
Summary of Overall Risks and Potential Benefits 
KRN23, a fully human mAb that binds and inhibits FGF23, is being developed as a potential 
therapeutic candidate for XLH, a rare genetic disorder characterized by chronic 
hypophosphatemia resulting from excess FGF23. By blocking the activity of FGF23, KRN23 
can restore phosphate, vitamin D, and bone metabolism homeostasis, and has the potential to 
improve the lives of children with this disorder by correcting or minimizing rickets, 
radiographic abnormalities, and skeletal deformities, and by promoting maximal growth 
potential while preventing the lifelong bone- and joint-related complications of rickets. 
This therapeutic approach directly targets the inherent dysregulation in XLH (i.e., excess 
FGF23). In contrast, supplementation therapy with phosphate and/or 1,25(OH)2D, is only 
partially effective and carries a significant burden and risk of ectopic mineralization, 
particularly nephrocalcinosis. 
Clinical studies to date have demonstrated that KRN23 treatment blocks FGF23 action and 
leads to a sustained increase in serum phosphorus levels due to increased TmP/GFR. 
Increased 1,25(OH)2D was also observed, as expected, based on the inhibition of the excess 
of FGF23. Bone formation and resorption markers also increased. Preliminary data in 
children with XLH suggest that KRN23 treatment may also improve rickets. No major safety 
concerns were observed with KRN23 in the population studied; there was no evidence of 
immunogenicity, and no evidence of left ventricular hypertrophy (LVH) based on 

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electrocardiogram (ECG) even though FGF23 levels were increased following KRN23 
treatment. Although ectopic mineralization is a known risk related to XLH disease and is 
exacerbated by oral phosphate and/or active vitamin D supplementation, KRN23 does not 
appear to be associated with progression of cardiac or renal ectopic mineralization beyond 
the natural course of pre-existing disease. 
KRN23 administered SC Q2W or Q4W at doses up to 2 mg/kg achieved the desired PD 
effect in children and evidence of a clinical effect in healing rickets, positioning KRN23 as a 
drug that could be administered twice per month by SC injection, which is a convenient and 
acceptable therapeutic regimen for a chronic condition.  
In conclusion, KRN23 inhibits the effects of FGF23, restoring phosphate, vitamin D, and 
bone metabolism homeostasis. In children with XLH, preliminary data suggest that KRN23 
treatment may improve rickets. By targeting excess FGF23 and increasing serum phosphorus 
levels, it is expected that rickets severity in children with XLH will be healed or reduced, 
leading to improved clinical outcomes and quality of life of children with XLH. To date, 
KRN23 has a favorable safety profile without evidence of increased ectopic mineralization or 
other concerns associated with the excess of FGF23. KRN23 has the potential to be an 
effective and safe treatment option for patients with XLH. 
5.4 
Study Rationale 
XLH is a disorder of hypophosphatemia, renal phosphate wasting, defective bone 
mineralization, and impaired growth plate or endochondral ossification caused by 
inactivating mutations in the PHEX gene (phosphate-regulating gene with homologies to 
endopeptidases on the X chromosome), and is the most common form of heritable rickets. 
In the absence of functional PHEX, release of FGF23 by osteocytes is greatly increased. 
Excess circulating FGF23 impairs conservation of phosphate by down-regulating NaPi-IIa 
and NaPi-IIc in the tubular cells and suppresses 1,25(OH)2D production, resulting in 
decreased intestinal absorption of calcium and phosphate. Chronic low serum phosphorus 
levels lead to rickets in children and osteomalacia in adults, the two major pathologic 
outcomes of the hypophosphatemia. Rickets is a disorder of open growth plates characterized 
by both defective bone mineralization and defective endochondral ossification, leading to 
reduced growth and skeletal deformities. Osteomalacia is characterized by a lack of proper 
mineralization, a prolonged mineralization process, and an accumulation of osteoid tissue 
with a consequent deterioration of bone remodeling (Shore et al. 2013). 
There is no available medicine that specifically treats the underlying pathophysiology of 
elevated FGF23-induced hypophosphatemia in XLH. The current therapy for pediatric XLH 
patients consists of multiple daily doses of oral phosphate often combined with doses of 
active vitamin D analogs. Dosing is individualized and depends on tolerability of the 
phosphate dose and the age, size, and growth of the child. The goal of therapy with 
phosphate and vitamin D is to sufficiently supplement the body’s pool of phosphate to allow 
mineralization of bone and improve skeletal outcomes; however, because supplementation 
therapy does not address the mechanism of urinary phosphate wasting, increasing phosphate 
through supplementation also increases renal phosphate throughput and urinary phosphate 

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concentrations, thus raising the risk of nephrocalcinosis. More therapeutic options that are 
efficacious, safe, and convenient, and that target the underlying pathophysiology of XLH 
(i.e., renal phosphate wasting induced by high FGF23 levels), are needed.  
KRN23 is a recombinant human IgG1 mAb that binds to and inhibits the activity of FGF23. 
Phase 1 and Phase 2 studies in adults and children (aged 5-12 years) with XLH have shown 
that KRN23 treatment increases serum phosphorus and 1,25(OH)2D levels and TmP/GFR. 
Interim Phase 2 data in children with XLH suggest KRN23 treatment also improves rickets 
severity with a favorable safety profile. 
Early treatment of children with XLH is associated with better growth and skeletal and 
outcomes. In retrospective studies, children beginning treatment before age 1 had 
consistently higher z scores and lower ALP levels than children starting treatment later 
(Makitie et al. 2003), (Quinlan et al. 2012) suggesting that growth deficits accumulated 
before treatment may lead to permanent height loss. The current study will provide 
information about the safety profile, dosing, and effect of KRN23 on phosphate metabolism 
in children 1 to 4 years of age, inclusive. In addition, this study will evaluate whether 
biweekly dosing of KRN23 improves rickets, growth, and lower extremity deformity in 
young children with XLH. 

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6 STUDY OBJECTIVES 
The primary objectives of the study are to: 
• Establish the safety profile of KRN23 for the treatment of XLH in children between 
1 and 4 years old  
• Determine the PD effects of KRN23 treatment on serum phosphorus and other PD 
markers that reflect the status of phosphate homeostasis in children between 1 and 4 years 
old with XLH 
Additional study objectives are to assess the following in children between 1 and 4 years old 
with XLH: 
• Effects of KRN23 on rickets 
• Effects of KRN23 on growth and lower extremity deformity  
• KRN23 drug concentration levels (PK) 
 

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7 INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan 
UX023-CL205 is a multicenter, open-label, Phase 2 study in children from 1 to 4 years old 
with XLH who are naïve to therapy or have previously received standard therapy with oral 
phosphate and active vitamin D to assess the safety, PD, and efficacy of KRN23 
administered via SC injections Q2W for a 64-week Treatment Period. Subjects may continue 
to receive KRN23 for an additional 96 weeks during the Extension Period. 
The study will enroll approximately 10 pediatric subjects between 1 and 4 years old, 
inclusive, with clinical findings consistent with  XLH including hypophosphatemia and 
radiographic evidence of rickets (at least 5 subjects will have a rickets severity score (RSS) at 
the knee of ≥1.5 points at Screening), and a confirmed PHEX mutation or variant of 
uncertain significance. To maintain a level of gender balance, no more than 70% of subjects 
of either gender will be enrolled. Those subjects who are receiving oral phosphate and active 
vitamin D therapy will discontinue treatment during Screening (after confirmation of PHEX 
mutation and rickets eligibility criteria) and for the duration of the study. Safety, PD, PK, and 
efficacy measures (rickets, growth, lower extremity deformity) will be evaluated throughout 
the study. 
All subjects will receive KRN23 at a starting dose of 0.8 mg/kg Q2W. The dose may be 
increased to 1.2 mg/kg at any time during the study if a subject meets the following 
dose-adjustment criteria: 1) two consecutive serum phosphorus measurements are below the 
normal range; 2) serum phosphorus has increased by < 0.5 mg/dL from baseline; and 3) the 
subject has not missed a dose of study drug that would account for the decrease in serum 
phosphorus.  
At any time during the study, if serum phosphorus increases above the ULN for age, the 
subsequent dose(s) will be withheld and the site will contact the medical monitor before 
dosing resumes. Once other causes of increased serum phosphorus are excluded, KRN23 
treatment will resume at half the total dose of the last dose received. Serum phosphorus will 
be followed through unscheduled serum phosphorus assessments. A subject will resume 
dosing at the previous full total dose level if they meet the same dose-adjustment criteria 
listed above.  
The study will be conducted in a pediatric population; as such, additional measures including 
a DMC have been incorporated into the study design. Where possible, measures to minimize 
pain and distress to the subject have been considered for this study protocol including the use 
of home health visits. Where possible, timing of blood draws for efficacy assessments has 
been coordinated with standard safety laboratory tests to minimize risk and discomfort and 
avoid unnecessary duplication of testing. The primary analysis is planned at Week 40. 
Additional efficacy and safety analyses will be conducted at Week 64. A final analysis will 
be conducted at the end of the study (“study completion”), which is defined as the date of the 
last protocol-specified visit/assessment (including telephone contact) for the last subject in 

