A Phase 2, Open-Label, Multicenter Study to Evaluate Safety, Tolerability, and Efficacy of Intracerebroventricular BMN 190 in Pediatric Patients < 18 Years of Age With CLN2 Disease
Phase: PHASE2
Conditions: Jansky-Bielschowsky Disease, Batten Disease, Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2, CLN2 Disease, CLN2 Disorder
Sponsor: BioMarin Pharmaceutical

 
 
 
 
    
 
 
 
 
 
 
Official Title:   A Phase 2, Open-Label, Multicenter Study to Evaluate Safety, 
Tolerability, and Efficacy of Intracerebroventricular BMN 190 in 
 
  
Pediatric Patients < 18 years of age with CLN2 Disease 
 
NCT Number:  NCT02678689 
 
Applicant/MAH: BioMarin Pharmaceutical Inc. 
 
Version Date: 05 February 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 2, Open-Label, Multicenter Study to Evaluate Safety, 
Tolerability, and Efficacy of Intracerebroventricular BMN 190 in 
Pediatric Patients < 18 years of age with CLN2 Disease 
Protocol Number: 
190-203 
Investigational Product: 
Cerliponase alfa (BMN 190), recombinant human tripeptidyl 
peptidase-1 (rhTPP1) 
IND/EudraCT Number: 
IND 122472 / EudraCT 2015-000891-85 
Indication: 
CLN2 disease due to tripeptidyl peptidase-1 (TPP1) deficiency 
Sponsor: 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Sponsor Medical Monitor: 
 MD 
, Rare Disease 
Study Design: 
Phase 2 open-label, multicenter study  
Comparison: 
Untreated historical controls (data from siblings affected by 
CLN2 disease and/or data from a CLN2 disease patient registry) 
Duration: 
Surgery/recovery of 14-28 days with treatment for at least 
144 weeks 
Dose: 
BMN 190 administered by intracerebroventricular (ICV) infusion 
every 14 days as follows: 
• 
Birth to < 6 months: 100 mg 
• 
6 months to < 1 year: 150 mg 
• 
1 year to < 2 years: 200 mg (first 4 doses), 300 mg 
(subsequent doses) 
• 
≥2 years: 300 mg 
Date of Original Protocol: 
23 October 2015 
Date of US-Specific Protocol: 27 April 2016 
Date of Amendment 1: 
31 January 2017 
Date of Amendment 2:  
17 March 2017  
Date of Amendment 3: 
05 May 2017 
Date of Amendment 4 
20 October 2017 
Date of Amendment 5 
17 December 2018 
Date of Amendment 6 
05 February 2019 
 
 
Property of BioMarin 
CONFIDENTIAL 
May not be divulged, published, or otherwise disclosed to others without prior written approval from 
BioMarin.  This study will be conducted according to the principles of Good Clinical Practice as 
described in the U.S. Code of Federal Regulations and the International Conference on Harmonisation 
Guidelines, including the archiving of essential documents. 
 
BioMarin is a registered trademark of BioMarin Pharmaceutical Inc. 
PI
PI

 
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CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY 
Amendment: 6 
Date: 05 February 2019 
 
SUMMARY OF CHANGES AND RATIONALE 
1. The purpose of this amendment is to correct an error in Protocol 190-203 
Amendment 5 in which  “Ophthalmology Assessments” (Baseline/First Infusion, 
Q48W, Study Completion/Early Termination) was inadvertently removed from the 
Schedule of Events (Table 9.1.1) and Study Procedures (Section 12). Ophthalmologic 
assessments for the 190-203 protocol should continue to be performed before the first 
infusion and every 48 weeks for the duration of the study.   
 
Refer to Section 25 for a summary of the amendment revisions. 

 
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2 
SYNOPSIS 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
NAME OF FINISHED PRODUCT: 
Cerliponase alfa (BMN 190) 
NAME OF ACTIVE INGREDIENT: 
recombinant human tripeptidyl 
peptidase-1 (rhTPP1) 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
Page:  
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
TITLE OF STUDY:  
A Phase 2, Open-Label, Multicenter Study to Evaluate Safety, Tolerability, and Efficacy of 
Intracerebroventricular BMN 190 in Pediatric Patients < 18 years of age with CLN2 Disease 
PROTOCOL NUMBER: 
190-203 
STUDY SITES: 
Approximately 4 clinical sites worldwide 
PHASE OF DEVELOPMENT: 
Phase 2 
STUDY RATIONALE:  
BMN 190 is a recombinant form of human tripeptidyl peptidase-1(TPP1), the enzyme deficient in 
CLN2 disease (also known as classical late-infantile CLN2, cLINCL, or Jansky-Bielschowsky 
disease), which is a type of Batten Disease. As an enzyme replacement therapy (ERT), 
intracerebroventricular (ICV) BMN 190 is expected to restore TPP1 enzyme activity in the brain 
and alter neurological disease progression. Given the urgent and severe unmet medical need in 
CLN2 disease, results in nonclinical models of disease and the BMN 190-201 clinical study, this 
study is designed to ascertain the safety and efficacy of treatment before significant disease burden 
occurs. 
CLN2 disease is a pediatric neurodegenerative disorder characterized predominantly by late 
infantile onset with subsequent rapid, irreversible clinical decline. Murine and canine models of 
CLN2 disease have shown significant treatment benefit with CNS delivery of BMN 190. 
TPP1-null dachshunds dosed with BMN 190 early in life had delayed onset of clinical signs, 
preserved motor and cognitive function, and prolonged life. Response to ERT earlier in this and 
other animal models, indicates the importance of early treatment.  
BMN 190 has been tested in children with CLN2 disease ≥ 3 years of age. Results from the 
190-201 study demonstrated a substantial improvement of the rate of clinical progression in 
children treated with BMN 190 compared with untreated historical controls. Further, in those 
children who had received at least 48 weeks of BMN 190 dosing, clinical scores stabilized, in 
contrast to matched historical untreated controls in which decline was rapid and profound in the 
majority of matches.  
Based on clinical and nonclinical information, it appears that early BMN 190 intervention has the 
potential of preventing or postponing clinical decline for a significant period. This protocol is 
intended to investigate the safety and tolerability of ICV-delivered BMN 190 in CLN2 patients. 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
NAME OF FINISHED PRODUCT: 
Cerliponase alfa (BMN 190) 
NAME OF ACTIVE INGREDIENT: 
recombinant human tripeptidyl 
peptidase-1 (rhTPP1) 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
Page:  
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
The efficacy of BMN 190 as a delay in disease progression will be evaluated relative to untreated 
historical controls (data from siblings affected by CLN2 disease and/or data from a CLN2 disease 
patient registry). 
OBJECTIVES: 
The primary objectives of this study include the following: 
• 
evaluate safety and tolerability of BMN 190 administered via intracerebroventricular 
(ICV) device 
• 
evaluate treatment effectiveness as a delay in progression of motor-language (ML) score 
on the Hamburg CLN2 clinical rating scale 
• 
assess immunogenicity of BMN 190 in CSF and serum  
Secondary objectives of this study include the following: 
• 
characterize the PK of BMN 190 in CSF and plasma 
• 
measure MRI parameters of disease progression 
• 
assess impact of treatment on the total Hamburg clinical rating scale 
• 
assess the time to disease manifestation for asymptomatic patients 
Exploratory objectives of this study include the following: 
• 
assess development achievement  
• 
assess abnormal involuntary movements 
• 
evaluate retinal anatomy using optical coherence tomography (OCT) 
• 
determine seizure onset, type and frequency 
• 
determine change in seizure activity 
• 
anti-epileptic treatment 
• 
assess quality of life  
• 
assess changes in EEG 
• 
assess changes in visual acuity 
• 
analysis of disease-related biomarkers from CSF and blood 
STUDY DESIGN AND PLAN: 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
NAME OF FINISHED PRODUCT: 
Cerliponase alfa (BMN 190) 
NAME OF ACTIVE INGREDIENT: 
recombinant human tripeptidyl 
peptidase-1 (rhTPP1) 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
Page:  
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
BMN 190 is a recombinant human TPP1 used for the treatment of CLN2 disease, which is 
predominantly a late infantile presentation of neuronal ceroid lipofuscinosis, one of the genetic 
isoforms of Batten disease.  
This is a Phase 2 open-label, multicenter study in pediatric patients < 18 years of age with CLN2 
disease, confirmed by deficiency of TPP1 enzyme activity and mutation of the CLN2 gene. The 
study is designed to assess disease progression in CLN2 patients treated with BMN 190 compared 
to natural history data from untreated historical controls (data from a CLN2 disease patient registry 
and data from siblings with CLN2 disease, when available). The comparison of treatment with 
untreated controls will be compared from the time of the initiation of study drug. Eligibility will be 
determined and study enrollment will occur before patients are admitted to the hospital for surgical 
implantation of an ICV access device. Baseline values will be recorded before the first infusion, 
which will occur at least 14 days from surgery and no more than 28 days after surgery. BMN 190 
is then administered every 14 days (± 3 days) by ICV infusion according to the patient’s age:  
• 
birth to < 6 months: 100 mg 
• 
6 months to < 1 year: 150 mg 
• 
1 year to < 2 years: 200 mg (first 4 doses), 300 mg (subsequent doses) 
• 
≥2 years: 300 mg 
 
Patients younger than 2 years will start the study at the dose level appropriate for their age and will 
transition to the dose level consistent with their age as they mature.  
The study will enroll at least 10 patients: at least 5 patients with a Hamburg CLN2 scale ML score 
≥ 5 points, at least 5 patients with a ML score < 5 points, and at least 5 patients < 2 years of age. 
The treatment period is at least 144 weeks. Upon study completion or early termination, all patients 
will be given the opportunity to participate in a postmarketing registry that will assess the long-
term safety and efficacy of BMN 190 for patients receiving commercial drug. 
Patients in this study will be required to have an ICV reservoir surgically implanted for 
administration of BMN 190. An MRI will be performed in advance of the procedure to ensure 
proper planning and placement of the ICV access device. Patients will be monitored closely in a 
nursing-intensive environment for 48 hours post-ICV device placement and after the start of the 
first drug infusion. Following ICV access device placement, subjects and their caregivers will be 
given written instructions providing details on signs and symptoms of concern for device 
complications and instruction on when to return to the site for device evaluation. These instructions 
should be provided by the institution and be based on local standard of care. An additional follow-
up phone call will be conducted within 48 hours of inpatient discharge for all visits.   

 
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Age-specific dosing will be initiated every 14 days (±3 days) from the date of first infusion. The 
normal infusion will be administered over 4 (±1) hours at a rate of 2.5 mL/hr; the dose will be 
determined by the patient’s age. Subjects not receiving the full 300 mg dose (administered in a 
total volume of 10 mL) will receive the appropriate volume at a rate of 2.5 mL/hr for over a shorter 
duration of time.  
 
Age 
Dose 
Rate 
Infusion Time 
birth to < 6 months 
100 mg 
2.5 mL/hr 
1.3 hours (±0.5 hr) 
6 months to < 1 year 150 mg 
2.5 mL/hr 
2 hours (±0.5 hr) 
1 year to < 2 years 
200 mg (first 4 
doses),  
 
300 mg 
(subsequent 
doses) 
2.5 mL/hr 
 
 
2.5 mL/hr 
2.7 hours (±1 hr) 
 
 
4 hours (±1 hr) 
≥2 years 
300 mg 
2.5 mL/hr 
4 hours (±1 hr) 
 
Dosing can be adapted in the judgement of the investigator (and in consultation with the medical 
monitor) to manage adverse events (AEs) as outlined in the table above. Should the dose-limiting 
AE resolve in the opinion of the investigator, the dosing at the full specified dose may resume.  
In patients younger than 2 years, dosing may also be adjusted by the sponsor in consultation with 
the investigator and medical monitor based on results from PK analysis, as follows: 
• 
Within a patient, if the observed CSF AUC0-t exceed the range of CSF AUC0-t 
characterized with the 300 mg dose in Study 190-201, the dose may be reduced to 50% of 
the recommended age-appropriate dose. 
• 
Within a patient, if the observed CSF AUC0-t is less than the range of CSF AUC0-t 
characterized with the 300 mg dose in Study 190-201, the dose may be increased to the 
recommended dose for the next oldest age group. 
For all infusions, subjects will be monitored in an appropriate inpatient setting for a minimum of 
24 hours from the start of the infusion. For the first infusion only, subjects will also return for a 

 
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follow-up visit to clinic 72 hours (and no later than the third calendar day) after the start of 
infusion. After all visits, the parent or legal guardian will be telephoned within 48 hours to 
determine health status.  
Efficacy will be measured using the 0 to 6-point ML score on the Hamburg CLN2 rating scale as 
the primary endpoint. The 12-point total score (motor, language, vision, and seizure subscales) on 
the Hamburg CLN2 scale, time to disease manifestation (for asymptomatic patients), and MRI 
measures of disease progression will be collected as secondary endpoints. Exploratory efficacy 
measures will include developmental status, involuntary movements, retinal anatomy using OCT, 
seizure frequency, change in seizure activity (as measured by Hamburg score), anti-epileptic 
treatment, quality of life metrics, changes in EEG, assessment of visual acuity, and analysis of 
disease-related biomarkers. 
The safety and tolerability of treatment will be assessed by collection of AEs, physical findings, 
vital signs, ECGs, and clinical laboratory tests. AEs will be assessed by the investigator for 
severity, seriousness, and relationship to study drug and/or the ICV access device. An AE 
occurring within 24 hours of the start or restart of BMN 190 infusion will be defined as a 
temporally related event (TRE).  
To date, there has been no anaphylaxis or anaphylactoid reactions in studies with BMN 190. 
However, in the event of a suspected anaphylactic reaction, serious hypersensitivity event, or 
severe hypersensitivity (defined as a hypersensitivity event of Grade 3 or higher), blood samples to 
assess C4, serum tryptase, and total IgE will be collected within 1 hour of the event and tested; a 
blood sample to assess drug-specific IgE will be collected no sooner than 8 hours after the event 
(or before the next infusion). 
In addition, the investigator must contact the BioMarin medical monitor within 1 business day if 
any AE is severe (Grade 3 or higher) or serious and requires any of the following:  
• 
infusion interruption, discontinuation, or modification (not due to blocked line) 
• 
administration of IV fluids, steroids, or antihistamines  
• 
administration of oxygen 
Before subsequent infusions, the study site investigator and BioMarin medical monitor will discuss 
the case and agree upon infusion modification or additional premedication, if necessary. Agreed 
upon dose modifications or introduction of additional premedication should be documented in the 
Case Report Forms and source files.  
AEs will be judged by relationship to study drug and to the ICV access device. Routine CSF 
surveillance will be performed by clinical laboratories and microbial studies each time the reservoir 
is accessed. If an infection is suspected, blood and CSF samples will be drawn for laboratory 
assessments. The subsequent course of therapy may include antibiotic therapy and catheter 
reposition or withdrawal. If BMN 190 treatment is suspended, BMN 190 may resume if no more 
than 4 consecutive doses are missed after the last given dose. 
Samples will also be taken to evaluate the BMN 190 immunogenicity in CSF and serum. 
NUMBER OF SUBJECTS PLANNED: 
At least 10 patients are expected to be enrolled: at least 5 patients with a Hamburg ML score 
≥ 5 points, at least 5 patients with a ML score < 5 points, and at least 5 patients < 2 years of age. 