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the study. As this is an open-label study, analyses may also be performed at additional time 
points.  
7.2 
Discussion of Study Design, Including Choice of Control Group 
This Phase 2 study is designed as an open-label clinical trial intended to provide information 
about the safety profile, dose-response, and effect of KRN23 on phosphate metabolism in 
children 1 to 4 years of age, inclusive, with XLH. In addition, this study will evaluate 
whether Q2W dosing of KRN23 improves rickets, growth, and lower extremity deformity in 
young children with XLH. No control group will be included. To demonstrate safety and 
efficacy in a controlled study, a larger randomized, Phase 3 study in children with a broader 
age range is being planned that will include two treatment arms: one group will receive 
KRN23 and one group will receive oral phosphate/active vitamin D therapy.  
7.3 
Selection of Study Population 
The study will enroll approximately 10 pediatric subjects between 1 and 4 years old with 
XLH who are naïve to therapy or have previously received standard therapy with oral 
phosphate and active vitamin D. To maintain a level of gender balance, no more than 70% 
of subjects of either gender will be enrolled.  
To ensure that appropriate subjects are selected, eligibility requirements include 
demonstrated hypophosphatemia, radiographic evidence of rickets (at least 5 subjects will 
have a minimum RSS score of 1.5 points at the knee), and genetic evidence consistent with a 
diagnosis of XLH. PHEX sequence variants will be classified according to the joint 
consensus recommendations of the American College of Medical Genetics and Genomics 
and the Association for Molecular Pathology (Richards et al. 2015). Patients with PHEX 
mutations classified as pathogenic, likely pathogenic, and possibly pathogenic will be 
included. Patients with PHEX variants of uncertain significance will also be included, as was 
recommended by experts in pediatric XLH. There are hundreds of variants of the PHEX gene 
and many of these have not yet been fully characterized.  
Children with XLH undergo a normal pubertal growth spurt. Post-pubertal height is predicted 
by pre-pubertal height, indicating that loss of height potential generally occurs prior to 
puberty. Several studies suggest that early height loss cannot be recovered and that earlier 
treatment leads to better growth outcomes (Makitie et al. 2003), (Quinlan et al. 2012). 
Thus, initiation of therapy at early ages is recommended to achieve improved height 
outcomes (Carpenter et al. 2011).  Interim data from an ongoing study in children aged 5-12 
years has shown KRN23 treatment at doses up to 2 mg/kg Q2W increases serum phosphorus 
and improves rickets severity. The present study will enroll children 1 to 4 years old to 
determine if the PK and PD profile of KRN23 is similar in younger children who may obtain 
maximum benefit from treatment. The study will also provide preliminary evidence of 
efficacy in healing rickets in younger children.  
The Sponsor has taken reasonable measures to ensure the protection and safety of this 
population. The blood volumes drawn and radiation exposure are within the required limits 

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for subjects under 5 years of age. Appropriate pediatric expertise will be available at all trial 
sites, and site personnel will be focused on minimizing risk, fear, pain, and distress during 
conduct of the study. 
7.3.1 
Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
1) Male or female, aged ≥1 year and < 5 years: 
2) PHEX mutation or variant of uncertain significance in either the patient or a directly 
related family member with appropriate X-linked inheritance 
3) Biochemical findings associated with XLH including:  
- Serum phosphorus < 3.0 mg/dL (0.97 mmol/L)* 
- Serum creatinine within age-adjusted normal range* 
4) Radiographic evidence of rickets; at least 5 subjects will be required to have a RSS at 
the knee of at least 1.5 points as determined by central read    
5) Willing to provide access to prior medical records for the collection of historical 
growth, biochemical, and radiographic data and disease history  
6) Provide written informed consent by a legally authorized representative after the 
nature of the study has been explained, and prior to any research-related procedures  
7) Must, in the opinion of the investigator, be willing and able to complete all aspects of 
the study, adhere to the study visit schedule and comply with the assessments  
* Criteria to be determined based on fasting (min. 4 hours) values collected Baseline 
7.3.2 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1) Unwilling to stop treatment with oral phosphate and/or pharmacologic vitamin D 
metabolite or analog (e.g., calcitriol, alfacalcidol) during the screening period and for 
the duration of the study 
2) Presence of nephrocalcinosis on renal ultrasound grade 4 based on the following 
scale: 
0 = Normal 
1 = Faint hyperechogenic rim around the medullary pyramids 
2 = More intense echogenic rim with echoes faintly filling the entire pyramid 
3 = Uniformly intense echoes throughout the pyramid 
4 = Stone formation: solitary focus of echoes at the tip of the pyramid 

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3) Planned or recommended orthopedic surgery, including staples, 8-plates or 
osteotomy, within the clinical trial period 
4) Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the 
age-adjusted normal limits* 
5) Presence or history of any condition that, in the view of the investigator, places the 
subject at high risk of poor treatment compliance or of not completing the study.   
6) Presence of a concurrent disease or condition that would interfere with study 
participation or affect safety  
7) History of recurrent infection or predisposition to infection, or of known 
immunodeficiency 
8) Use of any investigational product or investigational medical device within 30 days 
prior to screening, or requirement for any investigational agent prior to completion of 
all scheduled study assessments  
* Criteria to be determined based on fasting (min. 4 hours) values collected at Baseline 
7.3.3 
Removal of Subjects from Therapy or Assessment 
In accordance with the Declaration of Helsinki, subjects have the right to withdraw from the 
study at any time for any reason. The Investigator and Ultragenyx also have the right to 
remove subjects from the study. Ultragenyx must be notified of all subject withdrawals as 
soon as possible. Ultragenyx also reserves the right to discontinue the study at any time for 
either clinical or administrative reasons and to discontinue participation of an individual 
subject or investigator due to poor enrollment or noncompliance, as applicable. 
Subjects may be removed from the study for the following reasons: 
• Occurrence of an unacceptable AE 
• An illness that, in the judgment of the investigator or Ultragenyx, might place the subject 
at risk or invalidate the study  
• At the request of the subject, investigator, or Ultragenyx, for administrative or other 
reasons 
• Protocol deviation or noncompliance 
During the Extension Period, orthopedic surgery will be permitted if recommended by the 
investigator or consulting physician. Subjects who develop secondary or tertiary 
hyperparathyroidism may also remain on study; however, use of medication to suppress PTH 
(e.g. Sensipar®, cinacalcet, calcimimetics) is not permitted at any time during the study 
(Section 7.4.5.1). Subjects should be removed from study if treatment for 
hyperparathyroidism becomes medically necessary. 
If the reason for removal of a subject from the study is an AE, the AE and any related test or 
procedure results will be recorded in the source documents and transcribed onto the Case 

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Report Form (CRF). Each clinically significant abnormal laboratory value or other clinically 
meaningful abnormality should be followed until the abnormality resolves or until a decision 
is made that it is not likely to resolve. If such abnormalities do not return to normal within 
12 weeks after the last dose given, their etiology should be identified and Ultragenyx should 
be notified. All unscheduled tests must be reported to Ultragenyx immediately. 
If a subject discontinues from the study prematurely, every reasonable effort should be made 
to perform the Early Termination Visit procedures within four weeks of discontinuation, and 
to complete the protocol-specified Safety Follow-up, as applicable. 
7.3.3.1 
Stopping Rules 
A Data Monitoring Committee (DMC) will be established for Study UX023-CL205 and will 
act in an advisory capacity to monitor the safety of KRN23 on a routine basis through 
Week 64 (Section 7.6.4). The DMC may provide advice to Ultragenyx to aid in the 
determination of whether study enrollment should be paused or if the study should be 
stopped. If the Sponsor deems it appropriate to restart the trial following an internal safety 
review, this will be done only following approval by Regulatory Authorities. During the 
Extension Period, safety data will be reviewed by the Ultragenyx Study Safety Review Team 
(SSRT) on an ongoing basis. 
Individual subjects who experience any unexpected and possibly, probably, or definitely 
drug-related SAEs (Section 8.5.3) that represent a change in the nature or an increase in 
frequency of the serious event from their prior medical history will be assessed as to whether 
the subject will continue on the study.  
Individual subjects will be monitored for ectopic mineralization by renal ultrasound 
(Section 7.5.5.5). If new or clinically significant worsening in mineralization is considered 
clinically meaningful by the investigator and/or sponsor and related to study drug, the subject 
will be discontinued from the study. 
Regulatory Authorities, as well as the Institutional Review Board (IRB)/Ethics Committee 
(EC) will be informed should unexpected and possibly, probably, or definitely drug-related 
SAEs occur. A full clinical evaluation of the event will be performed in order to make a 
decision regarding what actions to take, including whether to recommend stopping the study. 
Regulatory Authorities, as well as IRBs/ECs, will be informed if the study is paused or 
stopped. 
7.4 
Treatment 
The study drug is manufactured, packaged, and labeled according to Good Manufacturing 
Practice (GMP) regulations. The study drug should be securely stored under conditions 
indicated in the IB. 