 
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DIAGNOSIS AND ENTRY CRITERIA: 
Pediatric patients (from birth to < 18 years of age) with confirmed CLN2 disease are eligible to 
participate in this study. Additional criteria for participation in this study are detailed below. 
Subjects must satisfy the following entry criteria in order to enroll in the study. 
Inclusion Criteria: 
• 
Diagnosis of CLN2 disease as determined by TPP1 enzyme activity (dried blood spot) in 
the fibroblasts and leukocytes available at Screening. Note: Blood for TPP1 enzyme 
activity and CLN2 gene analysis must be collected to be analyzed centrally.  
• 
Quantitative clinical assessment of the Hamburg motor-language aggregate score 3-6 at 
Screening, as defined in the Ratings Assessment Guideline.  
• 
< 18 years of age at the time of informed consent 
• 
Written informed consent from parent or legal guardian and assent from subject, if 
appropriate 
• 
Males and females who are of reproductive age should practice true abstinence, defined as 
no sexual activity, during the study and for 6 months after the study has been completed 
(or withdrawal from the study). If sexually active and not practicing true abstinence, males 
and females of reproductive age must use a highly effective method of contraception while 
participating in the study. 
• 
Ability to comply with protocol required assessments (ICV implantation, drug 
administration, laboratory sample collection, EEG, ECG, MRI, etc.) 
Exclusion Criteria: 
• 
Another inherited neurologic disease, e.g., other forms of CLN or seizures unrelated to 
CLN2 disease (patients with febrile seizures may be eligible) 
• 
Another neurological illness that may have caused cognitive decline (e.g., trauma, 
meningitis, hemorrhage) or interfere with disease rating (autism) before Screening 
• 
Percutaneous feeding tube placement prior to enrollment 
• 
Has received stem cell, gene therapy, or ERT  
• 
Contraindications for neurosurgery (e.g., congenital heart disease, severe respiratory 
impairment, or clotting abnormalities) 
• 
Contraindications for MRI scans (e.g., cardiac pacemaker, metal fragment or chip in the 
eye, aneurysm clip in the brain) 
• 
Episode of generalized motor status epilepticus within 4 weeks before the First Dose visit 
• 
Severe infection (e.g., pneumonia, pyelonephritis, or meningitis) within 4 weeks before the 
First Dose visit (enrollment may be postponed) 
• 
Presence of ventricular abnormality (hydrocephalus, malformation) 
• 
Presence of ventricular shunt 
• 
Has known hypersensitivity to any of the components of BMN 190 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
NAME OF FINISHED PRODUCT: 
Cerliponase alfa (BMN 190) 
NAME OF ACTIVE INGREDIENT: 
recombinant human tripeptidyl 
peptidase-1 (rhTPP1) 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
Page:  
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
• 
Has received any investigational medication within 30 days before the first infusion of 
study drug or is scheduled to receive any investigational drug other than BMN 190 during 
the course of the study  
• 
Has a medical condition or extenuating circumstance that, in the opinion of the 
investigator, might compromise the subject’s ability to comply with the protocol required 
testing or procedures or compromise the subject’s wellbeing, safety, or clinical 
interpretability 
• 
Pregnancy any time during the study; a female subject judged by the investigator to be of 
childbearing potential will be tested for pregnancy 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
NAME OF FINISHED PRODUCT: 
Cerliponase alfa (BMN 190) 
NAME OF ACTIVE INGREDIENT: 
recombinant human tripeptidyl 
peptidase-1 (rhTPP1) 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
Page:  
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
INVESTIGATIONAL PRODUCT, DOSE, ROUTE AND REGIMEN: 
BMN 190 will be administered by ICV infusion every 14 days (preferably in the morning) 
according to the patient’s age: 
• 
birth to < 6 months: 100 mg 
• 
6 months to < 1 year: 150 mg 
• 
1 year to < 2 years: 200 mg (first 4 doses), 300 mg (subsequent doses) 
• 
≥2 years: 300 mg 
Patients younger than 2 years will start the study at the dose level appropriate for their age and will 
transition to the dose level consistent with their age as they mature. 
Fasting for a minimum of 2 hours may be considered for the first infusion and subsequent infusions 
until the subject's reaction to the study drug is determined. When a feeding tube is used, the tube 
may be turned off 2 hours before infusion.  
The normal infusion will be administered over 4 (± 1) hours at a rate of 2.5 mL/hr; the dose will be 
determined by the patient’s age. Subjects not receiving the full 300 mg dose (administered in a 
total volume of 10 mL) will receive the appropriate volume at a rate of 2.5 mL/hr for over a shorter 
duration of time.  
Dosing can be adapted in the judgement of the investigator (and in consultation with the medical 
monitor) to manage adverse events (AEs) as outlined in the table above. Should the dose-limiting 
AE resolve in the opinion of the investigator, the dosing at the full specified dose may resume.  
In patients younger than 2 years, dosing may also be adjusted by the sponsor in consultation with 
the investigator and medical monitor based on results from PK analysis, as follows: 
• 
Within a patient, if the observed CSF AUC0-t exceed the range of CSF AUC0-t 
characterized with the 300 mg dose in Study 190-201, the dose may be reduced to 50% of 
the recommended age-appropriate dose. 
• 
Within a patient, if the observed CSF AUC0-t is less than the range of CSF AUC0-t 
characterized with the 300 mg dose in Study 190-201, the dose may be increased to the 
recommended dose for the next oldest age group. 
 
REFERENCE THERAPY, DOSE, ROUTE AND REGIMEN: 
Because practical and ethical concerns preclude contemporaneous or untreated control subjects, 
comparison will be with historical data from existing CLN2 disease registries and data from 
siblings with CLN2 disease, when available. 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
NAME OF FINISHED PRODUCT: 
Cerliponase alfa (BMN 190) 
NAME OF ACTIVE INGREDIENT: 
recombinant human tripeptidyl 
peptidase-1 (rhTPP1) 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
Page:  
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
DURATION OF TREATMENT: 
Treatment will continue for at least 144 weeks or until all procedures are completed or the subject 
discontinues from the study.  
CRITERIA FOR EVALUATION:  
Safety: 
• 
AEs and concomitant medication 
• 
routine clinical laboratory tests (hematology, chemistry, and urinalysis) 
• 
routine CSF surveillance (cell count, protein, glucose, and culture) 
• 
vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], heart rate, 
respiration rate, and temperature) 
• 
physical examination 
• 
neurological examination 
• 
electrocardiogram (ECG), 3 or 5-lead, 12-lead 
• 
immunogenicity, includes anti-BMN 190 total antibodies (TAb) and neutralizing 
antibodies (NAb) in CSF; TAb, NAb, total IgE, and drug-specific IgE in serum  
 
Efficacy: 
• 
Hamburg CLN2 disease rating scale with videotaping: 0 to 12 point total score (motor, 
language, visions, and seizure subscales) 
o Change in seizure activity (clinical [0 to 3 point Hamburg CLN2 rating scale, 
seizure subscale]) 
• 
Anti-epileptic treatment 
• 
Denver Development Scale II 
• 
Modified Unified Batten Disease Rating Scale Involuntary Movement Scale 
(mUBDRS-Movement) 
• 
Modified Unified Batten Disease Rating Scale Seizure Inventory (mUBDRS-Seizure) 
• 
Time to disease manifestation for asymptomatic patients (time to first seizure) 
• 
Assessments of visual acuity  

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
NAME OF FINISHED PRODUCT: 
Cerliponase alfa (BMN 190) 
NAME OF ACTIVE INGREDIENT: 
recombinant human tripeptidyl 
peptidase-1 (rhTPP1) 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
Page:  
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
Imaging: 
• 
Cranial MRI with measurements of atrophy and apparent diffusion coefficients  
• 
Optical coherence tomography (OCT) 
• 
Electroencephalogram (EEG) 
Quality of Life Tests: 
• 
PedsQL: Family Impact and infant/toddler modules  
• 
CLN2- specific QOL 
 
 
Pharmacokinetics: 
• 
area under the concentration-time curve from time 0 to infinity (AUC0-∞) 
• 
area under the concentration-time curve from 0 to time of last measurable concentration 
(AUC0-t) 
• 
maximum concentration (Cmax) 
• 
time to reach Cmax (Tmax) 
• 
elimination half-life (t1/2) 
• 
apparent clearance of drug (CL/F) 
• 
apparent volume of distribution based on terminal phase (Vz/F) 
Immunogenicity: 
• 
TAb and NAb in CSF; TAb, NAb, total IgE, and drug-specific IgE in serum 
Biomarkers: 
• 
Analysis of disease-related biomarkers from CSF and blood 
 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
NAME OF FINISHED PRODUCT: 
Cerliponase alfa (BMN 190) 
NAME OF ACTIVE INGREDIENT: 
recombinant human tripeptidyl 
peptidase-1 (rhTPP1) 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
Page:  
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
STATISTICAL METHODS:   
A Statistical Analysis Plan (SAP) will be written prior to final database lock that will provide 
details on the planned statistical analysis. If discrepancies exist between the statistical analysis as 
described in the protocol and the final SAP, the SAP will prevail. 
The primary efficacy endpoint is the 0 to 6-point ML score on the Hamburg CLN2 rating scale. 
The primary measure of efficacy is the rate of CLN2 decline. This analysis will include patients 
with a baseline ML score < 6 points and patients with a ML score < 6 points post-baseline. CLN2 
disease rating scale scores will be evaluated relative to natural history data in untreated historical 
controls (data from a CLN2 disease patient registry and data from siblings with CLN2 disease, 
when available).  
Time to disease manifestation will be assessed for asymptomatic patients. For all patients, an 
analysis of interest is time to first confirmed decline, defined as 2 consecutive CLN2 assessments 
(i.e., approximately 4 weeks apart) with scores less than the baseline CLN2 score. 
Secondary endpoints of key interest include measurements obtained from MRI of the brain, time to 
disease manifestation (asymptomatic patients), time to first confirmed CLN2 decline (all patients), 
and the 0 to 12-point total (motor/language/vision/seizure) Hamburg CLN2 scores.  
Endpoints will be presented descriptively. Secondary and exploratory endpoints may be compared 
with natural history data from untreated historical controls (data from a CLN2 disease patient 
registry and data from siblings with CLN2 disease, when available). 
Safety data will be summarized descriptively. 
Sample size was determined on the basis of clinical judgment. Statistical power was not a 
consideration. 

 
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3 
TABLE OF CONTENTS 
1 TITLE PAGE .......................................................................................................................1 
2 SYNOPSIS ...........................................................................................................................3 
3 TABLE OF CONTENTS ...................................................................................................14 
LIST OF TABLES ...................................................................................................................17 
LIST OF APPENDICES ..........................................................................................................17 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................18 
5 ETHICS..............................................................................................................................20 
5.1 Ethics Committees ....................................................................................................20 
5.2 Ethical Conduct of Study ..........................................................................................21 
5.3 Subject Information and Informed Consent ..............................................................21 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................23 
7 INTRODUCTION .............................................................................................................24 
7.1 Nonclinical Studies ...................................................................................................24 
7.2 Previous Clinical Studies ..........................................................................................25 
7.3 Study Rationale .........................................................................................................26 
7.4 Overall Risks and Benefits ........................................................................................27 
7.4.1 
Hypersensitivity Reactions ..........................................................................28 
7.4.2 
Risks of Intracerebroventricular Devices and Drug Administration ...........28 
8 STUDY OBJECTIVES ......................................................................................................31 
9 INVESTIGATIONAL PLAN ............................................................................................32 
9.1 Overall Study Design and Plan .................................................................................32 
9.1.1 
Screening .....................................................................................................42 
9.1.2 
Surgery and First Dose ................................................................................42 
9.2 Discussion of Study Design, including Choice of Control Group ............................43 
9.3 Selection of Study Population ...................................................................................44 
9.3.1 
Inclusion Criteria .........................................................................................44 
9.3.2 
Exclusion Criteria ........................................................................................45 
9.3.3 
Removal of Subjects from Treatment or Assessment .................................46 
9.3.4 
Subject Identification and Replacement ......................................................49 

 
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9.3.5 
Duration of Subject Participation ................................................................49 
9.4 Treatments .................................................................................................................49 
9.4.1 
Treatments Administered ............................................................................49 
9.4.2 
Identity of Investigational Product ..............................................................51 
9.4.3 
Storage .........................................................................................................51 
9.4.4 
Directions for Administration .....................................................................51 
9.4.5 
Method of Assigning Subjects to Treatment Groups ..................................55 
9.4.6 
Selection of Dose .........................................................................................55 
9.4.7 
Blinding .......................................................................................................58 
9.4.8 
Prior and Concomitant Medications ............................................................58 
9.4.9 
Treatment Compliance ................................................................................59 
9.5 Investigational Product Accountability .....................................................................59 
9.5.1 
Return and Disposition of Clinical Supplies ...............................................59 
9.6 Dietary or Other Protocol Restrictions......................................................................59 
9.7 Efficacy and Safety Variables ...................................................................................59 
9.7.1 
Efficacy Variables .......................................................................................60 
9.7.2 
Immunogenicity ...........................................................................................64 
9.7.3 
Safety Variables ..........................................................................................64 
9.7.4 
Pharmacokinetics Variables ........................................................................67 
9.7.5 
Vital Signs, Physical Examinations, and Other Observations.....................67 
10 REPORTING ADVERSE EVENTS .................................................................................70 
10.1 Safety Parameters and Definitions ............................................................................70 
10.1.1 Adverse Events ............................................................................................70 
10.1.2 Serious Adverse Events ...............................................................................70 
10.1.3 Adverse Events of Special Interest (AEoSI) ...............................................71 
10.2 Methods and Timing for Capturing and Assessing Safety Parameters .....................71 
10.2.1 Adverse Event Reporting Period .................................................................71 
10.2.2 Eliciting Adverse Events .............................................................................72 
10.2.3 Assessment of Seriousness, Severity, and Causality ...................................73 
10.3 Procedures for Recording Adverse Events ...............................................................75 
10.3.1 Recording Adverse Events on a eCRF ........................................................75 

 
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10.4 Reporting Requirements ...........................................................................................79 
10.4.1 Expedited Reporting Requirements .............................................................79 
10.4.2 IRB/IEC Reporting Requirements ...............................................................79 
10.5 Follow-up of Patients after Adverse Events .............................................................80 
10.6 Post-Study Adverse Events .......................................................................................80 
10.7 Urgent Safety Measures ............................................................................................80 
10.8 BioMarin Pharmacovigilance Contact Information ..................................................81 
11 APPROPRIATENESS OF MEASUREMENTS ...............................................................82 
11.1 Natural History Studies .............................................................................................82 
11.2 CLN2 Clinical Rating Scale ......................................................................................82 
11.3 Magnetic Resonance Imaging ...................................................................................83 
12 STUDY PROCEDURES ...................................................................................................85 
12.1 Screening ...................................................................................................................85 
12.2 Surgery Visit .............................................................................................................85 
12.3 Baseline Visit and First Infusion ...............................................................................86 
12.3.1 Baseline Visit ..............................................................................................86 
12.3.2 First Infusion ...............................................................................................87 
12.4 Every 2 Weeks ..........................................................................................................88 
12.5 Every 4 Weeks ..........................................................................................................89 
12.6 Every 8 weeks ...........................................................................................................89 
12.7 Every 12 Weeks ........................................................................................................89 
12.8 Every 24 Weeks ........................................................................................................90 
12.9 Every 48 Weeks ........................................................................................................91 
12.10 Study Completion or Early Termination Visit ..........................................................91 
12.11 Device Safety Follow-Up .........................................................................................92 
12.12 Safety Follow-Up ......................................................................................................93 
12.13 Study Termination ....................................................................................................94 
13 DATA QUALITY ASSURANCE .....................................................................................95 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................96 
14.1 Statistical Analysis Plan ............................................................................................96 
14.1.1 Interim Analyses ..........................................................................................96 

 
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14.2 Primary Efficacy Analysis ........................................................................................96 
14.2.1 Secondary Efficacy Analyses ......................................................................96 
14.2.2 Exploratory Analyses ..................................................................................97 
14.2.3 Immunogenicity Analysis ............................................................................97 
14.3 Pharmacokinetic Analysis .........................................................................................98 
14.4 Safety Analysis .........................................................................................................98 
14.5 Determination of Sample Size ..................................................................................99 
14.6 Changes in the Conduct of the Study or Planned Analyses ......................................99 
15 DATA REVIEW BOARD ...............................................................................................100 
16 COMPENSATION, INSURANCE, AND SUBJECT INJURY......................................101 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS ............................................102 
18 STUDY MONITORING AND AUDITING ...................................................................104 
19 RETENTION OF RECORDS .........................................................................................105 
20 USE OF INFORMATION AND PUBLICATION .........................................................106 
21 REFERENCES ................................................................................................................107 
22 INVESTIGATOR RESPONSIBILITIES ........................................................................109 
22.1 Conduct of Study and Protection of Human Subjects.............................................109 
23 SIGNATURE PAGE .......................................................................................................110 
24 APPENDICES .................................................................................................................111 
25 PROTOCOL AMENDMENT TEXT REVISIONS ........................................................113 
 
LIST OF TABLES  
Table 9.1.1:  Schedule of Events .............................................................................................37 
Table 9.4.1.1:  Age-Specific Dosing Schema for BMN 190 Administration ..........................50 
Table 9.7.3.3.1:  Clinical Laboratory Tests .............................................................................66 
Table 10.2.3.2.1:  Adverse Event Grading (Severity) Scale ....................................................73 
Table 10.2.3.3.1:  Causality Attribution Guidance ..................................................................74 
LIST OF APPENDICES 
Appendix 1: Adapted CLN2 Disease Rating Scale ...............................................................111 
 