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The amount of drug administered will be calculated based on a subject’s weight 
(Section 7.4.4). All subjects will receive KRN23 at a Q2W dosing regimen. Selection of 
doses and dose adjustments are described in Section 7.4.4. 
7.4.1 
Investigational Product 
KRN23 is a sterile, clear, colorless, and preservative-free solution supplied in single-use 
5-mL vials containing 1 mL of KRN23 at a concentration of 10 mg/mL or 30 mg/mL. 
KRN23 will be administered without dilution based on body weight (Section 7.4.4).  
Subjects will receive study drug via SC injection to the abdomen, upper arms, or thighs; the 
injection site will be rotated with each injection. After proper training by study personnel in 
SC injection technique, a parent or caregiver may administer KRN23 to the subject between 
site visits. Parents or caregivers will be instructed to follow the directions provided in the 
Instructions for Use. The parent or caregiver must have demonstrated competency in 
administration of SC injections, including study drug preparation, administration, and 
disposal, and this competency be documented, before unsupervised home administration will 
be permitted. Thereafter, study drug may be administered by a parent or caregiver at home, 
except for study weeks that correspond to a site visit when parent/caregiver administration is 
optional. Study personnel should periodically observe parent/caregiver administration of 
study drug to ensure they are using proper technique. For subjects whose parent/caregiver is 
unable to administer study drug, study drug will be administered at the study site or at home 
health visits for the remainder of the study. 
7.4.2 
Reference Therapy 
This is a single-arm, open label study. All subjects will receive KRN23. No placebo or 
reference therapy will be administered. 
7.4.3 
Method of Assigning Subjects to Treatment Groups 
Eligible subjects will be enrolled in the study and sequentially assigned an identification 
number. All subjects will receive active treatment with KRN23.  
7.4.4 
Selection of Doses  
The KRN23 dose planned for this study: 0.8 or 1.2 mg/kg Q2W is based on Week 40 data 
from an ongoing Phase 2 clinical study (UX023-CL201) that included 18 subjects 
(ages 5-12) receiving KRN23 at Q2W dosing and by PK/PD modeling extrapolated to 
patients aged 1-5 years. 
KRN23, administered Q2W at approximately 0.8 mg/kg for 40 weeks, increased serum 
phosphorus by an average of 0.7 mg/dL; increases of > 0.5 mg/dL were seen in 83.3% of 
subjects. No subjects experienced hyperphosphatemia even at upper doses of 1.3 mg/kg 
Q2W, providing a wide margin for safety. Serum 1,25(OH)2D concentrations and TmP/GFR 
levels also increased, demonstrating overall improved phosphorus homeostasis. The 

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increases in serum phosphorus and 1,25(OH)2D were sufficient to provide substantial healing 
of rickets (as assessed by RGI-C) in 8 of 9 subjects (88.9%) with more severe rickets (total 
RSS ≥ 1.5). 
Similar increases in serum phosphorus were extrapolated for younger patients (ages 1 to 
5 years) as estimated by PK/PD modeling. In simulations of a KRN23 starting dose of 
0.8 mg/kg, median minimum serum phosphorus changes from baseline are predicted to be 
0.830 mg/dL in patients aged 1 to 5 years. In simulations of a KRN23 escalated dose of 
1.2 mg/kg, median minimum serum phosphorus changes from baseline are predicted 
0.873 mg/dL in patients aged 1 to 5 years. Up to 95% of patients aged 1 to 5 years are 
expected to achieve an improvement of at least 0.5 mg/dL in serum phosphorus at the 
proposed dose. As was seen in Study UX023-CL201, these serum phosphorus increases are 
expected to be sufficient to improve bone disease in most pediatric patients administered 
KRN23 at the proposed dose and regimen. 
Thus, all subjects will receive KRN23 at a starting dose of 0.8 mg/kg. The dose may be 
increased to 1.2 mg/kg at any time if a subject meets the following dose adjustment criteria: 
1) two consecutive serum phosphorus measurements are below the normal range; 2) serum 
phosphorus has increased by < 0.5 mg/dL from baseline; and 3) the subject has not missed a 
dose of study drug that would account for the decrease in serum phosphorus.  
At any time during the study, if serum phosphorus increases above the ULN for age, the 
subsequent dose(s) will be withheld and the site will contact the medical monitor before 
dosing resumes. Once other causes of increased serum phosphorus are excluded, KRN23 
treatment will resume at half the total dose of the last dose received. Serum phosphorus will 
be followed through unscheduled serum phosphorus assessments. A subject will resume 
dosing at the previous full total dose level if they meet the same dose-adjustment criteria 
listed above.  
Dose adjustments may also be made based on the weight of the subject (Section 7.5.5.3). 
Any dose changes needed during the Extension Period will be implemented at clinic visits. 
7.4.5 
Prior and Concomitant Therapy 
Throughout the study, there should be no significant changes to a subject’s diet or medication 
schedule unless medically indicated. Investigators may prescribe any concomitant 
medications or treatments deemed necessary to provide adequate supportive care, except 
those listed in Section 7.4.5.1. All concomitant medications taken during the study will be 
recorded in the CRF with indication, dose information, and dates of administration. 
Any changes to concomitant medication will also be documented. 
7.4.5.1 
Prohibited Medications 
Medications that are known to affect bone or calcium and phosphorus metabolism will be 
prohibited during the study. Thus, to be eligible for the study, subjects must agree to 

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discontinue and/or not to use certain medications prior to randomization and for the duration 
of the study.  
• Pharmacologic vitamin D metabolites or analogs (e.g., calcitriol, alfacalcidol) (7-day 
washout required)  
• Oral phosphate (7-day washout required)  
• Adjunctive growth hormone  
• Aluminum hydroxide antacids (e.g., Maalox® and Mylanta®) or thiazide  
• Bisphosphonate therapy  
• Chronic use of systemic corticosteroids (short courses acceptable if indicated)  
• Parathyroid hormone suppressors (e.g. Sensipar®, cinacalcet, calcimimetics)  
• Any mAb therapy (other than study drug)  
NOTE: Oral phosphate treatment must be down-titrated slowly to avoid hypercalciuria. 
Vitamin D metabolites or analogs may be discontinued without titration. 
7.4.5.2 
Permitted Medications 
Other than the medications specifically prohibited in this protocol, subjects may receive 
concomitant medications as required. If serum 25-hydroxyvitamin D (25(OH)D) levels fall 
below 20 ng/mL, oral supplementation with non-active vitamin D formulations may be 
provided. Medications (investigational, prescription, over-the-counter, and herbal) and 
nutritional supplements taken during the 30 days prior to Screening visit will be reviewed 
and recorded. 
7.4.6 
Treatment Compliance 
Each administration of study drug will be recorded on the CRF. Parents or caregivers 
administering study drug will be instructed to follow the directions provided in the 
Instructions for Use. If a parent/caregiver is administering study drug, confirmation of dosing 
will be communicated to the study site during scheduled biweekly telephone visits; site 
personnel will record the related information about each administration of study drug on the 
CRF. If the parent or caregiver fails proper administration at any time, the investigator has 
discretion, in consultation with the Sponsor, to have the subject return to the site for 
subsequent study drug administration or reinstate home health visits for home administration.  
Empty vials will be returned to the study site for drug accountability records. 
If a subject does not receive a dose within 10 days of a scheduled dose, that dose should be 
skipped and the next dose will be administered at the next scheduled dosing visit. 

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7.5 
Study Procedures and Assessments 
7.5.1 
Schedule of Events 
The schedules of visits and assessments are provided in Table 2.1, Table 2.2, and Table 2.3. 
Home health visits may also be conducted at the investigational site depending on the 
preference of the subject and proximity of the subject to the clinic. Telephone visits may 
replace home health visits during the Extension Period for subjects whose parent or caregiver 
has been trained to administer study drug. Refer to the Study Reference Manual for 
additional details and a recommended schedule of specific assessments.  
Potential subjects will come in to the site for an initial screening visit and provide informed 
consent. All subjects will have bilateral knee x-rays obtained locally at the Screening Visit. 
Screening knee x-rays will be evaluated by central read to determine if the subject meets the 
eligibility criteria. Blood for PHEX mutation analysis will be collected for all subjects at the 
Screening Visit.  
Potential subjects with a previously identified PHEX mutation or variant of uncertain 
significance in either self or a family member with appropriate X-linked inheritance and 
confirmed rickets severity eligibility by central read (required for at least 5 subjects) may 
proceed to Baseline without waiting for the PHEX mutation analysis result. Potential subjects 
without a previously identified PHEX mutation will be notified of PHEX mutation results, 
and if presence of a mutation is confirmed, will have the baseline visit scheduled.   
Subjects who successfully pass the requirements at the Screening Visit will discontinue oral 
phosphate for a minimum of 7 days and active vitamin D therapy for a minimum of 7 days 
prior to the Baseline visit. The remaining screening assessments to confirm eligibility will be 
performed. At Screening/Baseline, renal ultrasound, ECG, and x-rays may be performed 
± 3 days of the clinic visit to accommodate scheduling availability. All Screening/Baseline 
assessments and inclusion/exclusion criteria must be satisfied prior to dosing. 
Clinic visits will occur at approximately 4-week intervals (± 3 days) for the first 24 weeks of 
the study. Thereafter, clinic visits will occur every 8 weeks (± 3 days) for the remainder of 
the Treatment Period.  During the Treatment Period, subjects may be monitored and dosed 
between site visits through a series of home health visits depending on the preference of the 
subject and the proximity of the subject to the site. The visit window for home health visits is 
± 3 days.   
During the Extension Period, clinic visits will occur at approximately 12-week intervals 
(±5 days). Biweekly home health visits or telephone visits will be conducted (±5 days) for 
administration of or to confirm administration of study drug, and for collection of AEs and 
concomitant medication information. 
For subjects who discontinue prior to completing the study, every reasonable effort should be 
made to perform the Early Termination visit procedures within 4 weeks of discontinuation. 
X-rays of the wrists and knees will not be performed at the Early Termination visit if 