 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
AEoSI 
adverse event of special interest 
BPV 
BioMarin Pharmacovigilance 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CLN2  
neuronal ceroid lipofuscinosis type 2 disease, also known as classical late infantile CLN2, 
cLINCL, or Jansky-Bielschowsky disease, a form of Batten Disease 
CNS 
central nervous system 
CRA 
clinical research associate 
CSF 
cerebrospinal fluid 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DRB 
Data Review Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EEG 
electroencephalogram 
ERT 
enzyme replacement therapy 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
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 
ICV 
intracerebroventricular 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
IT-L 
intrathecal lumbar 
ITQOL 
Infant Toddler Quality of Life Questionnaire 
MedDRA 
Medical Dictionary for Regulatory Activities 
ML 
Combined score of motor and language subscales on the adapted CLN2 disease rating scale 
MRI 
magnetic resonance imaging 
mUBDRS-
Movement 
Modified Unified Batten Disease Rating Scale Involuntary Movement Scale 

 
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mUBDRS-
Seizure 
Modified Unified Batten Disease Rating Scale Seizure Inventory 
NAb 
neutralizing anti-TPP1 antibody 
NCI 
National Cancer Institute 
NOAEL 
No-observed-adverse-effect-level 
OCT 
Optical Coherence Tomography 
PEDsQL 
Pediatric Quality of Life 
PEG 
percutaneous endoscopic gastrostomy 
PLT 
Preferential Looking Test 
PK 
pharmacokinetics 
QOL 
quality of life 
REC 
Research Ethics Committee 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDV 
source data verified 
SOI 
Statement of Investigator 
SUSAR 
suspected unexpected serious adverse reaction 
TAb 
total anti-TPP1 antibody 
TRE 
temporally related events 
TPP1 
tripeptidyl peptidase-1 
UBDRS 
Unified Batten Disease Rating Scale 
US 
United States 
 

 
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5 
ETHICS 
BioMarin aims to conduct its studies according to the highest scientific standards. 
The following sections articulate standards to which investigators are held accountable, as 
well as matters of compliance to document adherence to such standards. 
5.1 
Ethics Committees 
Investigators are expected to interact with ethics committee promptly, as required, during the 
course of the study. This includes, but is not limited to, providing appropriate documentation 
to support study initiation and maintaining appropriate flow of safety and other information 
during the course of the study and for study close-out activities. BioMarin (or designee) will 
assist investigators with access to timely and accurate information and with assurance of 
prompt resolution of any queries. 
Prior to initiating the study, the investigator will obtain written confirmation that the 
Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics 
Committee (REC) is properly constituted and compliant with International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) and Good Clinical Practice (GCP) requirements, applicable laws, and local 
regulations. A copy of the confirmation from the IRB/IEC/REC will be provided to BioMarin 
Pharmaceutical Inc. (BioMarin) or its designee.  
The principal investigator will provide the IRB/IEC/REC with all appropriate material, 
including, but not limited to, protocol, Investigator’s Brochure (IB), Informed Consent Form 
(ICF), compensation procedures, and any written information to be provided to study 
subjects, including all consent forms translated to the native language of the clinical site, or 
to languages of intended subjects, if they speak a language other than the native language.  
The study will be initiated and study drug supplies will be shipped to the site once 
appropriate documents from the IRB/IEC/REC, confirming unconditional approval of the 
protocol, ICF, and all subject recruitment materials, are obtained in writing by the principal 
investigator and copies are received by BioMarin or its designee. Documents approved by the 
IRB/IEC/REC shall reference the study by protocol title and BioMarin protocol number and 
include review and approval dates.   
BioMarin or its designee will ensure that appropriate study progress reports are made 
available to the IRB/IEC/REC and BioMarin by the principal investigator in accordance with 
applicable guidance documents and government regulations. 

 
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5.2 
Ethical Conduct of Study 
It is expected that investigators understand and comply with the letter and spirit of this 
protocol. This includes and is not limited to establishing and meeting enrollment 
commitments, including eligible patients in the study, adhering to diagnostic or other 
procedures as specified in the study, and assuring appropriate compliance with study 
medication. 
This study will be conducted in accordance with the following: 
• United States (US) Code of Federal Regulations (CFR) sections that address clinical 
research studies 
• Clinical Trial Directive 2001/20/EC and GCP Directive 2005/28/EC 
• Other national and local regulations, as applicable 
• ICH E6 R[2], where applicable 
• The ethical principles established by the Declaration of Helsinki 
Specifically, this study is based on adequately performed laboratory and animal 
experimentation, will be conducted under a protocol reviewed and approved by an 
IRB/IEC/REC and will be conducted by scientifically and medically qualified persons. In the 
opinion of the investigator and BioMarin, the potential benefits of the study outweigh the 
potential risks. The rights and welfare of subjects will be respected. Each subject, or his/her 
legally authorized representative, will provide written informed consent before any 
study-related test or evaluation is performed. 
5.3 
Subject Information and Informed Consent 
A properly written and executed ICF, in compliance with the Declaration of Helsinki, 
ICH E6 (Section 4.8), US 21 CFR §50, Directive 2001/20/EC and applicable local 
regulations, will be obtained for each subject prior to entering that subject in the study. 
The investigator will prepare the ICF and provide the documents to BioMarin for approval 
prior to submission to the IRB/IEC/REC. BioMarin and the IRB/IEC/REC must approve the 
documents before they are implemented. Copies of the approved ICF and, if applicable, 
subject information sheet, minor assent form, parental ICF, and all ICFs translated to a 
language other than the native language of the clinical site, must also be received by 
BioMarin or its designee prior to any study-specific procedure. 
A subject younger than 18 years (or defined as a minor, depending on the region) will 
provide written assent (if able) and his/her legally authorized representative (parent or legal 
guardian) will provide written informed consent for such subjects. The investigator will 

 
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provide copies of the signed ICF to each subject (or to the subject’s legally authorized 
representative) and will maintain the original in the subject’s study file. 

 
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6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
Prior to beginning the study, the investigator at each site must provide to BioMarin or 
designee a fully executed and signed Statement of Investigator (SOI) form. A US Food and 
Drug Administration (FDA) Form 1572 serves as an acceptable SOI form. If Form FDA 
1572 may not be used in a particular region, the investigator must provide a fully executed 
SOI on the form provided by the Sponsor. All sub-investigators must also be listed on 
Form 1572 or its equivalent SOI. Financial Disclosure Forms must be completed for all 
investigators and sub-investigators who will be directly involved in the treatment or 
evaluation of subjects in this study. 
The study will be administered and monitored by employees or representatives of BioMarin. 
Clinical Research Associates (CRAs) or trained designees will monitor each site on a 
periodic basis and perform verification of source documentation for each subject as well as 
other required review processes. BioMarin Pharmacovigilance (or designee) will be 
responsible for the timely reporting of serious adverse events (SAEs) to appropriate 
regulatory authorities as required. 
CSF laboratory evaluations and evaluations of clinical laboratory parameters (blood, urine) 
will be performed by local study site laboratories. Central laboratories will be used to 
evaluate TPP1 enzyme activity, genotype, electroencephalograms (EEGs), and magnetic 
resonance imaging (MRI) scans. Assessment of immunogenicity and exploratory biomarkers 
will be conducted by BioMarin. Additional details will be provided in the corresponding 
Study Laboratory Manual. 

 
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7 
INTRODUCTION 
CLN2 disease is a predominantly late infantile form of neuronal ceroid lipofuscinosis and 
one of the multiple genetic isoforms of Batten Disease. CLN2 is a very rare genetic disease 
characterized by the deficiency of the lysosomal serine protease TPP1, caused by mutations 
in the CLN2 gene. In the absence of TPP1, lysosomal storage materials normally metabolized 
by this enzyme accumulate as characteristic intracellular deposits in many organs; 
accumulation in the CNS leads to the neurodegenerative symptoms and, ultimately death. 
The onset of symptoms is typically between ages 2 and 4 (Chang, 2011); (Kurachi, 2000) 
with an average age of diagnosis of 4 years (Worgall, 2007). Patients typically present 
initially with seizures, followed by ataxia, myoclonus, impaired speech, cognitive decline, 
and developmental regression. A loss of vision follows psychomotor decline, with patients 
blind and non-ambulatory typically between 6 and 8 years of age. Patients enter into 
essentially a neurovegetative state during the later stages of the disease and feeding and 
tending to everyday needs become difficult. Disease progression is rapid with death typically 
occurring between 10 and 15 years of age. 
7.1 
Nonclinical Studies 
Nonclinical studies support the therapeutic benefit of BMN 190 with acceptable therapeutic 
index for patients with CLN2 disease. In animal models of CLN2 disease, 
intracerebroventricular (ICV) or intrathecal lumbar (IT-L) administration of BMN 190 
reduced pathologic deposition of storage materials, attenuated cognitive and motor decline, 
delayed disease progression, and extended lifespan. In TPP-null mice, restoration of TPP1 
enzyme activity reduced lysosomal storage accumulation, improved motor function, and 
extended lifespan (Sleat, 2008); (Xu, 2011). In TPP1-null dogs, BMN 190 also reduced 
lysosomal storage, preserved function, extended lifespan and delayed clinical signs of 
neurodegeneration (Vuillemenot, 2011; 
). 
BMN 190 concentrations in cerebrospinal fluid (CSF) remained above the lysosomal Kuptake 
for approximately 48 hours after single ICV or IT-L infusions in nonclinical studies (dog and 
monkey) with CSF dynamics similar to those in human (
 
). In these same species, CNS distribution of BMN 190 was 
extensive in many brain regions. Distribution and pharmacokinetics (PK) characteristics after 
ICV infusion of BMN 190 appear advantageous to IT-L administration for treatment of 
CLN2 disease. A mean CNS tissue half-life of approximately 2 weeks (range, 3.1 to 
87.2 days, depending on CNS site; 
) suggests biweekly dosing will sustain 
therapeutic BMN 190 levels in the CNS.  
PI
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Toxicity studies have not identified drug-related adverse effects when BMN 190 is 
administered by ICV or IT-L infusion to healthy animals or animals with CLN2 disease. 
Repeated BMN 190 administration was associated with inflammation and neuronal necrosis 
adjacent to the ventricles and ICV catheter track in dog 
 and was largely 
attributable to the long-term implantation of catheters and related infusion procedures as both 
untreated and treated animals exhibited the same findings. No findings in any of the 
nonclinical studies indicate adverse BMN 190-related effects on cardiovascular or central 
nervous systems. Electrocardiogram (ECG) analysis in cynomolgus monkeys revealed no 
changes in ECG waveform or heart rate after a single ICV infusion during the time of 
BMN 190 exposure in the CSF and plasma. Additionally, monthly neurologic and clinical 
examinations of Dachshunds administered BMN 190 in a repeat-dose studies revealed no 
clinical CNS signs in Dachshunds attributable to BMN 190 though onset of disease-related 
neurologic signs was delayed significantly following up to 48 mg BMN 190, compared with 
vehicle-treated controls. Treatment related safety events were primarily device related or 
associated with immune response to chronic dosing of heterologous protein. Given the 
overall tolerability of ICV-delivered BMN190, untoward systemic safety effects were 
considered unlikely in human.  
7.2 
Previous Clinical Studies 
BMN 190 has been studied in human clinical trials 190-201 and 190-202. Study 190-201 was 
a 48-week, international, multicenter phase 1/2 open-label dose-escalation study designed to 
assess the safety and efficacy of BMN 190 administered to patients with mild to moderate 
CLN2 disease by direct intracerebroventricular infusion to the CNS; Study 190-202 is the 
open-label extension of 190-201. These studies evaluated the safety, tolerability and efficacy 
of BMN 190 given as an infusion of 300 mg every 14 days given directly to the CNS using a 
permanently implanted intracerebroventricular (ICV) access device. A total of 24 patients 
with screening CLN2 motor-language scores ≥ 3 (0 to 6 point scale) and age ≥ 3 were 
enrolled into the 190-201 study. All completers without predefined stopping criteria were 
qualified to enroll into the long term extension, Study 190-202. 
All patients had successful surgical implantation of ICV access devices, with device 
complication rates consistent with what has been observed in the published literature.  
Interim results of the completed 48-week open-label study (190-201) and the ongoing 
extension study (190-202) have been published (Schulz, 2018). The primary outcome 
measure was the time until a 2-point decline in the score on the motor and language domains 
of the CLN2 Clinical Rating Scale (which ranges from 0 to 6, with 0 representing no function 
and 3 representing normal function in each of the two domains), which was compared with 
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the time until a 2-point decline in 42 historical controls. Additionally, rate of decline in 
motor–language score was compared between the two groups using data from baseline to the 
last assessment with a score of more than 0, divided by the length of follow-up (in units of 
48 weeks). 
Twenty-four subjects were enrolled in Study 190-201/190-202, 23 of whom constituted the 
efficacy population. Interim efficacy results demonstrated a statistically significant and 
durable treatment effect in attenuating disease progression as measured by CLN2 scores and 
in comparison to natural history. Of the 24 patients enrolled into Study190-201, all but 
2 subjects were in the active loss of function phase of the disease characterized by both 
notable disease burden and decline by a median value of 2 points per 48 weeks. In the 
23 subjects who received BMN 190 for at least 96 weeks in Study 190-201/ 190-202, the 
median time until a 2-point decline in the motor–language score was not reached and was 
345 days for historical controls. The mean (SD) unadjusted rate of decline in the motor–
language score per 48-week period was 0.27 (0.35) points in treated subjects and 2.12 (0.98) 
points in 42 historical controls (mean difference, 1.85; P < 0.001). Common AEs included 
convulsions, pyrexia, vomiting, hypersensitivity reactions, and failure of the intraventricular 
device. In 2 subjects, infections developed in the intraventricular device that was used to 
administer the infusion, which required antibiotic treatment and device replacement. 
PK analysis of ICV-delivered BMN 190 demonstrates concentrations and exposures that are 
three orders of magnitude greater in the CSF than in the plasma. 
No association was found between ADA, including drug-specific IgE positivity, and 
incidence or severity of hypersensitivity adverse events. 
Taken together, the response in the treated group is significant when compared to the loss of 
function predicted by natural history studies. The conclusions of treatment effect are constant 
across all analysis methodologies and sensitivity analyses. Most patients (87%) experience 
neurodegenerative stabilization, in which active decline in function is either halted (57%), 
has an early single point decline with no subsequent loss (22%) or actually improves function 
on treatment (9%). 
In conclusion, BMN 190 via ICV infusion is generally safe and well tolerated. BMN 190 
treatment demonstrated a durable and clinically meaningful therapeutic effect on attenuating 
disease progression compared to natural history. 
7.3 
Study Rationale 
BMN 190 is a recombinant form of human TPP1, the enzyme deficient in patients with 
CLN2 disease. As enzyme replacement therapy (ERT), BMN 190 is expected to restore 

 
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TPP1 enzyme activity in the brain and alter neurological disease progression. Given the 
urgent and severe unmet medical need in CLN2 disease and observations of safety and 
efficacy in neurologically relevant animal models of CLN2 disease, clinical development of 
BMN 190 ERT is justified. 
Murine and canine models of CLN2 disease (sharing the same genetic and enzymatic defect, 
TPP1 deficiency, as the human disorder) recapitulate the major human clinical signs and 
pathology, including neuron loss, tremor, ataxia, functional decline, and reduced lifespan 
(Awano, 2006); (Sleat, 2004). ERT with BMN 190 administered intrathecally in both models 
yielded pharmacologically significant benefit. Furthermore, when dosing started early in life 
(~2.5 months of age) in the TPP1-null dachshund model, BMN 190 significantly delayed 
onset of clinical signs, preserved motor and cognitive function, and prolonged life. The better 
pharmacological response to ERT in this and other animal models, when treatment was 
started closer to birth, indicates the importance of starting therapy as early in life as possible 
(Dierenfeld, 2010).  
The relationship of the start of therapy to overall clinical response will be evaluated in 
pediatric patients (from birth to < 18 years of age) with CLN2 disease treated with BMN 190 
compared to natural history data from untreated historical controls (data from a CLN2 
disease patient registry and data from siblings with CLN2 disease, when available). The 
comparison of treatment with untreated controls will occur from the time of the initiation of 
study drug. 
7.4 
Overall Risks and Benefits 
Nonclinical toxicity studies have not identified drug-related adverse effects associated with 
chronic ICV administration of BMN 190 to healthy or CLN2 animal models disease.  
BMN 190 has been studied in 24 patients in 5 clinical sites for Studies 190-201 and 190-202. 
The current clinical experience in human clinical trials demonstrates an acceptable 
benefit-risk profile to both the placement and chronic use of ICV access devices, and to 
infusion of BMN 190 at 300 mg every 14 days as demonstrated by interim efficacy and 
safety results summarized in Section 7.2. The efficacy objective of this study is to prevent 
patients from entering into the active rapid loss of function phase of the disease, or to 
attenuate further progression of disease. Monitoring and evaluation of specific adverse events 
of hypersensitivity reactions and device-related complications are discussed in Sections 7.4.1 
and 7.4.2. Given the severity of disease, clinical and nonclinical support, the overall risks and 
benefits support this protocol.  

 
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7.4.1 Hypersensitivity Reactions 
Hypersensitivity reactions, including anaphylaxis and less severe allergic reactions, are an 
identified risk for ERT in general, including BMN 190. Thus, anaphylaxis and less severe 
allergic reactions may occur during and following ICV infusion of BMN 190. Therefore, it is 
required that appropriately trained personnel and equipment for emergency resuscitation 
(including epinephrine) be available near the bedside during study drug infusion. For 
information regarding the reporting of hypersensitivity reactions, refer to Section 10.4.1.  
An allergic reaction is a disorder characterized by an adverse local or general response from 
exposure to an allergen. Allergic reaction may include a combination of the following 
symptoms: flushing or rash, fever, urticaria, dyspnea, symptomatic bronchospasm with or 
without urticaria, allergy-related edema/angioedema, hypotension, or anaphylaxis. Infusion 
of BMN 190 may provoke additional symptoms of allergic reactions not included in this list. 
The investigator will categorize the severity of an allergic reaction as described in 
Section 10.2.3.2.  
Anaphylaxis, a systemic, immediate hypersensitivity reaction, is the most severe form of 
hypersensitivity reaction. Symptoms may occur during or within hours following infusion of 
an agent and, generally, more rapid onset indicates more severe reaction; death may result. 
Managing anaphylaxis requires early recognition of signs and symptoms and clinicians well 
trained in the management of acute events. Symptoms of anaphylaxis may include 
involvement of skin and/or mucosal tissue (e.g., generalized hives, pruritus or flushing, 
swollen lips-tongue-uvula) respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, 
stridor, reduced peak expiratory flow, hypoxemia), and reduced blood pressure or end-organ 
dysfunction (e.g., hypotonia, syncope, incontinence).  
All AEs, including hypersensitivity, anaphylaxis and other allergic reactions that occur 
within 24 hours after infusion start or restart, regardless of the investigator’s assessment of 
study drug relationship, will be considered to be temporally related events (TREs). It is 
expected that the TREs of greatest clinical importance will be hypersensitivity reactions, but 
not all TREs may be allergic in nature. The risk of such reactions may be mitigated by 
specific measures, including pretreatment or infusion modification, as described in 
Section 9.4.4. 
7.4.2 Risks of Intracerebroventricular Devices and Drug Administration 
Patients in this study will be required to have an ICV reservoir surgically implanted for 
administration of BMN 190. An MRI will be performed in advance of the procedure to 
ensure proper planning and placement of the ICV access device. The ICV access device 

 
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placement procedure will be performed under general anesthesia by qualified surgeons and 
will include placement of an endotracheal breathing tube during the procedure. Patients will 
be monitored closely in a nursing-intensive environment for 48 hours post-ICV device 
placement and after the start of the first drug infusion. Following ICV access device 
placement, subjects and their caregivers will be given written instructions providing details 
on signs and symptoms of concern for device complications and instruction on when to 
return to the site for device evaluation. An additional follow-up phone call will be conducted 
within 48 hours of inpatient discharge for all visits. 
Risks associated with the procedure include sore throat, hoarseness, mouth pain, injury to the 
mouth or teeth, injury to blood vessels, aspiration and pneumonia. Although rare, unexpected 
severe complications with anesthesia can occur and include the possibility of infection, 
bleeding, drug reactions, blood clots, loss of sensation, loss of limb function, paralysis, 
stroke, brain damage, heart attack, or death.   
Common side effects after the procedure include nausea, vomiting, dry mouth, sore throat, 
shivering, sleepiness, mild hoarseness, and pain.  
The ICV access device will be available for first infusion ≥ 14 days after placement. 
First dose must take place within 28 days of placement. 
The use of ICV access devices can result in infections, intracerebral hemorrhage, reservoir 
leakage, and seizures (Karavelis, 1996), (Kronenberg, 1998). Additional surgery may be 
required to fix or replace the devices. The technical complication rate of one ICV reservoir 
study in 106 cancer patients was 10.3% with almost half of these complications requiring 
surgical revision (median time reservoirs were in place was 4.1 months ranging from 2 days 
to 4.6 years) (Lishner, 1990). The current complication rate for BMN 190 administration is 
consistent with this large series report. 
Patients will be monitored throughout the study for potential infections (high temperature, 
cough, rash, headache, mental status changes, swelling or drainage in the incision area) and 
signs of ICV reservoir leakage or failure (refer to Section 9.7.5.2). Material degradation of 
the ICV device reservoir has occurred after approximately 105 perforations of the ICV 
device in benchtop testing, and has been observed in clinical trials with approximately 
4 years of BMN 190 administration. Access device replacement should be considered prior to 
4 years of regular administration of Brineura; with the decision made on an individual subject 
level based on the medical judgment of the Investigator. The CSF will be monitored for signs 
of infection at each infusion. If a device infection is confirmed, the site will confer with the 
sponsor and neurosurgical support to manage the intervention including potential device 

 
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removal, treatment with appropriate antimicrobial medications, and the suitability and timing 
of replacement and re-initiation of therapy.  
All BMN 190 infusions are given in an inpatient setting with supportive measures present. 
For all infusions, patients will be monitored in an appropriate inpatient setting for a minimum 
of 24 hours from the start of the infusion. For the first infusion only, subjects will also return 
for a follow-up visit to clinic 72 hours (and no later than the third calendar day) after the start 
of infusion. After all visits, the parent or legal guardian will be telephoned within 48 hours to 
determine health status. 

 
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8 
STUDY OBJECTIVES 
The primary objectives of this study include the following: 
• evaluate safety and tolerability of BMN 190 administered via intracerebroventricular 
(ICV) device 
• to evaluate treatment effectiveness as a delay in progression of motor-language (ML) 
score on the Hamburg CLN2 clinical rating scale  
• assess immunogenicity of BMN 190 in CSF and serum  
Secondary objectives of this study include the following: 
• to characterize the pharmacokinetics of BMN 190 in CSF and plasma 
• measure MRI parameters of disease progression 
• assess impact of treatment on the total Hamburg clinical rating scale 
• assess the time to disease manifestation for asymptomatic patients  
Exploratory objectives of this study include the following: 
• assess development achievement 
• assess abnormal involuntary movements 
• evaluate retinal anatomy using optical coherence tomography (OCT) 
• determine seizure onset, type and frequency 
• determine change in seizure activity 
• anti-epileptic treatment 
• assess quality of life metrics  
• assess changes in EEG 
• assess changes in visual acuity 
• analysis of disease-related biomarkers from CSF and blood 

 
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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This will be a Phase 2 open-label, multicenter study in pediatric patients < 18 years of age 
with CLN2 disease, confirmed by deficiency of TPP1 enzyme activity and mutation of the 
CLN2 gene. The study is designed to assess disease progression in CLN2 patients treated 
with BMN 190 compared to natural history data from untreated historical controls (data from 
a CLN2 disease patient registry and data from siblings with CLN2 disease, when available). 
The comparison of treatment with untreated controls will be compared from the time of the 
initiation of study drug. A summary of events is provided by visit in Table 9.1.1 
The planned enrollment for this study is at least 10 patients: at least 5 patients with a 
Hamburg ML score ≥ 5 points, at least 5 patients with a ML score < 5 points, and at least 
5 patients < 2 years of age. Study eligibility will be determined and enrollment will occur 
before (≤ 21 days) subjects are admitted to the hospital for surgical implantation of an ICV 
access device. The Baseline visit to collect clinical scores and clinical laboratory parameters 
will be completed no more than 2 days before the first infusion.  
BMN 190 will be administered every 14 days from the date of the first infusion (+3 days) for 
at least 144 weeks according to the patient’s age:  
• birth to < 6 months: 100 mg 
• 6 months to < 1 year: 150 mg 
• 1 year to < 2 years: 200 mg (first 4 doses), 300 mg (subsequent doses) 
• ≥2 years: 300 mg 
 
Patients younger than 2 years will start the study at the dose level appropriate for their age 
and will transition to the dose level consistent with their age as they mature. Upon study 
completion or early termination, all patients will be given the opportunity to participate in a 
postmarketing registry that will assess the long-term safety and efficacy of BMN 190 for 
patients receiving commercial drug. 
Patients in this study will be required to have an ICV reservoir surgically implanted for 
administration of BMN 190. An MRI will be performed in advance of the procedure to 
ensure proper planning and placement of the ICV access device. Patients will be monitored 
closely in a nursing-intensive environment for 48 hours post-ICV device placement and after 
the start of the first drug infusion. Following ICV access device placement, subjects and their 
caregivers will be given written instructions providing details on signs and symptoms of 
concern for device complications and instruction on when to return to the site for device 

 
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evaluation. These instructions should be provided by the institution and be based on local 
standard of care. An additional follow-up phone call will be conducted within 48 hours of 
inpatient discharge for all visits.   
The first infusion will occur at least 14 days from surgery to implant the ICV reservoir and 
no more than 28 days after surgery. In the event that the ICV device is replaced, the next 
infusion will occur at least 14 days and no more than 28 days after surgery. All removed or 
replaced implantable ICV devices must be returned to BioMarin in order to evaluate the 
material integrity of the reservoir, and all other devices (as described in the Pharmacy 
Manual) except for infusion pumps, should also be returned. Age-specific dosing will be 
initiated every 14 days (±3 days) from the date of the first infusion. 
The normal infusion will be administered over 4 (±1) hours at a rate of 2.5 mL/hr; the dose 
will be determined by the patient’s age. Subjects not receiving the full 300 mg dose 
(administered in a total volume of 10 mL) will receive the appropriate volume at a rate of 
2.5 mL/hr for over a shorter duration of time (See Section 9.4.1).  
Dosing can be adjusted in the judgement of the investigator, upon consultation with the 
medical monitor, to manage AEs as outlined in Table 9.4.1.1. Should the dose-limiting AE 
resolve in the opinion of the investigator, and upon consultation with the medical monitor, 
dosing at the full dose may resume.  
In patients younger than 2 years, dosing may also be adjusted by the sponsor in consultation 
with the investigator and medical monitor based on results from PK analysis, as follows: 
• Within a patient, if the observed CSF AUC0-t exceed the range of CSF AUC0-t 
characterized with the 300 mg dose in Study 190-201, the dose may be reduced to 
50% of the recommended age-appropriate dose. 
• Within a patient, if the observed CSF AUC0-t is less than the range of CSF AUC0-t 
characterized with the 300 mg dose in Study 190-201, the dose may be increased to 
the recommended dose for the next oldest age group. 
Infusions will be performed in a 4-hour period (±1 hr). Generally, functional and QOL 
assessment should precede MRI and sampling, which should precede infusion; sample 
collection may occur when subjects are sedated for MRI. If a subject is discontinued from the 
study prematurely, an Early Termination visit should be scheduled within 3 days.  
For all infusions, subjects will be monitored in an appropriate inpatient setting for a 
minimum of 24 hours from the start of the infusion. For the first infusion only, subjects will 
also return for a follow-up visit to clinic 72 hours (and no later than the third calendar day) 
after the start of infusion. After all visits, the parent or legal guardian will be telephoned 
within 48 hours to determine health status. 

 
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Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], heart rate, 
respiration rate, and temperature) will be measured within 30 (±5) minutes before infusion 
start (or restart), every 30 (±5) minutes during infusion, 0.5 hours (±5 minutes), 1 hour 
(±5 minutes), and 4 hours (±15 minutes) after infusion end, and then every 4 hours 
(±15 minutes) for the next 16 hours. Blood pressure will be measured in the upper arm using 
an appropriately sized blood pressure cuff. If the patient’s blood pressure is abnormal (as 
compared to site-specific reference ranges), a manual blood pressure will be obtained by a 
trained healthcare professional. 
For the first infusion of BMN 190, continuous ECG monitoring (3- or 5-lead) will be 
performed for all subjects. The ECG should begin 15 (± 5 minutes) prior to infusion start, 
continue through infusion of BMN 190, and end after infusion of flushing solution. In the 
event that the subject has already received the first infusion of BMN 190, the next infusion 
will be monitored as above. If a 12-lead ECG is required during this time, continuous 
monitoring should be interrupted in order to obtain the 12-lead ECG. 
A standard ECG (12-lead), including heart rate, rhythm, intervals, axis, conduction defects, 
and anatomic abnormalities, will be performed 30 (±5) minutes after infusion end at the first 
infusion and every 24 weeks thereafter. In patients with present or past bradycardia, 
conduction disorders, or with structural heart disease, an ECG will be performed within 
30 minutes before the start of infusion (±5 minutes), at 2 hours (±15 minutes) during 
infusion, 30 (±5) minutes after infusion end, and 12 hours (±3 hours) after infusion end for 
each study drug infusion. 
Efficacy will be measured using the 0 to 6-point ML score on the Hamburg CLN2 rating 
scale as the primary endpoint. The 12-point total score (motor, language, vision, and seizure 
subscales) on the Hamburg CLN2 scale and MRI measures of disease progression will be 
collected as secondary endpoints. Exploratory efficacy measures will include developmental 
status, involuntary movements, retinal anatomy using OCT, seizure frequency, change in 
seizure activity (as measured by Hamburg score), seizure frequency, change in seizure 
activity (as measured by Hamburg score), anti-epileptic treatment, quality of life metrics, 
changes in EEG, assessment of visual acuity, and analysis of disease-related biomarkers. 
The safety and tolerability of treatment will be assessed by collection of AEs, physical 
findings, vital signs, ECGs, and clinical laboratory tests. AEs will be assessed by the 
investigator for severity, seriousness, and relationship to study drug and/or the ICV access 
device. 
Because hypersensitivity reactions may be associated with ERT administration, subjects 
should be pretreated with an age-appropriate dose of antihistamine (and antipyretic, if 

 
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appropriate) medication approximately 30 minutes (± 15 minutes) before infusion. Subjects 
may be pretreated, at the discretion of the Investigator, with age-appropriate sedative 
medication approximately 30 minutes (± 15 minutes) before BMN 190 infusion according to 
institution’s standard practices.   
A temporal relationship to study drug infusion will be utilized to define TREs. This should be 
distinguished from the clinical assessment of an infusion reaction. Thus, an AE occurring 
within 24 hours of the start or restart of BMN 190 infusion will be defined as a TRE.  
Some of the events that occur within the 24 hour period post-infusion may be 
hypersensitivity mediated. Hypersensitivity reactions are characterized by an adverse local or 
general response from exposure to an allergen. Symptoms of hypersensitivity reactions may 
include fever, chills/rigors, skin symptoms (urticaria, angioedema, rash), respiratory 
symptoms (dyspnea, wheezing, stridor), gastrointestinal symptoms (nausea, vomiting, 
abdominal pain) and/or cardiovascular changes (hypotension/hypertension). 
In severe cases, anaphylaxis – a systemic hypersensitivity reaction – may also occur.  
Anaphylaxis is the most severe form of hypersensitivity reaction in which symptoms may 
occur during or within hours of an infusion; if anaphylaxis goes untreated, death may result.  
Symptoms of anaphylaxis may include involvement of skin and/or mucosal tissue 
(e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula) respiratory 
compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, 
hypoxemia), and reduced blood pressure or end-organ dysfunction (e.g., hypotonia, syncope, 
incontinence). 
To date there has been no anaphylaxis or anaphylactoid reactions in studies with BMN 190. 
However, in the event of a suspected anaphylactic reaction, serious hypersensitivity event, or 
severe hypersensitivity (defined as a hypersensitivity event of Grade 3 or higher), blood 
samples to assess C4, serum tryptase, and total IgE will be collected within 1 hour of the 
event and tested; a blood sample to assess drug-specific IgE will be collected no sooner than 
8 hours after the event (or before the next infusion).  
In addition, the investigator must contact the BioMarin medical monitor (Section 10.8) 
within 1 business day if any AE is severe (Grade 3 or higher) or serious and requires any of 
the following:  

 
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• infusion interruption, discontinuation, or modification (not due to blocked line) 
• administration of IV fluids, steroids, or antihistamines  
• administration of oxygen 
Before subsequent infusions, the investigator and BioMarin medical monitor will discuss the 
case and agree upon infusion modification or additional premedication. Agreed upon dose 
modifications or introduction of additional premedication should be documented in the Case 
Report Forms and source files. 
Another possible AE is infection from the indwelling ICV catheter. If an infection is 
suspected, blood and CSF samples will be drawn for assessments. The subsequent course of 
therapy may include antibiotic therapy and catheter reposition or withdrawal. If BMN 190 
treatment is suspended, BMN 190 may resume if no more than 4 consecutive missed doses 
elapse after the last given dose. 
A schedule of planned assessments during the study is provided in Table 9.1.1. 
 