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post-treatment x-rays have been performed within 3 months (hands/wrists and knees) or 
6 months (standing long legs) of Early Termination.  
A follow-up safety telephone call will take place 5 weeks (+ 5 days) after the Week 160 visit 
to determine if the subject is receiving KRN23 therapy under commercial use or another 
mechanism and to collect information on any ongoing or new AEs, SAEs, and concomitant 
medications. An additional safety visit will take place 10 weeks ± 5 days (approximately 
5 times the elimination half-life) after the ET visit for those subjects who discontinue 
treatment before the Week 160 visit, or for those subjects who complete the Week 160 visit 
and do not continue on KRN23 through commercial use or another mechanism. This safety 
visit will not occur for subjects who complete the Week 160 visit and are documented to be 
continuing on KRN23 on commercial use or through another mechanism.  
7.5.2 
Pharmacodynamic Assessments 
KRN23 binds to and inhibits FGF23, which is an important regulator of serum phosphorus 
levels. Serum phosphorus levels will be measured as a key PD assessment in this study. 
Serum 1,25(OH)2D, urinary phosphorus, and serum levels of ALP will also be assessed to 
determine the PD profile of KRN23 in children 1-4 years old.  
7.5.2.1 
Serum Phosphorus  
Serum samples will be obtained following a minimum fasting time of 4 hours and prior to 
study drug administration (if applicable). Samples should be obtained in the morning at 
approximately the same time for each visit due to known fluctuations in serum phosphorous 
levels associated with circadian rhythm. The time of sample collection and the duration of 
fasting will be noted on the CRF. Subjects who live more than 45 minutes from the site may 
stay overnight on the night before the site visit to facilitate fasting sample collection. 
Serum phosphorus levels will be assessed by the local lab at Baseline for eligibility; a second 
sample will be sent to the central laboratory for the Baseline measure. Serum phosphorus 
levels will also be determined by central laboratory at Weeks 1, 4, 8, 12, 15, 20, 32, 40, 48, 
56, 64, and every 12 weeks thereafter through Week 160 (or Early Termination) and at the 
Safety Visit (if applicable). Where possible, the blood sample obtained for serum phosphorus 
will be assessed as part of the standard clinical laboratory safety tests (Section 7.5.5.7) to 
reduce the number and volume of blood draws. Refer to the Study Reference Manual for 
additional details on serum phosphorus measurements. 
7.5.2.2 
Additional Pharmacodynamic Markers 
To demonstrate the positive impact of KRN23 on bone metabolism and phosphate 
homeostasis, additional PD markers will be assessed, including serum 1,25(OH)2D and 
urinary phosphorus. These measures will directly reflect the mechanism by which KRN23 
restores phosphorus homeostasis by inhibiting excess FGF23.  

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Fasting spot urine will be used for measurements of urinary phosphorus, creatinine, and 
calcium. Spot urine collection will be performed pre-treatment at Baseline and at Weeks 4, 
12, 15, 20, 32, 40, 48, 56, and 64, 112, 160/ Early Termination and at the Safety Visit (if 
applicable) as indicated in the Schedules of Events (Table 2.1, Table 2.2 and Table 2.3). 
Urine samples will be sent to the central lab for analysis. The duration of fasting time for all 
PD parameters will be recorded on the CRF. 
7.5.2.3 
Serum Alkaline Phosphatase 
Children with XLH have low bone turnover as a result of chronic hypophosphatemia. Serum 
levels of alkaline phosphatase will be measured at Baseline and at Weeks 20, 40, 64, 112, 
and 160/ Early Termination visits as indicated in the Schedules of Events (Table 2.1, 
Table 2.2, and Table 2.3). 
7.5.3 
Clinical Efficacy Measures 
The goal of therapy in children with XLH is to correct or minimize rickets, radiographic 
abnormalities, and skeletal deformities, and to promote maximal growth potential. 
The clinical efficacy measures to be evaluated in this study will seek to determine the ability 
of KRN23 treatment to achieve these goals. 
7.5.3.1 
Radiographs 
Bilateral anteroposterior (AP) knee radiographs will be taken at the Screening Visit to 
confirm eligibility and at the Week 40, Week 64, Week 112, and Week 160 (or Early 
Termination) visits. Screening knee radiographs will be read centrally; an RSS score of at 
least 1.5 points at the knee is required for eligibility in at least 5 subjects. Bilateral 
posteroanterior (PA) hand/wrist radiographs will be taken at Baseline and at the Week 40, 64, 
112, and 160 (or Early Termination, if applicable) study visits. Standing long-leg radiographs 
will be taken at Baseline, Week 40, 64, 112, and 160 (or Early Termination, if applicable). 
Knee and hand/wrist radiographs will be taken at Early Termination if post-baseline 
radiographs have not been obtained within 3 months of termination.  Standing long leg 
radiographs will be taken at Early Termination if post-baseline radiographs have not been 
obtained within 6 months of termination. Radiographs will be read centrally and will be 
interpreted. Changes in the severity of rickets and epiphyseal (growth plate) abnormalities 
will be assessed by central readings using two methods, a disease-specific qualitative 
Radiograph Global Impression of Change (RGI-C) scoring system and the RSS method.  
A disease-specific qualitative RGI-C scoring system will be used. Pairs of wrist, knee and 
standing long leg images from treated subjects will be presented to a rater with the 
Screening/Baseline image on the left and the later image (Week 40 or 64, or Early 
Termination) on the right. Raters will be asked to assess change in rickets severity in the 
wrists and knees and extent of bowing in the legs using a 7-point ordinal RGI-C scale score 
ranging from -3 (very much worse, or severe worsening of rickets) to +3 (very much better, 
or complete or near complete healing of rickets). Ratings will be performed by 3 independent 
pediatric radiologists. X-ray pairs will be presented for review in random order and the 

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radiologists will not be provided access to the protocol, subject identifiers, or information 
related to KRN23 treatment. 
The RSS system is a 10-point radiographic scoring method that was developed to assess the 
severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal 
fraying and cupping and the proportion of the growth plate affected (Thacher et al. 2000). 
With the RSS method, each radiograph is scored individually by a central rater who is 
blinded to subject number and radiograph sequence. 
7.5.3.2 
Growth 
Short stature is one of the predominant features in growing children with XLH. Growth of 
the legs and trunk has been shown to be uncoupled in XLH and related to serum phosphate 
levels (Zivicnjak et al. 2011). Growth will be measured by changes in standing height or 
recumbent length (and percentiles) prior to and following treatment. Recumbent length will 
be measured in subjects <2 years old or those unable or unwilling to stand for the 
measurement. Standing height/recumbent length measurements prior to treatment will be 
abstracted from medical records where available. To assess growth during KRN23 treatment, 
recumbent length/standing height will be measured by a clinical evaluator at Baseline and 
Weeks 12, 24, 40 and 64, at 24-week intervals during the Extension Period, and at the 
Week 160 (or Early Termination) visits. Historical growth records may be used to evaluate 
change in growth velocity.  
7.5.4 
Pharmacokinetic Assessment 
To assess KRN23 concentration and allow evaluation of the PK/PD relationship in children 
aged 1-4 years, serum KRN23 levels will be evaluated as a PK parameter in this study. 
A blood sample will be obtained prior to dosing (if applicable) at Weeks 1, 4, 12 and 40, 64, 
and at the Week 160 (or Early Termination) visit. For each sample collection, the time 
elapsed since last study drug administration will be determined.  
7.5.5 
Safety Measurements 
Safety will be evaluated by the incidence, frequency, and severity of AEs and SAEs, 
including clinically significant changes from baseline to scheduled time points in vital signs, 
weight, and physical examination, GFR, clinical laboratory evaluations (including additional 
KRN23/XLH biochemical parameters of interest such as serum calcium, intact parathyroid 
hormone (iPTH), 25-hydroxyvitamin D (25(OH)2D), amylase, lipase, and creatinine; and 
urinary calcium and creatinine), concomitant medications, and ECG. Ectopic mineralization 
safety assessments include renal ultrasound. The development of anti-KRN23 antibodies and 
dose limiting toxicities (DLTs) will also be assessed.  
7.5.5.1 
Medical History 
General medical information includes subject demographics (date of birth, ethnicity, and sex) 
and a history of major medical illnesses, diagnoses, and surgeries. The height of both parents 

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will also be recorded. The review will also include an assessment of symptoms and 
conditions associated with XLH and SOC (e.g., oral phosphate/active vitamin D) treatment. 
Subjects must be willing to provide access to prior medical records for the collection of 
biochemical and radiographic data, as well as disease history. The specific diagnosis of XLH 
will be recorded, along with date of onset, clinical presentation, and date and method of 
diagnosis. Any available family history of XLH will be noted, including any available 
previous PHEX mutation analysis results for the subject or relevant family members with 
appropriate X-linked inheritance pattern.  
XLH treatment history and relevant concomitant medications will be recorded (start date, 
stop date, dose, dose regimen). Previous treatments may include calcitriol and oral phosphate 
and/or other adjunctive therapy. Medications include investigational, prescription, 
over-the-counter, herbal and nutritional supplements. Any relevant concomitant therapy, 
including physical/occupational therapy will be recorded. Use of pain medications will also 
be recorded. Refer to Section 7.4.5.1 for prohibited medications during the study. 
7.5.5.2 
Vital Signs 
Vital sign measurements will be obtained as indicated in the Schedules of Events (Table 2.1, 
Table 2.2, and Table 2.3). Vital signs will include seated systolic blood pressure and diastolic 
blood pressure measured in millimeters of mercury (mm Hg), heart rate in beats per minute, 
respiration rate in breaths per minute, and temperature in degrees Celsius (°C). Blood 
pressure measurements will be obtained only in children aged 3 years or above at study entry 
or beginning when a subject turns 3 years of age and will only be obtained at clinic visits. 
Vital signs measured at home health visits will include heart rate in beats per minute and 
temperature (°C).  
US Department of Health and Human Services guidelines for Blood Pressure Measurement 
in Children will be used as a reference for BP measurement (NHLBI 2005).  
Subjects will be instructed to refrain from exercise for at least 30 minutes before and until 
completion of BP measurements. They will also be instructed to refrain from playing video 
games, or other activities that may affect BP until all measurements are obtained. At each 
study visit, before BP determination, arm circumference is measured (in centimeters) with a 
plastic measuring tape at the midpoint of the upper arm between the acromium (tip of 
shoulder) and olecranon (tip of elbow) and a cuff is then selected so that the length of the 
cuff bladder is equal to 80% to 100% of the arm circumference. Effort should be made to use 
the same BP measuring device for subsequent BP measurements during site visits. After 
5 minutes of rest, pulse and BP measurements begin. The BP measurements are obtained by 
auscultation of the brachial artery using the first Korotkoff sound for systolic BP (SBP) and 
the fifth Korotkoff sound for diastolic BP (DBP).  
At the Screening Visit, BP should be measured 3 times, 30 seconds apart at the beginning of 
each visit; 3 additional BP measurements, 30 seconds apart, should be obtained at the end of 
the study visit after all procedures have been performed. Thus, there will be 2 average BP 