 
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Table 9.1.1:  Schedule of Events  
Assessments and Events 
Screeninga 
 
Baseline/First Infusion 
Treatment 
Period Weeks 1 
to 144 
Study 
Completion / 
Early 
Termination 
Device 
Safety 
Follow-Up 
Safety 
Follow-Up 
≤ 21 days 
prior to ICV 
Surgery 
 
<2 Days 
prior to first 
dose 
First Infusion Visit 
(Days 1-6) 
Visit every 2 
weeks (±3 days) 
Proximity to  
last dose (+3 
days) 
4 weeks after 
device 
removal (±3 
days) 
6 months 
after last 
dose ±1week 
Informed consent/assenta 
X 
ICV Surgery and Recovery (14-28 days) k 
 
 
 
 
 
 
CLN2 Genotypeb 
Xb 
 
 
 
 
 
 
Blood for TPP1 Activity and 
CLN2 gene analysis b 
X 
 
 
 
 
 
 
CLN2 disease rating scalec 
X 
X 
 
Q4W 
X 
X 
X 
Videotaping (CLN2 disease rating 
scale)c 
X 
X 
 
Q12W 
X 
 
 
Verify criteria for study entry  
X 
 
 
 
 
 
 
ECG, 3- or 5-leadd 
 
 
Xd 
 
 
 
 
ECG, 12-leade 
 
X 
X 
Q24W 
X 
 
X 
EEG, standard awakef 
 
X 
 
Q24W 
X 
 
 
Cranial MRIg 
X 
X 
 
Q24W 
X 
 
 
CSF (cell count, protein, glucose, 
and culture)h 
 
 
D1, D6 
Q2W 
X 
 
 
Device patency/infectioni 
 
 
D1, D6 
Q2W 
 
 
 
Administer study drugj 
 
 
D1 
Q2W 
 
 
 
Phone follow-upk 
 
 
 
Within 48 hours after inpatient discharge each visitk 
CSF / plasma for PKl 
 
 
D1 
Q24W 
X 
 
 
CSF / blood for disease-related 
biomarkersm 
 
 
D1 
CSF: Q2W 
(Wks 1-71), Q8W 
X 
 
 

 
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Assessments and Events 
Screeninga 
 
Baseline/First Infusion 
Treatment 
Period Weeks 1 
to 144 
Study 
Completion / 
Early 
Termination 
Device 
Safety 
Follow-Up 
Safety 
Follow-Up 
≤ 21 days 
prior to ICV 
Surgery 
 
<2 Days 
prior to first 
dose 
First Infusion Visit 
(Days 1-6) 
Visit every 2 
weeks (±3 days) 
Proximity to  
last dose (+3 
days) 
4 weeks after 
device 
removal (±3 
days) 
6 months 
after last 
dose ±1week 
(Wks 79-145) 
Blood: Q8W 
(Wks 1-49), 
Q12W 
(Wks 61-145) 
CSF/serum for immunogenicityn 
 
X 
Q12W 
X 
X (serum 
only) 
X (serum 
only) 
Vital signso 
 
 
D1 
Q2W 
X 
X 
X 
Complete physical examinationp 
X 
X 
 
Q48W 
X 
 
X 
Brief physical examinationp 
 
 
D1, D6 
Q2W 
 
X 
 
Height and weight assessments 
 
X 
 
Q24W 
X 
 
X 
Neurological examinationp 
 
X 
 
Q12W 
X 
X 
 
Blood/urine for clinical lab testsq 
 
X 
D2 
Q4W x 2 
(Wks 1-9), then 
Q8W x 5 
(Wks 17-49), then 
Q12W 
(Wks 61-145) 
X 
X 
X 
Modified Unified Batten Disease 
Rating Scale Involuntary 
Movement Scale 
 
X 
 
Q12W 
 
 
 
Modified Unified Batten Disease 
Rating Scale Seizure Inventory  
 
X 
 
Q12W 
 
 
 
Optical coherence tomographyr 
 
X 
 
Q24W 
X 
 
 

 
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Assessments and Events 
Screeninga 
 
Baseline/First Infusion 
Treatment 
Period Weeks 1 
to 144 
Study 
Completion / 
Early 
Termination 
Device 
Safety 
Follow-Up 
Safety 
Follow-Up 
≤ 21 days 
prior to ICV 
Surgery 
 
<2 Days 
prior to first 
dose 
First Infusion Visit 
(Days 1-6) 
Visit every 2 
weeks (±3 days) 
Proximity to  
last dose (+3 
days) 
4 weeks after 
device 
removal (±3 
days) 
6 months 
after last 
dose ±1week 
PedsQLs 
 
X 
 
Q12W 
X 
 
 
Denver II Developmental Scalet 
 
X 
 
Q12W 
X 
 
 
CLN2-specific QoL questionnaires 
X 
X 
 
Q12W 
X 
 
 
Ophthalmologic assessments 
 
X 
 
Q48W 
X 
 
 
Visual acuity testingu 
 
X 
 
Q12W 
X 
 
 
Pregnancy testing (in females of 
childbearing potential)v 
X 
 
 
 
X 
 
 
Adverse events, including 
ongoing seizure historyw 
X 
Continuous monitoring 
Prior and concomitant 
medications, including anti-
epileptic treatmentsx 
X 
Continuous monitoring 
Hypersensitivity Labsy 
 
 
As needed, only in the event of suspected anaphylactic reaction, serious or severe hypersensitivity y 
ICV Device Removalz 
 
 
 
 
 
Xz 
 
 
Baseline values will be recorded no more than two days before the first infusion, which will occur at least 14 days from surgery and no more than 28 days after surgery. Thereafter, study 
visits will be every 2 weeks ±3 days from the date of the first infusion. If a subject is discontinued from the study prematurely, an Early Termination visit should be scheduled within 
3 days.  
a Written informed consent must be obtained before study procedures begin. All screening procedures are to be completed ≤ 21 days prior to the ICV implant surgery. Sponsor approval must 
be obtained prior to ICV implant surgery. 
b Diagnosis of CLN2 disease determined by TPP1 enzyme activity (dried blood spot) in the fibroblasts and leukocytes available at Screening. In addition, blood for TPP1 enzyme activity 
and CLN2 gene analysis will be collected to be analyzed centrally.  
c Two domains (motor and language) of the Hamburg CLN2 disease rating scale will be tested at Screening (entry criterion). All 4 domains (motor, language, vision, and seizure) of the 
Hamburg CLN2 scale will be tested at Baseline visit prior to first infusion, every 4 weeks during the treatment period, at Early Termination/ Study Completion visit, at the 4-week Device 

 
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Safety follow-up, and at the 6-month Safety follow-up visit. CLN2 rating scale evaluations will be videotaped every 12 weeks, and at the Early Termination/ Study Completion Visit. 
CLN2 assessments should precede MRI and blood and CSF sampling. 
d For the first infusion of BMN 190, continuous ECG monitoring (3- or 5-lead) will be performed for all subjects. The ECG should begin 15 (± 5 minutes) prior to infusion start, continue 
through infusion of BMN 190, and end after infusion of flushing solution. In the event that the subject has already received the first infusion of BMN 190, the next infusion will be 
monitored as above. If a 12-lead ECG is required during this time, continuous monitoring should be interrupted in order to obtain the 12-lead ECG. 
e A standard ECG (12-lead), including heart rate, rhythm, intervals, axis, conduction defects, and anatomic abnormalities, will be recorded. ECG will be performed 30 (±5) minutes after 
infusion end at the first infusion and every 24 weeks thereafter. In patients with present or past bradycardia, conduction disorders, or with structural heart disease, an ECG will be 
performed within 30 minutes before the start of infusion (±5 minutes), at 2 hours (±15 minutes) during infusion, 30 (±5) minutes after infusion end, and 12 hours (±3 hours) after infusion 
end. 
f At each timepoint, a standard awake electroencephalogram (EEG) will be recorded within 2 days before infusion. 
g The Screening Cranial MRI will be performed prior to surgery to ensure proper planning and placement of the ICV access device. MRI should precede blood and CSF sampling. A ±4-
week window is allowed for this assessment and the scan may be performed at the same time as a scheduled infusion. 
h CSF (for cell count with differential, protein, glucose, and culture) will be collected within 30 (±5) minutes before every infusion (or within 1 week of the Early Termination visit). During 
the first infusion, CSF (for cell count, protein, glucose, and culture) will be collected within 30 (±5) minutes before the infusion (Day 1). 
i Device and surgical location of the device should be observed prior to each infusion for any swelling or signs of infection of the scalp or surrounding area.  
j Because hypersensitivity reactions may be associated with ERT administration, subjects should be pretreated with age-appropriate doses of antihistamine (and antipyretic, if appropriate) 
medication approximately 30 minutes (± 15 minutes) before BMN 190 infusions. 
k  Subjects will be monitored in a nursing-intensive setting for a minimum of 48 hours post-ICV device placement and after the start of the first drug infusion. Following ICV access device 
placement, subjects and their caregivers will be given written instructions providing details on signs and symptoms of concern for device complications and instruction on when to return 
to the site for device evaluation. An additional follow-up telephone call will be conducted within 48 hours after inpatient discharge for all visits.   
l Samples of CSF and plasma for PK analysis will be collected within 15 minutes before infusion start, and 0.25, 4, 8, 20 (±5 minutes), 72, and 120 (±15 minutes) hours after infusion end. 
Samples will be collected on Day 1, and Weeks 25, 49, and 97. There will be no PK samples collected at Week 73 or after Week 97. 
m Samples of blood and CSF will be collected prior to infusion. Collection of CSF will be every 2 weeks from Weeks 1 to 71 and every 8 weeks from Weeks 79 to 145; blood will be 
collected every 8 weeks from Weeks 1 to 49 and every 12 weeks from Weeks 61 to 145. 
n Samples of blood (serum) and CSF will be collected for TAb and NAb testing before the first infusion (Baseline or Week 1 before the infusion), every 12 weeks thereafter, and at the Study 
Completion Visit. Samples of blood (serum) will be collected for TAb testing at the Device Safety Follow-Up and Safety Follow-Up visits (or within 1 week of the Early Termination 
visit). Collection must precede infusion. NAb will be tested at baseline and at subsequent time points when TAb is positive. Samples of blood (serum) will be collected to assess baseline 
total and drug-specific IgE levels in the event of later hypersensitivity reactions requiring additional lab work (as outlined in note x below). 
o Vital signs (SBP, DBP, heart rate, respiration rate, and temperature) will be measured within 30 (±5) minutes before infusion start (or restart), every 30 (±5) minutes during infusion, 
0.5 hours (±5 minutes), 1 hour (±5 minutes), and 4 hours (±15 minutes) after infusion end, and then every 4 hours (±15 minutes) for the next 16 hours. Blood pressure will be measured in 
the upper arm using an appropriately sized blood pressure cuff. If the patient’s blood pressure is abnormal (as compared to site-specific reference ranges), a manual blood pressure will be 
obtained by a trained healthcare professional.  

 
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p Details on complete and brief physical examinations and neurological examination are provided in Section 9.7.5. 
q Collection of samples for clinical laboratory assessments should precede infusion. Collection will be every 4 weeks for 2 assessments (Weeks 1-9), every 8 weeks for 5 assessments 
(Weeks 17-49), and then continue at a frequency of every 12 weeks thereafter (Weeks 61-145).  
r OCT should precede infusions. In order to limit the need for sedation to perform this assessment, measurement should be obtained while the subject is also under sedation for MRI 
acquisition. 
s Quality of life will be assessed using the PedsQL (including both a Parent Report for Toddlers and a Family Impact Module) and a CLN2 disease-based QoL instrument. If done on the 
same day, assessment of QOL should precede MRI, infusion, and other procedures. PedsQL parent report for appropriate age of subject. 
t  If done on the same day, assessment of the Denver II Scale should precede MRI and sampling. 
u All subjects will undergo Preferential Looking Testing every 12 weeks. In addition, for those children who retain the cognitive function to adhere to testing, the Lea Vision Test or E Hook 
(or Tumbling E) Vision Test should also be performed during the same assessment. Visual acuity testing can be performed either before or after the infusion (± 3 days), but should be 
performed at a time (relative to infusion) that can be repeated consistently between study visits. The subject must not be sedated at the time of visual acuity testing. 
v  Pregnancy in a patient or partner should be reported within 24 hours of the site becoming aware of the pregnancy and will continue through 6 months after the last dose of study drug. 
Refer to Section 10.3.1.10 for further information.  
w From signed ICF to first dose of  study drug only SAEs related to study mandated procedures are reported. From implantation of ICV device all devices related events are reported. All 
AEs and SAEs will be recorded starting with the first dose of study drug in Study 190-203 until 6 months after either the last administration of study drug or the Early Termination visit. A 
Safety Follow-Up visit will also be performed within 6 months after the last administration of study drug or Early Termination. The 6-month Safety Follow-Up Visit will be waived for 
subjects who begin receiving study drug in another BioMarin-sponsored study or registry within this 6-month period. For subjects who do not participate in an extension study or registry 
after the last dose of study drug, the 4-week Device Safety and 6-month Safety follow-up visit will capture information regarding ongoing events at the time of the last dose or new events 
related to study drug. 
x Medications (prescription, over-the-counter, and herbal) and nutritional supplements taken during the 30 days before informed consent will be recorded in the eCRF at Screening. At each 
subsequent visit (or within 1 week of the Early Termination visit), change in any medication (dosage, frequency, new medication, or cessation) since the previous visit will be recorded in 
the eCRF. Any concomitant medication added or discontinued during the study should be recorded in the eCRF (or within 1 week of the Early Termination visit). Subjects may be taking 
anticonvulsants and medications for myoclonus, tremor, agitation, and pain. Investigators will be asked to keep these regimens constant throughout the study, unless changes are required 
due to lack of efficacy or toxicity. Use of non-drug therapies such as physical and occupational therapy should also be noted in the eCRF. 
y In the event of a suspected anaphylactic reaction, serious hypersensitivity event, or severe hypersensitivity (defined as a hypersensitivity event of Grade 3 or higher), blood samples to 
assess C4,serum tryptase, and total IgE will be collected within 1 hour of the event and tested; a blood sample to assess drug-specific IgE will be collected no sooner than 8 hours after the 
event (or before the next infusion).  
z Following either the study completion visit (Week 145) or the Early Termination Visit, arrangements should be made for removal of the ICV access device. All removed or replaced 
implantable ICV devices must be returned to BioMarin in order to evaluate the material integrity of the reservoir, and all other devices (as described in the Pharmacy Manual) except for 
infusion pumps, should also be returned.  If the subject intends to continue to receive BMN 190 following participation in this study (e.g., via commercial product, use in a registry, or 
another BMN 190 study), then the device does not need to be removed. Device removal should occur no more than 4 weeks after the last administration of study drug. A device removal 
safety follow-up visit will be performed within 4 weeks (± 3 days) from removal of the ICV access device.   

 
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9.1.1 Screening 
Before any study-related procedure is performed, parents or legal guardians will provide 
informed consent for study-eligible patients. Patients will be assessed to determine whether 
they meet study entry criteria (Section 9.3) and are suitable candidates for implantation of an 
ICV access device. The diagnosis of CLN2 disease is determined by TPP1 enzyme activity 
(dried blood spot) in the fibroblasts and leukocytes available at Screening. In addition, blood 
for TPP1 enzyme activity and CLN2 gene analysis will be collected to be analyzed centrally. 
Screening procedures are to be completed ≤ 21 days prior to the ICV reservoir implant 
surgery. 
CLN2 rating scales will be performed in full (Appendix 1). Study entry will require a 
2-domain ML score of 3-6, as defined in the Ratings Assessment Guideline. The Ratings 
Assessment Guidelines provide detailed instructions on rating scale assessment, and the 
Imaging Charter provides instructions on MRI evaluation by a centralized facility. In 
addition, a complete physical examination will be conducted. 
In order to ensure appropriate patients are enrolled in the study (including those with the 
necessary CLN2 ML scores at Screening), a confirmation of patient study eligibility will be 
provided to the Investigator by BioMarin. Surgery should not be performed until this 
approval is obtained. Information that must be provided for Sponsor approval includes (but is 
not limited to) patient age, results of TPP1 enzyme activity, results of CLN2 genotype testing 
(if available) and Screening ML score. 
9.1.2 Surgery and First Dose 
Study subjects will be admitted to the hospital for surgical implantation of an 
MRI-compatible ICV access device in the lateral ventricle of the right hemisphere; surgery 
and anesthesia will be under the direction of a neurosurgeon (refer to Study Pharmacy 
Manual for compatible ICV reservoirs and cannula). An MRI will be performed prior to the 
surgery to ensure proper planning and placement of the ICV access device. Generally, 
surgery and postoperative care will be determined by standards of care at the study centers 
and specific clinical needs of the subject. Subjects will be monitored in a nursing-intensive 
setting for a minimum of 48 hours post-ICV device placement and after the start of the first 
drug infusion. Following ICV access device placement, subjects and their caregivers will be 
given written instructions providing details on signs and symptoms of concern for device 
complications and instruction on when to return to the site for device evaluation. 
An additional follow-up telephone call will be conducted within 48 hours after inpatient 
discharge for all visits.   

 
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The first infusion will occur at least 14 days from surgery to implant the ICV reservoir and 
no more than 28 days after surgery. In the event that the ICV device is replaced, the next 
infusion will occur at least 14 days and no more than 28 days after surgery. At the first (and 
each subsequent) study drug administration, the investigator will evaluate the patency, 
location, and skin integrity of the reservoir. Access to the device is performed using strict 
sterile technique. Skin covering the reservoir is inspected for an appropriate needle insertion 
site. The needle insertion site must be intact, without evidence of breakdown, wound, 
infection or rash. The needle used is a small gauge non-boring tip. Once the reservoir has 
been accessed, the needle is immobilized to ensure minimal movement or risk of removal. 
If the needle dislodges during an infusion, it may not be reinserted, as sterility has been 
compromised. Guidance for assessing the reservoir devices for leakage and replacement is 
provided in the Study Pharmacy Manual. At the discretion of the investigator and/or 
neurosurgeon, the reservoir may be replaced during the clinical study. 
9.2 
Discussion of Study Design, including Choice of Control Group 
This study must be performed in patients with CLN2 disease because neither ICV access 
device implantation nor potential development of TPP1 autoimmunity, and their unknown 
long-term health consequences, are acceptable risks for healthy volunteers. However, these 
risks in a patient population are balanced by the near certainty of severe disability and death 
within a few years. 
The diagnosis of CLN2 disease determined by TPP1 enzyme activity (dried blood spot) in 
the fibroblasts and leukocytes available at Screening. In addition, blood for TPP1 enzyme 
activity and CLN2 gene analysis will be collected to be analyzed centrally.  
Because CLN2 disease is fatal in childhood, the study population must be children. Because 
therapeutic benefit is unlikely in advanced CLN2 disease, given the extensive depletion of 
cortical neurons, lack of extensive CLN2 disease progression is required for study 
participation, resulting in a study population comparable to that of a TPP1 gene therapy study 
(Worgall, 2008). Safety evaluation would also be limited in advanced patients, who are 
essentially in a vegetative state. 
A clinical rating scale, the Hamburg Scale, was developed to document the natural history of 
CLN2 disease (Steinfeld, 2002). A modified form of that scale, the Modified Hamburg Scale, 
demonstrated statistically significant slowing of neurologic decline in subjects receiving gene 
therapy intervention when compared with decline among control subjects (Worgall, 2008). 
A second CLN2 disease rating scale, the Weill Cornell Scale (Dyke, 2012); (Worgall, 2007), 
has also been used to evaluate CLN2 disease severity with highly comparable results. 

 
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Although all 4 domains of the Hamburg rating scale will be completed (Appendix 1), the 
motor and language domains are most useful for this study. Language and motor are the 
earliest domains to lose function, therefore the aggregate CLN2 motor-language scale are 
appropriate metrics for screening and efficacy. To be eligible for study participation, motor 
and language domains administered during Screening must document CLN2 disease 
progression with a 2-domain ML score of 3-6 for these 2 domains, as defined in the Ratings 
Assessment Guideline. The planned patient enrollment of at least 10 patients is to include at 
least 5 patients with a combined ML score ≥ 5 points (mild disease) and at least 5 patients 
with a ML score < 5 points (moderate disease) to ensure that an equal number of patients 
with mild and moderate disease are enrolled. In addition, at least 5 patients < 2 years of age 
will be enrolled. The effectiveness endpoint will compare motor and language subscale 
scores of treated study subjects with those of untreated patients acquired from the natural 
history data of CLN2 disease registries and data from siblings with CLN2 disease, when 
available. 
The remaining 2 domains in the rating scale (Appendix 1) are less likely to be informative for 
this study. In order to capture the seizure and movement disorder manifestations of CLN2 
disease in more detail, adapted domains from the Unified Batten Disease Rating Scale 
(UBDRS) are incorporated into the protocol. The UBDRS domains record involuntary 
movements and seizures according to type, frequency and severity (Kwon, 2011).  
Because of practical (limited number of available patients) and ethical (neurosurgery in 
children with fatal neurologic disease) concerns, this study design cannot involve 
contemporaneous, matched, randomized, blinded, or untreated control 
subjects (Arkin, 2005); (Crystal, 2004.). Motor and language subscales and total scores for 
the Hamburg CLN2 disease scale will be compared with historical natural history data from 
the registry at the University Medical Center in Hamburg, Germany and/or data from siblings 
with CLN2 disease, as appropriate. 
9.3 
Selection of Study Population 
Pediatric patients (from birth to < 18 years of age) with confirmed CLN2 disease progression 
may be eligible to participate in this study. Additional criteria for participation in this study 
are detailed below. Subjects must satisfy the following criteria in order to enroll in the study: 
9.3.1 Inclusion Criteria 
• Diagnosis of CLN2 disease as determined by TPP1 enzyme activity (dried blood 
spot) in the fibroblasts and leukocytes available at Screening. Note: Blood for TPP1 
enzyme activity and CLN2 gene analysis must be collected to be analyzed centrally.  

 
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• Quantitative clinical assessment of the Hamburg motor-language aggregate score 
3-6 at Screening, as defined in the Ratings Assessment Guideline.  
• < 18 years of age at the time of informed consent 
• Written informed consent from parent or legal guardian and assent from subject, if 
appropriate 
• Males and females who are of reproductive age should practice true abstinence, 
defined as no sexual activity, during the study and for 6 months after the study has 
been completed (or withdrawal from the study). If sexually active and not practicing 
true abstinence, males and females of reproductive age must use a highly effective 
method of contraception while participating in the study. 
• Ability to comply with protocol required assessments (ICV implantation, drug 
administration, laboratory sample collection, EEG, ECG, MRI, etc.) 
 
9.3.2 Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
• Another inherited neurologic disease, e.g., other forms of CLN or seizures unrelated 
to CLN2 disease (patients with febrile seizures may be eligible) 
• Another neurological illness that may have caused cognitive decline (e.g., trauma, 
meningitis, hemorrhage) or interfere with disease rating (autism) before Screening 
• Percutaneous feeding tube placement prior to enrollment 
• Has received stem cell, gene therapy, or ERT  
• Contraindications for neurosurgery (e.g., congenital heart disease, severe respiratory 
impairment, or clotting abnormalities) 
• Contraindications for MRI scans (e.g., cardiac pacemaker, metal fragment or chip in 
the eye, aneurysm clip in the brain) 
• Episode of generalized motor status epilepticus within 4 weeks before the First Dose 
visit 
• Severe infection (e.g., pneumonia, pyelonephritis, or meningitis) within 4 weeks 
before the First Dose visit (enrollment may be postponed) 
• Presence of ventricular abnormality (hydrocephalus, malformation) 
• Presence of ventricular shunt 
• Has known hypersensitivity to any of the components of BMN 190 

 
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• Has received any investigational medication within 30 days before the first infusion 
of study drug or is scheduled to receive any investigational drug other than BMN 190 
during the course of the study  
• Has a medical condition or extenuating circumstance that, in the opinion of the 
investigator, might compromise the subject’s ability to comply with the protocol 
required testing or procedures or compromise the subject’s wellbeing, safety, or 
clinical interpretability 
• Pregnancy any time during the study; a female subject judged by the investigator to 
be of childbearing potential will be tested for pregnancy 
9.3.3 Removal of Subjects from Treatment or Assessment 
Subjects (or their legally authorized representatives) may withdraw consent for study 
participation any time without prejudice; investigators must withdraw from the study any 
such subject. At the discretion of investigator clinical judgment, a subject may be withdrawn 
from the study any time. When possible, an Early Termination visit should be scheduled 
(Section 12.10). 
It is a priority of the study to maximize study subject retention and adherence to 
study-specific procedures. Since study data completeness may affect integrity and accuracy 
of study results, any subject who suspends or discontinues study treatment should be 
encouraged to continue study-specific procedures for the remainder of the study. Subjects 
may suspend or discontinue study medication but should be encouraged to be evaluated per 
study-specific visit schedule and to undergo all required study procedures and assessments. 
The investigator (or designee) must contact the BioMarin medical monitor when a subject 
discontinues from the study. BioMarin reserves the right to discontinue the study at any time 
for either clinical or administrative reasons and to discontinue participation of an individual 
investigator or study site for poor enrollment or noncompliance with the protocol or 
regulatory requirements. 
Reasons for which the investigator or BioMarin may withdraw a subject from the study 
include, but are not limited to, the following: 
• Subject experiences a serious or intolerable AE 
• Subject develops a clinically significant laboratory abnormality 
• Subject requires medication or medical procedure prohibited by the protocol 
• Subject does not adhere to study requirements specified in the protocol 
• Subject was erroneously admitted into the study or does not meet entry criteria 

 
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• Subject is lost to follow-up 
If a subject fails to return for a scheduled visit, a documented effort must be made to 
determine the reason. If the subject cannot be reached by telephone, a certified letter should 
be sent to the subject (or the subject’s legally authorized representative, if appropriate) 
requesting that s/he contact the investigator. A copy of this letter and any response should be 
kept in the study records. If the subject cannot be contacted or fails to respond, the subject 
will be considered lost to follow-up.  
The investigator (or designee) must explain to each subject before enrollment in the study 
that the subject’s protected health information obtained during the study may be shared with 
the study sponsor, regulatory agencies, and IRB/IEC/REC. It is the responsibility of the 
investigator (or designee) to obtain written permission to use protected health information per 
country-specific regulations, such as HIPAA in the US, from each subject or (legally 
authorized representative, if appropriate). If permission to use protected health information is 
withdrawn, it is the investigator’s responsibility to obtain a written request to ensure that no 
further data will be collected from the subject, and the subject will be removed from the 
study. 
9.3.3.1 
Stopping Criteria  
As described in Section 10.2.3.2, all AEs, including toxicity of study drug, will be assessed 
according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
AEs (CTCAE) v. 4.0 
Hypersensitivity reactions, including anaphylaxis and less severe allergic reactions, are 
identified risks of ERT. For hypersensitivity or allergic-type reactions, unacceptable 
drug-related toxicity shall be defined as a NCI CTCAE v. 4.0 Grade 3 or higher AE that is 
study-drug related in the opinion of the investigator and meets either of the following criteria:  
• Shows no improvement with medical intervention, such as infusion interruption, 
infusion rate reduction, or administration of intravenous antihistamine, oxygen, 
intravenous fluids, or steroids; or  
• Recurs during subsequent infusions at the same or worse severity and intensity, 
despite any of the following: premedication with appropriate antihistamines, 
antipyretics, or steroids; and modification of infusion rate.  
Instances of unacceptable drug-related toxicity should be discussed by the investigator with 
the BioMarin medical monitor. A subject who experiences unacceptable drug-related toxicity 
may be withdrawn from study treatment after consultation with the BioMarin medical 
monitor.  

 
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The normal infusion will be administered over 4 (±1) hours at a rate of 2.5 mL/hr; the dose 
will be determined by the patient’s age. Subjects not receiving the full 300 mg dose 
(administered in a total volume of 10 mL) will receive the appropriate volume at a rate of 
2.5 mL/hr for over a shorter duration of time (See Section 9.4.1). Dosing can be adjusted in 
the judgement of the investigator, upon consultation with the medical monitor, to manage 
AEs as outlined in Table 9.4.1.1.  
For all events not hypersensitivity or allergic-type reactions, the following will apply: 
• If a subject has a Grade 3 or higher AE based on NCI CTCAE v. 4.0 that, in the 
investigator’s opinion, is not related to the subject’s underlying disease, 
consideration will be given to discontinuing the subject from treatment depending 
on the nature of the event and its persistence. This decision will be made by the 
investigator in consultation with the BioMarin medical monitor, who may consult 
the Data Review Board (DRB).  
• If two subjects experience the same NCI CTCAE v. 4.0 Grade 3 AE, or if one 
subject has a Grade 4 AE that, in the investigator’s opinion, is not related to the 
underlying disease, the BioMarin medical monitor will consult the DRB to 
evaluate the risk/benefit of continuing the study. 
Another possible AE is infection from or failure of the indwelling ICV catheter. If an 
infection is suspected, blood and CSF samples will be drawn for assessment. The subsequent 
course of therapy, which is guided by site neurosurgical standards of care, may include 
antibiotic therapy, catheter reposition, or catheter withdrawal. If BMN 190 treatment is 
suspended, BMN 190 may resume if no more than 4 consecutive missed doses elapse after 
the last given dose. 
If BMN 190 treatment is suspended for any reason, study participation may resume if no 
more than 4 consecutive doses were missed from the prior given dose. 
If two or more subjects experience unacceptable drug-related toxicity, BioMarin may 
suspend further enrollment in the study pending a review of the data and upon consultation 
with the DRB. Depending on the nature and severity of the unacceptable drug-related 
toxicity, dosing of subjects already enrolled in the study may be continued or suspended 
pending further review. BioMarin will consult the DRB to aid in evaluating the risks of 
continuing the study and options for modification of the study to minimize subject risk. 
Subjects who have a loss of 3 or more points on the combined motor and language 
components of the Hamburg CLN2 rating scale in any 1 year period may be discontinued at 
the discretion of the Investigator.  