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recordings for the Screening Visit (one being the average of the first 3 BP recordings at the 
beginning of the visit and the second, the average of the additional 3 BP recordings at the end 
of the study visit). At the baseline and post-baseline visits, 3 BP measurements 30 seconds 
apart, should be obtained at the beginning of the study visit. The average of the three BP 
measurements is recorded as the participant’s BP for the study visit.  
In addition, after subjects are deemed eligible to participate in the study, if available, 
historical BP measurements will be obtained from the subjects’ medical records and 
documented in the past medical history BP recordings section of case report form.  
7.5.5.3 
Weight  
Weight will be obtained using a scale and recorded in kilograms at specified site visits 
(Table 2.1, Table 2.2, and Table 2.3). Weight measurements will be used to calculate the 
appropriate KRN23 dose to be administered. Weight from the previous site visit will be used 
to calculate KRN23 dose. 
7.5.5.4 
Physical Examination 
Complete physical examinations will be performed at Screening, Baseline, and at the 
Week 24, 40, and 64 study visits, at 12-week intervals during the Extension Period (or at 
Early Termination), and at the Safety Visit (if applicable). Physical examinations will include 
assessments of general appearance; head, eyes, ears, nose, and throat; the cardiovascular, 
dermatologic, lymphatic, respiratory, gastrointestinal, genitourinary, musculoskeletal, and 
neurologic systems. The genitourinary exam scope should be non-invasive, as per age-
appropriate standard of care, and at the investigator’s discretion based on clinical judgement.  
7.5.5.5 
Renal Ultrasound and Glomerular Filtration Rate 
Renal ultrasounds will be conducted at Screening and the Week 40, 64, and 160 (or Early 
Termination) visit.  
Baseline and all post-treatment renal ultrasounds will be evaluated by a trained central reader 
blinded to subject data to evaluate changes in calcifications and all other renal abnormalities 
from baseline (i.e. screening assessment). Ultrasonographic findings of nephrocalcinosis will 
be graded on a 5-point scale (Verge et al. 1991). 
The eGFR will be calculated by using the Bedside Schwartz equation (Schwartz et al. 2009). 
7.5.5.6 
Electrocardiogram 
A standardized 12-lead ECG will measure PR, QRS, QT, and QTc at Baseline and Weeks 12, 
40, and 64, and at the Week 160 (or Early Termination) visit. The goal is to evaluate both for 
changes associated with LVH, as well as for changes in conductivity and intervals. ECG 
administration procedures will be standardized and results will be read centrally by qualified 

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personnel blinded to subject data. The ECG results will be assessed for any clinically 
significant abnormality or relevant changes from baseline. 
7.5.5.7 
Clinical Laboratory Tests for Safety 
A comprehensive serum metabolic panel (Chem-20), complete blood count, and urinalysis 
(when possible) will be used as routine screens to assess KRN23 safety. Certain analytes 
(i.e., serum phosphorus) in the routine Chem-20 panel are also designated as PD/efficacy 
parameters in this study. Additional KRN23/XLH biochemical parameters of interest include 
serum 1,25(OH)2D, calcium, creatinine, and iPTH; and urinary phosphorus, calcium, and 
creatinine.  
Blood and urine samples will be collected at Screening and regular intervals throughout the 
study as indicated in the Schedules of Events (Table 2.1, Table 2.2, and Table 2.3).  
Fasting for a minimum of 4 hours is required prior to each blood draw or urine collection; the 
duration of fasting will be recorded on the CRF. Subjects who live more than 45 minutes 
from the site may stay overnight on the night before the site visit to facilitate fasting sample 
collection. Clinical laboratory parameters to be assessed for safety are provided in 
Table 7.5.5.7.1. See the Study Reference Manual for details on sample collection and 
processing.  

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Table 7.5.5.7.1: 
Clinical Laboratory Assessments 
Chemistry 
Hematology 
Urinalysis1 
1,25(OH)2D2 
Hematocrit 
Appearance 
25(OH)2D 
Hemoglobin 
Color 
Alanine aminotransferase (ALT) 
Platelet count 
pH 
Alkaline phosphatase (ALP) 2  
Red blood cell (RBC) count 
Specific gravity 
Amylase 
White blood cell (WBC) count 
Ketones 
Aspartate aminotransferase (AST) 
Mean corpuscular volume (MCV) 
Protein  
Bilirubin (direct and total) 
Mean corpuscular hemoglobin (MCH) 
Glucose  
Blood urea nitrogen (BUN) 
MCH concentration 
 
Calcium (total) 
 
 
Chloride 
 
 
Carbon dioxide (CO2) 
 
 
Cholesterol (total) 
 
 
Creatinine 
 
 
Gamma-glutamyl transpeptidase 
(GGT) 
 
 
Glucose 
 
 
FGF23 
 
 
Intact parathyroid hormone (iPTH) 
 
 
Lactate dehydrogenase (LDH) 
 
Spot Urine 
Lipase 
 
Calcium 
Phosphorus2 
 
Creatinine 
Potassium 
 
Phosphorus 
Protein (albumin and total) 
 
 
Sodium 
 
 
Uric acid 
 
 
1Urinalysis to be conducted if possible based on urine volume collected. 
2Also designated as a PD/efficacy parameter 
 
Subjects who experience a SAE possibly or probably related to study drug or other AE of 
concern may, at the discretion of the Investigator (and/or medical monitor), have additional 
blood samples taken for safety laboratory tests.  

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7.5.5.7.1 
Fibroblast Growth Factor 23 
Serum FGF23 concentrations will be measured at the Baseline, Week 24, Week 64, and 
Week 160/Early Termination visits in all subjects using a validated assay run by a central lab. 
Blood samples will be collected after a minimum fasting time of 4 hours and prior to drug 
administration. 
7.5.5.7.2 
Anti-KRN23 Antibody Testing 
To determine the immunogenicity profile of KRN23 in children aged 1-4 years with XLH, 
blood samples will be obtained for anti-KRN23 antibody (ADA) testing at Baseline and 
Weeks 4, 12, 40, 64, and Week 160/Early Termination visits. PK samples will be obtained on 
post-baseline days of ADA testing to assess potential neutralizing effects if ADA are 
detected. The formation of anti-KRN23 antibodies in human serum will be determined using 
a validated ECLA and a 2-tiered strategy: screening assay and specificity confirmation assay. 
If the development of anti-KRN23 antibodies is suspected in a given subject, samples may be 
obtained at additional time points on a case-by-case basis, if warranted. 
7.5.5.8 
Concomitant Medications/Therapies 
Concomitant medications and therapies will be reviewed and recorded in the subject’s CRF 
at each study visit to the investigational site and during home health visits. Between site 
visits during the Extension Period, concomitant medications and therapies will be reviewed 
by telephone call from the study site to the subject’s parent/caregiver every 2 weeks and 
recorded in the subject’s CRF if home health visits have been replaced by parent/caregiver 
study drug administration. 
Medications (investigational, prescription, over-the-counter, and herbal) and nutritional 
supplements taken during the 30 days prior to Screening will be reviewed and recorded. 
Therapies (physical therapy, occupational therapy as well as mobility and walking devices, 
including ankle-foot orthosis, braces, cane, crutches, walker, wheelchair etc.) utilized during 
the 30 days prior to Screening will also be reviewed and recorded. At each subsequent visit 
(or telephone call), change in medications and therapies since the previous visit will be 
recorded. A discussion of concomitant medications and therapies is provided in Section 
7.4.5. 
7.5.5.9 
Dose Limiting Toxicity 
A DLT is defined as the occurrence of any of the following:  
• Unexpected SAEs occurring during treatment considered to be either definitely, probably, 
or possibly related to the investigational product  
• A confirmed serum phosphorus level of ≥ 6.5 mg/dL (defined as hyperphosphatemia) at 
any time after dosing  

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If a subject experiences a DLT, the planned dosing for that subject will be evaluated by the 
Investigator and medical monitor. The outcome of this investigation will determine the 
subjects’ continuation or withdrawal from the study. 
7.5.5.10 
Adverse Events 
All AEs will be recorded from the time the subject’s parent/guardian signs the informed 
consent through the final safety protocol-defined follow-up (telephone or visit). 
The determination, evaluation, reporting, and follow-up of AEs will be performed as outlined 
in Section 8.5. At each visit, subjects will be asked about any new or ongoing AEs since the 
previous visit. Assessments of AEs will occur at each visit to the investigational site, at home 
health visits, and at telephone visits.  
Clinically significant changes from baseline in physical examination findings, vital signs, 
clinical laboratory parameters, renal ultrasounds, GFR, and ECGs will be recorded as AEs or 
SAEs, if deemed appropriate by the investigator. 
7.5.6 
Appropriateness of Measurements 
The assessments and timing of assessments used in this study, and the variables analyzed, 
are typical of those used to evaluate hypophosphatemia, renal reabsorption, vitamin D 
metabolism, and skeletal defects in subjects with XLH. The primary goals of treatment in 
pediatric XLH patients are to correct or minimize rickets/osteomalacia, radiographic 
abnormalities, and skeletal deformities and improve growth outcomes (Carpenter et al. 2011). 
KRN23 binds to and inhibits FGF23. FGF23 plays an important role in phosphate 
homeostasis, as such, serum phosphorus levels will be the primary PD marker of KRN23 
efficacy in this study. 
Additional assessments are included both as PD measures and safety indicators of potential 
secondary complications associated with treatment, including serum calcium, 1,25(OH)2D 
and urinary calcium, creatinine, and phosphorus, as hypercalciuria may occur in the absence 
of hypercalcemia.  Intact PTH (iPTH) levels are routinely measured as a part of standard oral 
phosphate and active vitamin D therapy in XLH, as secondary hyperparathyroidism is 
common. ALP will be measured as a biochemical marker of bone turnover, which may 
provide an indication of treatment effect. Where possible, timing of assessments has been 
coordinated with standard safety laboratory tests to minimize risk and discomfort and avoid 
unnecessary duplication of testing. 
Radiographs are routinely recommended during the initial evaluation of XLH, and to 
evaluate healing of rickets and skeletal deformities. Growth will be measured and may be 
compared with historical growth measurements to determine a change in growth velocity 
before and after KRN23 treatment. 
The safety parameters to be evaluated in this study include standard assessments such as 
recording of medical history, AEs and SAEs, physical examination, vital signs, serum 
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Routine, non-invasive procedures will provide relevant indicators of possible renal and 
cardiac risk; renal ultrasounds will be used to detect any calcinosis in susceptible organs. 
Since elevated free FGF23 has been associated with LVH in patients with chronic kidney 
disease, ECGs will examine the potential risk in XLH subjects.  
The study will be conducted in a pediatric population; as such, additional safety measures 
including home health care visits and a DMC have been incorporated into the study design.  
Where possible, measures to minimize pain and distress to the subject have been considered 
for this study protocol. The maximum blood volume obtained throughout the Treatment 
Period is estimated to be approximately 169 mL. Any unscheduled blood draws would be in 
addition to this volume. 
7.6 
Statistical Methods and Determination of Sample Size 
A general description of the statistical methods to be used to analyze the safety and efficacy 
of the study drug is outlined below. The analyses planned in this protocol will be expanded in 
the statistical analysis plan (SAP) to include detailed description of the analyses. The SAP 
will be finalized and approved prior to the database lock. Any deviations from the analyses 
described in the protocol and SAP will be noted in the clinical study report. 
7.6.1 
Determination of Sample Size 
Approximately 10 children aged 1-4 years with XLH will be enrolled in the study. 
This sample size is considered appropriate to evaluate the KRN23 dose and PD relationship 
to confirm if the profile is similar in these younger children to that observed in older children 
(age 5-12) in the Phase 2 study UX023-CL201. Preliminary clinical efficacy assessments will 
also be evaluated in this study. To demonstrate safety and efficacy in a controlled study, a 
larger randomized, Phase 3 study in children with a broader age range is being planned that 
will include two treatment arms: one group will receive KRN23 and one group will receive 
oral phosphate/active vitamin D therapy. 
7.6.2 
Analysis Populations 
7.6.2.1 
Efficacy Analysis Set 
The Efficacy Analysis population will consist of all subjects who receive at least one dose of 
study drug and have at least one post-study drug measurement. 
7.6.2.2 
Safety Analysis Set 
The Safety Analysis Set will consist of all subjects who receive at least one dose of study 
drug. 
7.6.2.3 
Pharmacokinetic and Pharmacodynamic Analysis Set 
The PK/PD analyses sets will consist of all subjects who receive at least one dose of study 
drug and have evaluable blood samples. 

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7.6.3 
General Principles 
Descriptive statistics will be used to summarize the data. For continuous variables, the mean, 
standard deviation, median, interquartile range (Q1, Q3), minimum, and maximum will be 
provided. For discrete data, the frequency and percent distributions will be provided. 
Statistical tests will be two-sided at the alpha = 0.05 significance level. Two-sided 95% 
confidence intervals will also be presented.  
The completeness of the data affects the integrity and accuracy of the final study analysis.  
Therefore, every effort will be made to ensure complete, accurate and timely data collection, 
and to avoid missing data. The procedures for handling missing, unused, or spurious data, 
along with the detailed method for analyses will be presented in the SAP. In general, missing 
data will be treated as missing and no statistical imputation method will be used unless stated 
otherwise.  
No adjustment on multiplicity will be made for statistical comparisons unless stated 
otherwise. 
7.6.3.1 
Subject Accountability 
The number of subjects who received study treatment will be summarized. The reason for 
study treatment discontinuation and study discontinuation will also be summarized.  
7.6.3.2 
Demographics and Baseline Characteristics 
Demographics (age, gender, and race) and other baseline disease characteristics will be 
summarized using descriptive statistics. 
7.6.3.3 
Pharmacodynamic Analyses 
The primary efficacy endpoint is the change from baseline over time in serum phosphorus. 
PD parameters and their respective change from baseline will be summarized at each time 
point.  A repeated measure model  will be used for assessing the change from baseline at 
each time point.  In the case when model assumption is not met, analyses using alternative 
methods such as non-parametric tests will be performed. 
7.6.3.4 
Clinical Efficacy Analysis 
The radiographic measures including RGI-C global score, RGI-C long leg score and RSS 
scores and the change from baseline of RSS scores will be summarized at Weeks 40,  64, 
112, and 160. RGI-C global score at Week 40 will be the key rickets assessment. 
An Analysis of Covariance (ANCOVA) model will be used for assessing the RGI-C score 
and the change from Baseline of RSS score at Week 40. At Weeks 64, 112, and 160, RGI-C 
global score over time will be analyzed using the repeat measurement model that includes 
visit as a categorical variable, and adjusted for baseline age and rickets severity. The RGI-C 

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long leg score and change from baseline in RSS total score over time will be analyzed using 
the same method. 
Growth parameters such as recumbent length/standing height will be summarized at each 
time point. The z scores and percentiles and their respective change from baseline of standing 
height will be summarized. In addition, the growth velocity will be evaluated for recumbent 
length/standing height. The SAP will provide additional details on the planned efficacy 
analyses.   
7.6.3.5 
Pharmacokinetics Analyses 
PK parameters will be summarized at each time point. 
7.6.3.6 
Safety Analyses 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
The incidence and frequency of AEs will be summarized by System Organ Class, Preferred 
Term (PT), relationship to study drug, and severity. All reported AEs with onset during the 
treatment (i.e., treatment-emergent AEs) will be included in the analysis. For each AE, the 
percentage of subjects who experienced at least 1 occurrence of the given event will be 
summarized by treatment group. The numbers (frequency) and incidence rates of AEs and 
SAEs will be summarized during exposure to KRN23 throughout the study including the 
continuation period. Special attention will be given to those subjects who died, discontinued 
treatment due to an AE, or experienced a SAE (e.g., summaries, listings, and narrative 
preparation may be provided, as appropriate).  
Clinical laboratory data will be summarized by the type of laboratory test. Reference ranges 
and markedly abnormal results will be used in the summary of laboratory data. Descriptive 
statistics will be calculated for each laboratory analyte at baseline and at each scheduled time 
point. A shift table for iPTH at each scheduled visit will be provided to assess the normality 
over time. A listing of subjects with any markedly abnormal laboratory results will be 
provided. The frequency and percentage of subjects who experience abnormal clinical 
laboratory results (i.e. outside of reference ranges) and/or clinically significant abnormalities 
will be presented for each clinical laboratory measurement.  
The SAP will provide additional details on the planned safety analyses. 
7.6.4 
Timing of Analysis 
Analysis of select safety and efficacy variables will be conducted at Week 40; a full analysis 
of safety and efficacy variables will be conducted at the end of the Treatment Period 
(Week 64). The final analysis of long-term safety and efficacy variables will be completed at 
the end of the study (“study completion”), which is defined as the date of the last 
protocol-specified visit/assessment (including telephone contact) for the last subject in the 
study. 