 
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Subjects with a score of 0 on the combined motor and language components of the Hamburg 
CLN2 rating scale at two consecutive visits will be discontinued from treatment. 
9.3.4 Subject Identification and Replacement  
Each subject will be assigned a unique subject identifier, which will be on all eCRF pages. 
In legal jurisdictions where use of initials is not permitted, a substitute identifier will be used. 
Subjects who discontinue the study will not be replaced. 
9.3.5 Duration of Subject Participation 
Subject participation will involve surgical implantation of the ICV access device followed by 
14 to 28 days of post-operative recovery and will continue for at least 144 weeks of treatment 
for all subjects. Treatment will continue until all procedures are completed, the subject 
withdraws consent and discontinues from the study, is discontinued from the study by the 
investigator, or the study is terminated by BioMarin. A Safety Follow-Up visit will be 
conducted 6 months after the final BMN 190 infusion, but will not be required if the subject 
enrolls in an extension study, registry, or otherwise has continued access to BMN 190 within 
6 months after the last infusion (refer to Section 10.2.1 for AE/SAE reporting instructions). 
BioMarin reserves the right to discontinue the study any time for clinical or administrative 
reasons and to discontinue participation of an individual investigator or site for clinical or 
administrative reasons, including, but not limited to, poor enrollment or noncompliance with 
procedures of the protocol or GCP. 
9.4 
Treatments 
BioMarin or its designee will provide the study site with study drug sufficient for study 
completion. BioMarin or its designee will be responsible for shipping study drug to clinical 
sites. 
9.4.1 Treatments Administered 
BMN 190 will be administered by ICV infusion every 14 days (+3 days), preferably in the 
morning, according to the patient’s age:  
• birth to < 6 months: 100 mg 
• 6 months to < 1 year: 150 mg 
• 1 year to < 2 years: 200 mg (first 4 doses), 300 mg (subsequent doses) 
• ≥2 years: 300 mg 
 

 
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Patients younger than 2 years will start the study at the dose level appropriate for their age 
and will transition to the dose level consistent with their age as they mature. 
Fasting for a minimum of 2 hours may be considered for the first infusion and subsequent 
infusions until the subject's reaction to the study drug is determined. When a feeding tube is 
used, the tube may be turned off 2 hours before infusion.  
The normal infusion will be administered over 4 (±1) hours at a rate of 2.5 mL/hr; the dose 
will be determined by the patient’s age. Subjects not receiving the full 300 mg dose 
(administered in a total volume of 10 mL), will receive the appropriate volume at a rate of 
2.5 mL/hr for over a shorter duration of time (see Table 9.4.1.1 below). 
Table 9.4.1.1:  Age-Specific Dosing Schema for BMN 190 Administration 
Age 
Dose 
Rate 
Infusion Time 
Dose Modification Options (AEs) 
birth to < 6 
months 
100 mg 
2.5 mL/hr 
1.3 hours (±0.5 hr) 
• Reduce infusion rate and administer 
drug over 2 hours 
• Reduce the dose by 50% administered 
over the 1.3 ( ± 0.5) hours  
• Reduce the infusion rate and administer 
50% of the target dose over 2 hours 
6 months to < 
1 year 
150 mg 
2.5 mL/hr 
2 hours (±0.5 hr) 
• Reduce infusion rate and administer 
drug over 3 hours 
• Reduce the dose by 50% administered 
over the 2 ( ± 0.5) hours  
• Reduce the infusion rate and administer 
50% of the target dose over 3 hours 
1 year to 
< 2 years 
200 mg (first 
4 doses),  
 
300 mg 
(subsequent 
doses) 
2.5 mL/hr 
 
 
2.5 mL/hr 
2.7 hours (±1 hr) 
 
 
4 hours (±1 hr) 
• Reduce infusion rate and administer 
drug over 4 hours (200 mg); 6 hours (300 
mg) 
• Reduce the dose by 50% administered 
over the 2.7 ( ± 1) hours (200 mg); 4 ( ± 
1) hours (300 mg) 
• Reduce the infusion rate and administer 
50% of the target dose over 4 hours (200 
mg); 6 hours (300 mg) 
≥2 years 
300 mg 
2.5 mL/hr 
4 hours (±1 hr) 
• Reduce infusion rate and administer 
drug over 6 hours 
• Reduce the dose by 50% administered 
over the standard time of 4 ( ± 1) hours 
• Reduce the infusion rate and administer 
50% of the target dose over 6 hours  
 
Dosing can be adjusted in the judgement of the investigator, upon consultation with the 
medical monitor, to manage AEs as outlined above. Should the dose-limiting AE resolve in 

 
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the opinion of the investigator, and upon consultation with the medical monitor, dosing at the 
full dose may resume. 
In patients younger than 2 years, dosing may also be adjusted by the sponsor in consultation 
with the investigator and medical monitor based on results from PK analysis, as follows: 
• Within a patient, if the observed CSF AUC0-t exceed the range of CSF AUC0-t 
characterized with the 300 mg dose in Study 190-201, the dose may be reduced to 
50% of the recommended age-appropriate dose. 
• Within a patient, if the observed CSF AUC0-t is less than the range of CSF AUC0-t 
characterized with the 300 mg dose in Study 190-201, the dose may be increased to 
the recommended dose for the next oldest age group. 
9.4.2 Identity of Investigational Product 
9.4.2.1 
Product Characteristics and Labeling 
The study drug label includes, but is not limited to, the following information: lot number, 
required storage conditions, a precautionary statement, expiry date, study number, and 
BioMarin name and address.   
9.4.3 Storage 
At the study site, all study drugs must be stored under conditions specified in the 
Investigator’s Brochure and Study Pharmacy Manual in a secure area accessible only to the 
designated pharmacists and clinical site personnel. All study drugs must be stored and 
inventoried, and inventories must be carefully and accurately documented according to 
applicable local, state, and federal regulations, ICH GCP, and study procedures. 
9.4.4 Directions for Administration 
Surgical implantation of an ICV reservoir will take place prior to study drug administration. 
The investigator will evaluate the patency, location, and skin integrity of the reservoir at each 
study drug administration (refer to the Study Pharmacy Manual). At each administration, the 
investigator will draw 1-2 ml of CSF into the device cannula to check for patency prior to 
administering the study drug. This volume of CSF is also to be used for laboratory testing 
(cell count, protein, glucose, and culture) as noted in Table 9.1.1. Access to the device is 
performed using strict sterile technique. Skin covering the reservoir is inspected for an 
appropriate needle insertion site. The needle insertion site must be intact, without evidence of 
breakdown, wound, infection or rash. The needle used is a small gauge non-boring tip. Once 
the reservoir has been accessed, the needle is immobilized to ensure minimal movement or 
risk of removal. If the needle dislodges during an infusion, it may not be reinserted, as 
sterility has been compromised. At the discretion of the investigator and/or neurosurgeon, the 

 
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reservoir may be replaced during the clinical study. Refer to Section 7.4.2 for risks associated 
with the implantation procedure. 
All study subjects will be administered BMN 190 by ICV infusion every 14 days (+3 days), 
preferably in the morning. Fasting for a minimum of 2 hours may be considered for the first 
infusion and subsequent infusions until the subject's reaction to the study drug is determined. 
When a feeding tube is used, the tube may be turned off 2 hours before infusion. Study 
procedures for each study visit should precede study drug infusion unless otherwise 
specified. The date, time, volume, and concentration of each dose of study drug administered 
to each subject will be recorded in the dispensing log provided for the study as well as on the 
appropriate eCRF. The Study Pharmacy Manual provides further instructions on preparation 
and administration of study drug.  
Subjects will be admitted to the hospital for every BMN 190 infusion. For all infusions, 
subjects will be monitored in an appropriate inpatient setting for a minimum of 24 hours 
from the start of the infusion. For the first infusion only, subjects will also return for a 
follow-up visit to clinic 72 hours (and no later than the third calendar day) after the start of 
infusion. After all visits, the parent or legal guardian will be telephoned within 48 hours to 
determine health status. 
Because hypersensitivity reactions may be associated with ERT administration, subjects 
should be pretreated with age-appropriate doses of antihistamine (and antipyretic, if 
appropriate) medication approximately 30 minutes (± 15 minutes) before BMN 190 
infusions. Subjects may be pretreated, at the discretion of the Investigator, with age-
appropriate sedative medication approximately 30 minutes (± 15 minutes) before BMN 190 
infusion according to institution’s standard practices. Clinical, developmental, and QOL 
assessments are to be performed before premedication for infusions. 
The normal infusion will be administered over 4 (±1) hours at a rate of 2.5 mL/hr; the dose 
will be determined by the patient’s age. Subjects not receiving the full 300 mg dose 
(administered in a total volume of 10 mL) will receive the appropriate volume at a rate of 
2.5 mL/hr for over a shorter duration of time (see age-specific dosing table in Section 9.4.1). 
Uniform infusion rate should be ensured by use of a syringe pump with appropriate delivery 
range, delivery rate accuracy, and alarms for incorrect delivery or occlusion. If the dose 
needs to be stopped for safety or other reasons, it may be restarted at the same rate and 
completed so long as the total dose is administered within 10 hours of preparation of the dose 
syringes.  
Dosing can be adjusted in the judgement of the investigator, upon consultation with the 
medical monitor, to manage AEs as outlined in Table 9.4.1.1. Should the dose-limiting AE 

 
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resolve in the opinion of the investigator, and upon consultation with the medical monitor, 
dosing at the full dose may resume.  
In patients younger than 2 years, dosing may also be adjusted by the sponsor in consultation 
with the investigator and medical monitor based on results from PK analysis, as follows: 
• Within a patient, if the observed CSF AUC0-t exceed the range of CSF AUC0-t 
characterized with the 300 mg dose in Study 190-201, the dose may be reduced to 
50% of the recommended age-appropriate dose. 
• Within a patient, if the observed CSF AUC0-t is less than the range of CSF AUC0-t 
characterized with the 300 mg dose in Study 190-201, the dose may be increased to 
the recommended dose for the next oldest age group. 
9.4.4.1 
Safety Monitoring 
Following ICV access device placement, subjects and their caregivers will be given written 
instructions providing details on signs and symptoms of concern for device complications 
and instruction on when to return to the site for device evaluation. Patients will be admitted 
to the hospital for every BMN 190 infusion.  For all infusions, subjects will be monitored in 
an appropriate inpatient setting for a minimum of 24 hours from the start of the infusion.  
For the first infusion only, subjects will also return for a follow-up visit to clinic 72 hours 
(and no later than the third calendar day) after the start of infusion. After all visits, the parent 
or legal guardian will be telephoned within 48 hours to determine health status. 
Vital signs (Section 9.7.5.1) will be measured within 30 (±5) minutes before infusion start or 
restart, every 30 (±5) minutes during infusion, 0.5 hours (±5 minutes), 1 hour (±5 minutes), 
and 4 hours (±15 minutes) after infusion end, and then every 4 hours (±15 minutes) for the 
next 16 hours. Blood pressure will be measured in the upper arm using an appropriately sized 
blood pressure cuff. If the patient’s blood pressure is abnormal (as compared to site-specific 
reference ranges), a manual blood pressure will be obtained by a trained healthcare 
professional.  
For the first infusion of BMN 190, continuous ECG monitoring (3- or 5-lead) will be 
performed for all subjects. The ECG should begin 15 (± 5 minutes) prior to infusion start, 
continue through infusion of BMN 190, and end after infusion of flushing solution. In the 
event that the subject has already received the first infusion of BMN 190, the next infusion 
will be monitored as above. If a 12-lead ECG is required during this time, continuous 
monitoring should be interrupted in order to obtain the 12-lead ECG. 
A standard ECG (12-lead), including heart rate, rhythm, intervals, axis, conduction defects, 
and anatomic abnormalities, will be performed 30 (±5) minutes after infusion end at the first 
infusion and every 24 weeks thereafter. In patients with present or past bradycardia, 

 
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conduction disorders, or with structural heart disease, an ECG will be performed within 
30 minutes before the start of infusion (±5 minutes), at 2 hours (±15 minutes) during 
infusion, 30 (±5) minutes after infusion end, and 12 hours (±3 hours) after infusion end for 
each study drug infusion. 
Subjects require regular monitoring for adverse events and epileptic seizures by appropriately 
trained personnel throughout the duration of the infusion. If epileptic seizures develop, the 
infusion may be interrupted at the discretion of the investigator. Because hypersensitivity 
reactions (anaphylaxis or general allergic) may occur, it is required that appropriately trained 
personnel and equipment for emergency resuscitation (including epinephrine) be available 
near the bedside during study drug infusion. In case emergency treatment is needed, all 
subjects should have an intravenous line during infusion. If the prior 3 study drug infusions 
were completed without significant adverse events, an intravenous access line does not have 
to be placed prior to infusion as consistent with local hospital policies. However, supplies for 
placing emergency access and all emergency medication must be readily available should 
they be needed. For information regarding the reporting of hypersensitivity reactions, refer to 
Section 10.4.1.  
Symptoms of hypersensitivity reactions may include fever, chills/rigors, skin symptoms 
(urticaria, angioedema, rash), respiratory symptoms (dyspnea, wheezing, stridor), 
gastrointestinal symptoms (nausea, vomiting, abdominal pain), and/or cardiovascular 
changes (hypotension/hypertension). If more severe symptoms, such as angioedema (tongue 
or throat swelling) or stridor, develop, the infusion should be stopped. 
To date there has been no anaphylaxis or anaphylactoid reactions in studies with BMN 190. 
However, in the event of a suspected anaphylactic reaction, serious hypersensitivity event, or 
severe hypersensitivity (defined as a hypersensitivity event of Grade 3 or higher), blood 
samples to assess C4, serum tryptase, and total IgE will be collected within 1 hour of the 
event and tested; a blood sample to assess drug-specific IgE will be collected no sooner than 
8 hours after the event (or before the next infusion). 
Safety assessments will be conducted during and after each infusion. Subjects may be 
required to stay for a longer observation period at the investigator’s discretion. If an AE 
consistent with a hypersensitivity reaction (Section 7.4.1) is observed, appropriate 
intervention may include infusion interruption, infusion rate decrease, or administration of 
antihistamine, oxygen, fluids, or steroids. If infusion is restarted after interruption, the initial 
rate should be approximately one-half the rate at which the reaction occurred. Further detail 
for infusion modification is provided in the Study Pharmacy Manual. 

 
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The parent or legal guardian will be instructed to contact the investigator to discuss any AE 
subsequent to discharge.  
The use of ICV access devices can result in infections, intracerebral hemorrhage from 
chronic reservoir use, reservoir leakage, and seizures (Karavelis, 1996) (Kronenberg, 1998). 
Additional surgery may be required to fix or replace the devices. Patients will be monitored 
throughout the study for potential infections (high temperature, cough, rash, headache, 
swelling or drainage in the incision area) and signs of ICV reservoir leakage or failure (refer 
to the Study Pharmacy Manual).  
Because of the inherent safety considerations surrounding the implanted device, 
arrangements should be made for the subject to have the ICV access device removed no more 
than 4 weeks after either the Study Completion visit or the Early Termination visit.  
All removed or replaced implantable ICV devices must be returned to BioMarin in order to 
evaluate the material integrity of the reservoir, and all other devices (as described in the 
Pharmacy Manual) except for infusion pumps, should also be returned.  If the subject intends 
to continue to receive BMN 190 following participation in this study (e.g., via commercial 
product, use in a registry, or another BMN 190 study), then the device does not need to be 
removed. Following device removal, subjects should return to the site 4 weeks (±3 days) later 
for a safety follow-up visit. 
9.4.5 Method of Assigning Subjects to Treatment Groups 
Subjects will be enrolled as they become available and without attention to any entry 
criterion or other patient characteristic.  
9.4.6 Selection of Dose 
BMN 190 will be administered by ICV infusion every 14 days (+3 days) according to the 
patient’s age:  
• birth to < 6 months: 100 mg 
• 6 months to < 1 year: 150 mg 
• 1 year to < 2 years: 200 mg (first 4 doses), 300 mg (subsequent doses) 
• ≥2 years: 300 mg 
 
Patients younger than 2 years will start the study at the dose level appropriate for their age 
and will transition to the dose level consistent with their age as they mature. 
The 300 mg dose level was derived from dose levels used in the TPP1-null dachshund study 
(Vuillemenot, 2011). Pharmacological effects, including functional improvement and life 
extension, have been robustly demonstrated in TPP1-null dachshunds at 4 mg and 

 
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16 mg dose levels. Since TPP1 activity in brain tissue is proximally related to CNS 
lysosomal storage materials, scaling by brain mass is judged to be predictive of the human 
therapeutic dose. Human-equivalent doses were calculated by brain mass scaling. The human 
brain on average achieves about 75% of adult mass by age 2 and 100% by age 5 
(Giedd, 1996). If adult human brain mass is 1400 g, the range for healthy children aged 2 to 
7 years would be 1050 to 1400 g. Given progressive brain atrophy in CLN2 disease patients, 
an average mass of 1000 g was assumed, producing a scaling factor of 20-fold based on 
average dachshund brain mass of 50 g.  
The no-observed-adverse-effect level (NOAEL) which also yielded clinical disease benefit 
from nonclinical studies in Dachshund was 48 mg, which would correspond to 960 mg in 
human.  
BMN 190 dose scaling by brain mass has been used to target similar drug concentrations in 
CNS tissue and scaled doses have yielded similar PK in CSF when applied across species 
(i.e., dog, monkey and human). This approach supports a dose of 300 mg every 14 days 
down to 1 year of age, where the human brain has reached approximately 68-73% of its adult 
mass, or 0.94 kg and 0.97 kg for females and males, respectively (Dekaban, 1978). Subjects 
less than 1 year of age will receive a reduced dose, scaled by brain mass, and will escalate to 
the next dose level as they age on the study. As an additional precaution, subjects aged 
between 1 to < 2 years will receive an initial dose of 200 mg for the first 4 doses to assess the 
safety, tolerability and PK of BMN 190 before being escalated to the 300 mg dose level. This 
dosing plan enables enrollment of subjects who are younger than 2 years of age. 
The age-specific dose of BMN 190 will be infused at a uniform rate of 2.5 mL/hour for all 
subjects, thus requiring shorter total infusion times for subjects administered doses lower 
than 300 mg. The total infusion volume and infusion rate is within the physiologic functional 
range in relation to the brain volume, CSF volume and CSF turnover rate of children 
< 3 years of age. The total volume of CSF in an infant is approximately 50 mL, thus the total 
volume of BMN 190 infused (3.3 mL) is less than 10% of this volume. Furthermore, since at 
least 2 mL of CSF will be collected prior to each infusion for surveillance laboratory testing, 
the total drug volume infused is not expected to be of physiologic consequence as it pertains 
to changes in intracerebral pressure.  
CSF production rates in humans have been calculated to be 0.3–0.4 ml/min, which translates 
to an hourly production rate of approximately 20 ml (Pappenheimer, 1962). A more recent 
retrospective study of 100 children (61 males, 39 females; age 0.02 to 15.7 years) with 
hydrocephalus due to various causes measured hourly CSF production output as reflected by 
the output through an external ventricular drainage (EVD) (Yasuda, 2002). The mean (SD) 