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7.6.5 
Data Monitoring Committee 
An independent DMC that includes members with expertise in metabolic bone disease, 
cardiology and nephrology and the conduct of clinical trials in children will act in an 
advisory capacity to monitor subject safety on a routine basis through the Treatment Period 
(Week 64). The DMC will meet approximately twice a year. The roles and responsibilities of 
the DMC will be defined in the DMC Charter. During the Extension Period, safety data will 
be reviewed by the SSRT on an ongoing basis.  
8 STUDY CONDUCT 
8.1 
Ethics 
8.1.1 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC)  
The IRB/EC must be a properly constituted board or committee operating in accordance with 
21 CFR Part 56, "Institutional Review Boards."  This protocol, any protocol amendments, the 
associated informed consent forms (ICFs), and the informed consent procedures must be 
submitted to the IRB/EC for review and must be approved before the enrollment of any 
subject into the study.  Investigational Product may not be shipped to the investigator until 
Ultragenyx or its designee has received a copy of the letter or certificate of approval from the 
IRB/EC for the protocol and any protocol amendments, as applicable. 
All subject recruitment and/or advertising information must be submitted to the IRB/EC and 
Ultragenyx or its designee for review and approval prior to implementation.  IRB/EC 
approval of any protocol amendments must be received before any of the changes outlined in 
the amendments are put into effect, except when the amendment has been enacted to protect 
subject safety.  In such cases, the chair of the IRB/EC should be notified immediately and the 
amendment forwarded to the IRB/EC for review and approval. 
8.1.2 
Ethical Conduct of Study 
This protocol is written in accordance with the principles established by the 18th World 
Medical Assembly General Assembly (Helsinki, 1964) and subsequent amendments and 
clarifications adopted by the General Assemblies. The sponsor and investigator will make 
every effort that the study described in this protocol is conducted in full conformance with 
those principles, current FDA regulations, ICH Good Clinical Practices (GCP) guidelines, 
and local ethical and regulatory requirements.  Should a conflict arise, the sponsor and 
investigator will follow whichever law or guideline affords the greater protection to the 
individual subject.  The investigator will also make sure he or she is thoroughly familiar with 
the appropriate administration and potential risks of administration of the Investigational 
Product, as described in this protocol and the IB, prior to the initiation of the study. 

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8.1.3 
Subject Information and Consent 
Appropriate forms for documenting written informed consent will be provided by the 
investigator and reviewed and approved by Ultragenyx or its designee before submission to 
the IRB/EC.  Ultragenyx or its designee must receive a copy of the IRB/EC's approval of the 
ICF before the shipment of Investigational Product to the study site. 
It is the Investigator's responsibility to obtain signed written informed consent from each 
potential study subject prior to the conduct of any study procedures.  This written informed 
consent will be obtained after the methods, objectives, requirements, and potential risks of 
the study have been fully explained to each potential subject.  The Investigator must explain 
to each subject that the subject is completely free to refuse to enter the study or to withdraw 
from it at any time. Subjects under the age of 18 years (or 16 years, depending on the region) 
will provide written assent (if possible), and his/her legally authorized representative (parent 
or legal guardian) will provide written informed consent for such subjects.   
The method of obtaining and documenting informed consent and the contents of the ICF will 
comply with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of 
Human Subjects,” the Health Insurance Portability and Accountability Act (HIPAA) 
regulations, and all other applicable regulatory requirements.  Subjects will be given a copy 
of the signed ICF and will be provided any new information during the course of the study 
that might affect their continued participation in the study.  The investigator or a qualified 
designee will be available to answer each subject's questions throughout the study, and all of 
the subject's questions must be answered to the subject's satisfaction.  If the protocol is 
amended and the ICF is revised, each subject will be required to provide written informed 
consent again using the revised ICF. 
Receipt of written informed consent will be documented in each potential subject’s CRF.  
The signed ICF will remain in each subject's study file and must be available to the study 
monitor(s) at all times. 
8.2 
Investigators and Study Administrative Structure 
Each investigator must provide Ultragenyx and/or its designee a completed and signed Form 
FDA 1572 and a Financial Disclosure Form.  All sub-investigators must be listed on Form 
FDA 1572 and Financial Disclosure Forms must be completed for all sub-investigators listed 
on Form FDA 1572. 
Ultragenyx and/or its designee will be responsible for managing and monitoring the clinical 
trial to ensure compliance with FDA and ICH GCP guidelines. Ultragenyx's trained 
designated representative (the monitor) will conduct regular visits to the clinical site, to 
perform Source Document Verification (SDV).  The monitor will verify the investigator's 
ongoing qualifications, to inspect clinical site facilities, and to inspect study records, 
including proof of EC/IRB review, with the stipulation that patient confidentiality will be 
maintained in accordance with local and federal regulations, including HIPAA requirements. 

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A Coordinating Investigator will be identified for this multicenter trial. The Coordinating 
Investigator will be selected on the basis of active participation in the trial, thorough 
knowledge of the therapeutic area being studied, and the ability to interpret data. 
The Coordinating Investigator will read and sign the Clinical Study Report.   
8.3 
Investigational Product Accountability 
While at the clinical site, Investigational Product must be stored in a secure limited access 
location at controlled temperature as described in the IB and according to product packaging. 
The storage facility must be available for inspection by the study monitor at any time during 
the study. In the home setting, study drug should be handled as directed by study personnel. 
A drug accountability record must be maintained for all Investigational Product received, 
dispensed, returned, and/or lost during the study.  This record must be kept current and made 
available to the study monitor for inspection. During the Extension Period, subject caregivers 
will retain empty vials and return them to the study site as directed by study personnel for 
drug accountability. Following the close-out of the study, all unused Investigational Product 
must be returned to Ultragenyx and/or its designee unless other instructions have been 
provided for final disposition of the Investigational Product.  
8.4 
Data Handling and Record Keeping 
8.4.1 
Case Report Forms and Source Documents 
The investigator is required to initiate and maintain, for each subject, an adequate and 
accurate case history that records all observations and other data related to the study for that 
subject.  A validated Electronic Data Capture (EDC) system will be used for entry of the data 
into electronic CRFs.  Data must be recorded on CRFs approved by Ultragenyx or its 
designee.  All information recorded on CRFs for this study must be consistent with the 
subject's source documentation.   
Initial data entry and any changes to the data will be made only by Ultragenyx-authorized 
users, and data entries and changes will be captured in an electronic audit trail.  
An explanation of any data change should be recorded in the CRF.  All data entered in to the 
CRF must be verifiable; therefore, CRFs will be routinely checked for accuracy, 
completeness, and clarity and will be cross-checked for consistency with source documents, 
including laboratory test reports and other subject records by Ultragenyx or its designee.  
The Investigator must allow direct access to all source documents. 
8.4.2 
Data Quality Assurance 
Monitoring and auditing procedures developed by Ultragenyx and/or its designee will be 
implemented to ensure compliance with FDA and ICH GCP guidelines. Ultragenyx's 
designated representative (the monitor) will contact the investigator and conduct regular 
visits to the study site. The monitor will be expected and allowed to verify the investigator's 
qualifications, to inspect clinical site facilities, and to inspect study records, including proof 

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of IRB/EC review, with the stipulation that subject confidentiality will be maintained in 
accordance with local and federal regulations, including HIPAA requirements. The monitor 
will also be responsible for confirming adherence to the study protocol, inspecting CRFs and 
source documents, and ensuring the integrity of the data. CRFs will be checked for accuracy, 
completeness, and clarity and will be cross-checked for consistency with source documents, 
including laboratory test reports and other subject records. Instances of missing or 
uninterruptable data will be resolved in coordination with the investigator. 
The monitor will also investigate any questions concerning adherence to regulatory 
requirements. Any administrative concerns will be clarified and followed. The monitor will 
maintain contact with the site through frequent direct communications with the study site by 
e-mail, telephone, facsimile, and/or mail. The investigator and all other site personnel agree 
to cooperate fully with the monitor and will work in good faith with the monitor to resolve 
any and all questions raised and any and all issues identified by the monitor. 
The investigator understands that regulatory authorities, the IRB/EC, and/or Ultragenyx or its 
designees have the right to access all CRFs, source documents, and other study 
documentation for on-site audit or inspection and will retain this right from the start of the 
study to at least 2 years after the last approval of a marketing application or for at least 
2 years after clinical development of the study drug for the indication being studied has been 
discontinued. The investigator is required to guaranty access to these documents and to 
cooperate with and support such audits and inspections. 
8.4.3 
Record Retention 
All study records must be retained for at least 25 years after the end of the clinical trial or in 
accordance with national law. 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 25 years.  Ultragenyx must be notified and will assist with retention should the 
Investigator/institution be unable to continue maintenance of subject files for the full 
25 years. All study records must be stored in a secure and safe facility. 
8.5 
Reporting and Follow-up of Adverse Events 
8.5.1 
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether 
or not related to the medicinal (investigational) products. 
Suspected Adverse Reaction is any AE for which there is a reasonable possibility that the 
drug caused the AE. For the purposes of expedited safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the drug and the AE. 

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Suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any adverse event caused by a drug. 
Life-threatening adverse event or life-threatening suspected adverse reaction is an adverse 
event or suspected adverse reaction that, in the view of either the investigator or sponsor, 
places the patient or subject at immediate risk of death. It does not include an adverse event 
or suspected adverse reaction that, had it occurred in a more severe form, might have caused 
death. 
SAE or serious suspected adverse reaction is an AE or suspected adverse reaction that at any 
dose, in the view of either the investigator or sponsor, results in any of the following 
outcomes:  
• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or disability (substantial disruption of the ability to 
conduct normal life functions) 
• A congenital anomaly/birth defect 
Note that hospitalizations planned prior to study enrollment (e.g. for elective surgeries) are 
not considered SAEs. Hospitalizations that occur for pre-existing conditions that are 
scheduled after study enrollment are considered SAEs. 
Important medical events that may not result in death, be immediately life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition.   
8.5.2 
Severity of Adverse Events 
Wherever possible, the severity of all AEs will be graded using the NCI CTCAE version 4.0. 
The majority of AEs can be graded using this system.  
If an AE cannot be graded using the CTCAE criteria, it should be graded as mild, moderate, 
severe, life-threatening, or death using the following definitions. 
• Mild (Grade 1): Awareness of signs or symptoms, but easily tolerated and are of a minor 
irritant type, causing no loss of time from normal activities.  Symptoms do not require 
therapy or a medical evaluation; signs and symptoms are transient. 
• Moderate (Grade 2): Events introduce a low level of inconvenience or concern to the 
participant and may interfere with daily activities, but are usually improved by simple 
therapeutic measures; moderate experiences may cause some interference with 
functioning. 

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• Severe (Grade 3): Events interrupt the participant’s normal daily activities and generally 
require systemic drug therapy or other treatment; they are usually incapacitating. 
• Life-threatening (Grade 4): Events that place the participant at immediate risk of death 
or disabling. 
• Death (Grade 5): Events that result in death. 
To make sure there is no confusion or misunderstanding of the difference between the terms 
"serious" and "severe," which are not synonymous, the following note of clarification is 
provided.  The term "severe" is often used to describe the intensity (severity) of a specific 
event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may 
be of relatively minor medical significance (such as severe headache).  This is not the same 
as "serious" 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.  Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations. 
8.5.3 
Relationship of Adverse Events to Study Drug 
The investigator will assess the potential relationship of the AE to study drug using the 
following descriptions. 
Categories of attributions for “Unrelated” events: 
• Unrelated:  This category applies to an AE that is clearly not related to the 
investigational agent/procedure. 
• Unlikely Related:  This category applied to an AE that is doubtfully related to the 
investigational agent/procedure.  
Categories of attributions for “Related” events: 
• Possibly Related: This category applies to an AE that may be related to the 
investigational agent/procedure. 
• Probably Related: This category applies to an AE that is likely related to the 
investigational agent/procedure.  
• Definitely Related: This category applies to an AE that is clearly related to the 
investigational agent/procedure. 
For the purposes of reporting to regulatory agencies, AEs deemed as Definitely, Probably or 
Possibly Related will be considered Related and those deemed Unrelated or Unlikely Related 
will be considered Unrelated. 

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8.5.4 
Adverse Event Reporting 
8.5.4.1 
General 
All AEs (i.e. any new or worsening in severity or frequency of a preexisting condition) with 
onset after the subject signs consent for study participation must be promptly documented on 
the CRF. The Investigator is responsible for evaluating all AEs, obtaining supporting 
documents, and ensuring documentation of the event is adequate. Details of the AE must 
include severity, relationship to study drug, duration, and outcome.  
All AEs will be collected from the time that the subject signs informed consent through the 
final protocol-defined safety follow-up contact (telephone call or visit). In addition, the 
Investigator should report any AE that occurs after this time period that is believed to have a 
reasonable possibility of being associated with study drug.  
AEs ongoing at the final protocol-defined safety follow-up contact (telephone call or visit) 
should have a comment in the source document by the Investigator that the event has 
recovered, recovered with sequelae, or stabilized.  
8.5.4.2 
Serious Adverse Events, Serious Adverse Drug Reactions, and Requirements 
for Immediate Reporting 
Ultragenyx or its designee must be notified of the occurrence of any SAE that occurs during 
the reporting period within 24 hours of the Investigator, designee, or site personnel’s 
knowledge of the event. SAEs will be reported by completing and submitting SAE report 
forms to Ultragenyx or designee.   
Follow-up SAE information must be submitted in a timely manner as additional information 
becomes available. All SAEs regardless of relationship to study drug must be followed to 
resolution or stabilization if improvement is not expected.  
All deaths, regardless of causality, occurring from signing of the informed consent until the 
final protocol-defined safety follow-up contact (telephone call or visit) are to be reported as 
SAEs to Ultragenyx or its designee within 24 hours of knowledge.   
8.5.5 
Communication Plan 
8.5.5.1 
Serious Adverse Drug Reaction Reporting 
Ultragenyx or its designee will submit suspected unexpected serious adverse reactions 
(SUSAR) to appropriate Regulatory Authorities (including Competent Authorities in all 
Member States concerned), ECs, and Investigators as per local laws and regulations. Fatal 
and life-threatening SUSARs will be submitted no later than 7-calendar days of first 
knowledge of the event and follow-up information submitted within an additional eight days. 
All other SUSARs will be submitted within 15-calendar days of first knowledge of the event.  

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The Investigator will notify the IRBs/Research Ethics Boards (REB)/ECs of SAEs, in 
accordance with IRB/REB/EC requirements and local laws and regulations. A copy of this 
notification must be provided to Ultragenyx or its designee. 
8.5.5.2 
Urgent Safety Matters and Non-SUSAR Reporting 
Principal Investigators are required to report any urgent safety matters to Ultragenyx or its 
designee within 24 hours. Ultragenyx or its designee will inform the Regulatory Authorities, 
ECs, and Investigators of any events (e.g. change to the safety profile of KRN23, major 
safety findings) that may occur during the clinical trial that do not fall within the definition of 
a SUSAR but may affect the safety of subjects participating in the clinical trials, as required, 
in accordance with applicable laws and regulations. The reporting period for urgent safety 
issues is the period from the signing of the ICF through the final protocol-defined safety 
follow-up contact (telephone call or visit). 
The Investigator will notify the IRBs/ REB/ECs of urgent safety matters, in accordance with 
IRB/REB/EC requirements and local laws and regulations. A copy of this notification must 
be provided to Ultragenyx or its designee. 
Non-SUSARs will be maintained in the Ultragenyx safety database and provided in annual 
and/or periodic reports as per local laws and regulations. Ultragenyx or its designee will 
prepare and submit annual safety reports and/or other aggregate periodic summary reports to 
Regulatory Authorities and ECs, as per local laws and regulations.  
8.5.6 
Review of Safety Data 
An independent DMC will act in an advisory capacity to monitor subject safety on a routine 
basis through the Treatment Period (Week 64). The DMC will meet approximately twice a 
year to review aggregate safety data and provide advice regarding the safety of subjects and 
the continuing scientific validity of the study. The DMC may also be asked to review 
SUSARs that represent changes in the nature or an increase in the frequency of events and 
may provide recommendations regarding continued subject participation. During the 
Extension Period, safety data will be reviewed by the SSRT on an ongoing basis.  
 
Potential safety signals identified during the DMC reviews or any other process during the 
conduct of the study will be escalated to the appropriate internal Ultragenyx safety governing 
bodies. Any action indicated by Ultragenyx safety governing bodies will be communicated 
accordingly to all stakeholders, e.g. Regulatory Authorities, ECs, IRBs, and Investigators. 

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8.5.7 
Safety Contact Information 
Drug Safety 
Medical Monitor 
PrimeVigilance 
Fax:     
 
e-mail:
 
Javier San Martin, MD 
Telephone:   
 
Mobile:         
 
e-mail:         
 
 
8.6 
Financing and Insurance 
Financing and insurance for this clinical trial will be addressed in clinical trial agreements 
with the study site. 
8.7 
Publication Policy 
Any publication or presentation by the investigator and/or the Institution based on data or 
results resulting from the Ultragenyx study shall only be done in strict accordance with the 
Publication section in the Clinical Trial Agreement executed between Ultragenyx and the 
Institution and/or the investigator. 
PPD
PPD
PPD
PPD
PPD

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S. 2011. "Anti-FGF-23 neutralizing antibodies ameliorate muscle weakness and 
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Aono, Y, Yamazaki, Y, Yasutake, J, Kawata, T, Hasegawa, H, Urakawa, I, Fujita, T, Wada, 
M, Yamashita, T, Fukumoto, S, and Shimada, T. 2009. "Therapeutic effects of anti-
FGF23 antibodies in hypophosphatemic rickets/osteomalacia." J Bone Miner Res 24 
(11):1879-88. 
Beck-Nielsen, SS, Brock-Jacobsen, B, Gram, J, Brixen, K, and Jensen, TK. 2009. "Incidence 
and prevalence of nutritional and hereditary rickets in southern Denmark." Eur J 
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Burnett, CH, Dent, CE, Harper, C, and Warland, BJ. 1964. "Vitamin D-Resistant Rickets. 
Analysis of Twenty-Four Pedigrees with Hereditary and Sporadic Cases." Am J Med 
36:222-32. 
Carpenter, TO, Imel, EA, Holm, IA, Jan de Beur, SM, and Insogna, KL. 2011. "A clinician's 
guide to X-linked hypophosphatemia." J Bone Miner Res 26 (7):1381-8. 
Carpenter, TO, Imel, EA, Ruppe, MD, Weber, TJ, Klausner, MA, Wooddell, MM, 
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Protocol Number: UX023-CL205
Protocol Amendment 2
12 June 2017
ul+rogeny^
phormaceutical
10 SIGNATURE PAGE
Protocol Title: An Open-Label, Phase 2 Study to Assess the Safety, Pharmacodynamics, and
Efficacy ofKRN23 in Children from 1 to 4 Years Old with X-Linked Hypophosphatemia
(XLH)
Protocol Number: UX023-CL205 Amendment 2
I have read Protocol UX023-CL205 Amendment 2. I agree to conduct the study as detailed
in this protocol and in compliance with the Declaration of Helsinki, Good Clinical Practices
(GCP) and all applicable regulatory requirements and guidelines.
Investigator Signature Date
Printed Name:
Accepted for the Sponsor:
As the Sponsor representative, I confirm that Ultragenyx will comply with all Sponsor
obligations as detailed in all applicable regulations and guidelines. I will ensure that the
Investigator is informed of all relevant information that becomes available during the conduct
of this study
Javier San Martin, MD Date
Vice President, Clinical Sciences
Ultragenyx Pharmaceutical Inc.
Confidential Page 68
PPD
PPD
PPD