 
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hourly rate of CSF output was 8.1 (5.2) mL/h. A regression analysis indicated that the age 
and body weight appeared to correlate with the hourly CSF output. The regression equation 
is as follows: hourly CSF output = 2.78 – 2.23(male = 0, female = 1) + 0.97 log (age in 
years) + 2.26 log (body weight in kg). Thus, the predicted hourly CSF output even for a 
6 month old child be approximately 2.5 to 4.7 mL, which exceeds the hourly rate of 
BMN-190 infusion of 2.5 mL, suggesting that the infusion rate is compatible with CSF 
physiology.  
Lastly, this dosing strategy also has the added benefits of shortening the total infusion time 
for infants (approximately 1.3 to 1.5 hours) and toddlers (approximately 2.7 hours) and 
decreasing the possibility of dosing errors (since the smaller volume will be administered at a 
consistent rate). 
The PK of BMN 190 will be assessed in this study to further confirm the appropriateness of 
this approach. In children younger than 2 years, dosing may be adjusted based on PK as 
described in Section 9.4.1. 
9.4.6.1 
Selection of Timing of Dose for Each Subject 
A mean CNS half-life of approximately 2 weeks (
) suggests biweekly dosing 
may sustain therapeutic BMN 190 levels in the CNS. BMN 190 concentrations in CSF 
remained above the lysosomal Kuptake for approximately 48 hours after single ICV or IT-L 
infusions in species with CSF dynamics similar to those in human (Vuillemenot, 2014), 
(Vuillemenot, 2011); 
). In these same species (dog and monkey), CNS 
distribution of BMN 190 was extensive in many brain regions.  
9.4.6.2 
Selection of Infusion Volume and Rate 
The nonclinical studies in the dachshund and cynomolgus monkey utilized an infusion rate of 
approximately 5% of the total CSF volume per hour.  This was expected to represent a safe 
infusion rate that would minimize changes in total CSF volume and intracranial pressure.  
The dachshunds received ICV infusions at a rate of 0.6 mL/hour for 2-4 hours, while 
monkeys received 0.88 mL/hour for 3.6 hours. No effects were observed in these studies 
indicative of safety concerns due to the infusion rate. In the CLN2 patient population, the 
estimated CSF volume is approximately 100 mL. For the proposed clinical trial, a volume of 
10 mL infused over a 4 hour period represents an infusion rate of 2.5% of the total CSF 
volume per hour, which is approximately half the rate that had no safety effects in the 
nonclinical studies.  
PI
PI

 
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Therefore, we expect that 10 mL infused over 4 hours would be safe in CLN2 patients. 
This infusion rate has been used, with acceptable results, in the 48-week, Phase 1 / 2, 
190-201 clinical trial (completed) and ongoing 190-202 extension study.  
In subjects less than 2 years of age, the infusion volume will be reduced in accordance with 
their age-specific dose (Section 9.4.1) to account for differences in brain mass and CSF 
volume in younger subjects. 
9.4.7 Blinding 
This is a single-arm, open-label study. Study site assessments of safety and clinical severity 
will be performed without blinding to treatment and subjects will be enrolled as they become 
eligible. 
As defined in the Imaging Charter, oversight of MRI evaluation will be performed by 
independent radiologists at a central imaging facility. The interpreting radiologists and 
software analysis will be blinded to subject and time on study. All subject-identifying 
information will be redacted before endpoints are assessed. 
Oversight of EEG evaluation will be performed by an independent epileptologist at a central 
facility. The interpreting epileptologists and software analysis will be blinded to subject and 
time on study. All subject-identifying information will be redacted before endpoints are 
assessed. 
9.4.8 Prior and Concomitant Medications 
Medications (prescription, over-the-counter, and herbal) and nutritional supplements taken 
during the 30 days before informed consent will be recorded in the eCRF at Screening. 
At each subsequent visit (or within one week of the Early Termination visit), change in any 
medication (dosage, frequency, new medication, or cessation) since the previous visit will be 
recorded in the eCRF.  
Any concomitant medication added or discontinued during the study should be recorded in 
the eCRF (or within 1 week of the Early Termination visit). 
Subjects may be taking anticonvulsants and medications for myoclonus, tremor, agitation, 
and pain. Investigators will be asked to keep these regimens constant throughout the study, 
unless changes are required due to lack of efficacy or toxicity.   
Use of non-drug therapies such as physical and occupational therapy will also be noted in the 
eCRF. 

 
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9.4.9 Treatment Compliance 
Study drug will be administered to subjects at the study site by a qualified professional. Date, 
time, volume, and concentration of each dose must be recorded in the dispensing log as well 
as on the appropriate eCRF. In the event that a dose of study treatment is missed or 
incomplete, the investigator should record the reason and any other pertinent information on 
the eCRF as appropriate. 
9.5 
Investigational Product Accountability 
The investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of study drug received by each subject and study drug lost, or accidentally or 
deliberately destroyed. The investigator or designee must retain all unused or expired study 
supplies until the study monitor (on-site CRA) has confirmed accountability data. 
9.5.1 Return and Disposition of Clinical Supplies 
Unused study drug must be kept in a secure location for accountability and reconciliation by 
the study monitor. The investigator or designee must provide an explanation for any 
destroyed or missing study drug or study materials. 
Unused study drug may be destroyed on site, per the site’s standard operating procedures, but 
only after BioMarin has granted approval for drug destruction. The monitor must account for 
all study drug in a formal reconciliation process prior to study drug destruction. All study 
drug destroyed on site must be documented. Documentation must be provided to BioMarin 
and retained in investigator study files. If a study site is unable to destroy study drug 
appropriately, the site may return unused study drug to a BioMarin-designated facility for 
destruction. The return of study drug or study drug materials must be accounted for on a 
Study Drug Return Form provided by BioMarin. 
All study drug and related materials should be stored, inventoried, reconciled, and destroyed 
or returned according to applicable state and federal regulations and study procedures. 
9.6 
Dietary or Other Protocol Restrictions 
There are no dietary or other protocol restrictions for this study. Subjects who require a PEG 
(percutaneous endoscopic gastrostomy) tube as the standard of care during the course of the 
study will be allowed to continue in the study. When a feeding tube is used, the tube may be 
turned off 2 hours before infusion. 
9.7 
Efficacy and Safety Variables 
Efficacy will be measured using the 0 to 6-point ML score on the Hamburg CLN2 rating 
scale as the primary endpoint. The 12-point total score (motor, language, vision, and seizure 

 
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subscales) on the Hamburg CLN2 scale, time to disease manifestation (for asymptomatic 
patients), and MRI measures of disease progression will be collected as secondary endpoints.  
Exploratory efficacy measures will include developmental status, involuntary movements, 
retinal anatomy using OCT, seizure frequency, change in seizure activity (as measured by 
Hamburg score), anti-epileptic treatment, quality of life metrics, changes in EEG, assessment 
of visual acuity, and analysis of disease-related biomarkers.  
Timing of study assessments is detailed in the Schedule of Events (Table 9.1.1).  
9.7.1 Efficacy Variables 
9.7.1.1 
CLN2 Clinical Rating Scale 
Disease severity will be evaluated by the CLN2 clinical rating scale (Steinfeld, 2002); 
(Worgall, 2008). This scale consists of 4 domains with intrinsic content validity. Within each 
domain, a score from 0 to 3 is assigned and overall scores are calculated by summing the four 
domain scores for a final rating of 0 (severely impaired) to 12 (normal). 
Since the motor and language domains are most relevant to CLN2 disease progression 
(Section 9.2), they will be used to assess study eligibility and efficacy (Appendix 1). To be 
eligible for study participation, motor/gait and language domains administered during 
Screening must document confirmed CLN2 disease progression by a total score of 3-6 for 
these 2 domains, as defined in the Ratings Assessment Guideline. 
Raters will be identified as qualified practitioners, who have been trained on the definitions 
and implementation of the CLN2 disease rating scale. All raters at all sites will be required to 
pass a training session designed to standardize the definitions and scale anchor points across 
the study, before study ratings take place. Whenever possible, a single rater should evaluate 
each enrolled patient for the duration of treatment. Further, patient ratings should take place 
at the same time in the study visit, preferably in the morning before procedures and/or 
infusion takes place. CLN2 scale assessments should be done prior to pretreatments for 
BMN 190 infusion. 
9.7.1.1.1 Videotaping 
Rating scale assessments will be videotaped in a standardized manner across all study sites. 
The Ratings Assessment Guidelines provide detailed instructions for videotaping. All CLN2 
disease scale evaluations will be videotaped. Videotapes are used to corroborate clinical 
assessments and there are no efficacy outcomes associated with analysis of videotapes. 

 
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9.7.1.2 
Magnetic Resonance Imaging 
All image data will be acquired on a 1.5 Tesla MRI platform. Study MRIs will include 
localizer, 3D T1-weighted sagittal, T2-weighted gradient-echo, diffusion-weighted axial and 
FLAIR axial acquisitions, as specified in the Imaging Charter. Total scanner time is less than 
60 minutes and is expected to be accomplished in the majority of subjects with sedation. 
Volumetric analysis of images will be done by estimating both volume of total cortical grey 
matter and proportion of the cranial CSF. 
All patients will have an MRI without contrast prior to implantation of the ICV access 
device, to ensure proper planning and placement.  No study assessments associated with an 
MRI will be performed at the time of this MRI, and any readings taken during this MRI will 
not be included in the analysis of study data. 
An MRI scan also should be performed whenever infection or shunt dysfunction is suspected 
by the investigator. In this case, according to the Imaging Charter, the MRI should be with or 
without intravenous contrast with at least T1-weighted axial and sagittal aspects. For 
suspected meningitis, an MRI of the brain should be performed with and without contrast, 
according to the Imaging Manual. 
9.7.1.3 
Denver Development Scale II 
The Denver II is a revision and update of the Denver Developmental Screening Test. 
Both tests were designed to monitor the development of infants and preschool-aged children. 
The tests cover four general functions: personal social (such as smiling), fine motor adaptive 
(such as grasping and drawing), language (such as combining words), and gross motor (such 
as walking). Ages covered by the tests range from birth to 6 years. 
9.7.1.3.1 Modified Unified Batten Disease Rating Scale Involuntary Movement 
Inventory  
The modified Unified Batten Disease Rating Scale (mUBDRS) Involuntary Movement 
inventory is a rating scale that measures the type, frequency and severity of common 
involuntary movements associated with CLN2 disease such as myoclonus and dystonia.   
9.7.1.4 
Optical Coherence Tomography 
Optical coherence tomography (OCT) is a non-invasive imaging test that uses light waves to 
take cross-sectional pictures of the retina’s layers in order to measure their thickness. These 
measurements can aid in early detection and treatment for retinal diseases. OCT will be 
performed locally and should precede infusions. In order to limit the need for sedation to 

 
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perform this assessment, measurement should be obtained while the subject is also under 
sedation for MRI acquisition. 
OCT images will be collected by BioMarin, to be assessed by BioMarin personnel or 
designees. 
9.7.1.5 
Modified Unified Batten Disease Rating Scale Seizure Inventory 
The mUBDRS Seizure Inventory measures the type and frequency of seizures in CLN2 
patients in the prior 3 month interval. The inventory is completed with the aid of 
caregiver/family member recall in the period between study visits. 
9.7.1.6 
PedsQL 
The PedsQL™ Generic Core Scales are designed to measure Quality of Life in children and 
adolescents. The assessments are brief, practical and developmentally appropriate. 
The instrument is responsive to clinical change over time (Msall, 2005). The four parent 
reports cover the ages from 1-12 months, 13-24 months, 2-4 years, and ≥ 5 years, and include 
questions regarding physical, emotional, and social functioning, with school functioning 
where applicable. Patients who become older than age 5 during the study will no longer be 
assessed using this tool. 
9.7.1.7 
CLN2-specific QoL Questionnaire 
The CLN2-specific QoL Questionnaire is a disease specific supplement to the PedsQL using 
the same format and quantitation. The questionnaire is a novel instrument that was designed 
in collaboration with patient family and advocacy groups to capture elemental care and 
quality of life issues in late infantile CLN2 disease.  
9.7.1.8 
Electroencephalogram 
A standard awake EEG will be recorded within 2 days before each infusion. If a clinically 
significant abnormality is noted, the investigator or designee will evaluate whether study 
enrollment or continuation is appropriate; a clinically significant abnormality will be 
recorded under Medical History during Screening. 
9.7.1.9 
Assessments of Visual Acuity 
The Preferential Looking Test (PLT) is a method of assessing visual acuity in infants and 
children with limited cognitive function. The PLT assesses the acuity of children who are 
unable to identify pictures, shapes, or letters, and is particularly useful in children with 
physical and/or mental disabilities. The principle of the test is that a young child will choose 
to look towards an interesting visual stimulus (“target”) rather than a plain stimulus. 
The child is presented with two stimulus fields, one with stripes and the other with a 

 
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homogeneous gray area of the same average luminance as the striped field. The location of 
the stripes is randomly alternated. Typically, infants and children will look at the more 
interesting stripes (if they can detect them) rather than at the blank field. Teller, Keeler, and 
LEA Grating Acuity Cards have been standardized to assess grating (resolution) visual acuity 
in infants and nonverbal children using the principles of Preferential Looking.  
Other standardized versions of the LEA Test System use symbols or numbers to assess visual 
acuity in children who do not know how to read the letters of the alphabet that are typically 
used in an eye chart, but require higher cognitive function than PLT. The symbols are likely 
to be more useful in the CLN2 patient population. Similarly, the E-Hook or Tumbling E chart 
has been standardized to use rows of the letter "E" in various orientations. The patient is 
asked to point to where the limbs of the E are pointing "up, down, left or right." Depending 
on how far down the chart the patient can "read", his or her visual acuity is quantified.  
All subjects will perform PLT. Use of standardized Teller, Keeler, or LEA Grating Cards to 
perform PLT are all acceptable based on institutional standards and availability of personnel 
experienced in performing the assessments. The choice of testing materials should be 
consistent for all patients at each investigational site. In addition, for those children who 
retain the cognitive function to adhere to testing, the Lea Vision Test or Tumbling E Vision 
Test should also be performed during the same assessment using standardized techniques. 
The choice of additional assessments for higher functioning children (eg, LEA symbol or 
Tumbling E) should be made based on availability of experienced and qualified personnel to 
perform the assessment and should remain consistent throughout the study. Whenever 
possible, all tests of visual acuity should be performed by the same tester.  
The tests of visual acuity may be done either before or after drug infusion based on logistical 
considerations and ease for the subject and study personnel. However, the timing should 
remain consistent for all subsequent assessments. Patients must be alert and not influenced by 
any sedating medications. 
9.7.1.10 
Biomarkers 
Blood and CSF samples will be collected from subjects at the time points indicated in 
Table 9.1.1 and may be used to evaluate biochemical, molecular, cellular, and genetic aspects 
relevant to CLN2 disease, and to develop the assays used for these evaluations. Collection 
should precede study drug infusion.  
Exploratory genetic research to study or try to discover genes that are not yet known to be 
associated with CLN2 disease is optional.  

 
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All biomarker samples collected in this study may be used for exploratory biomarker 
research. In addition, samples collected in this study may be used for exploratory use once 
the primary use has been completed.  
9.7.2 Immunogenicity 
Immunogenicity tests will be performed at a specialty laboratory using validated 
immunogenicity assays on serum and CSF samples. Samples of blood (serum) and CSF will 
be collected for TAb and NAb testing before the first infusion (Baseline or Week 1 before the 
infusion), every 12 weeks thereafter, and at the Study Completion Visit. Samples of blood 
(serum) will be collected for TAb testing at the Device Safety Follow-Up and Safety 
Follow-Up visits (or within 1 week of the Early Termination visit). Collection must precede 
infusion. NAb will be tested at baseline and at subsequent time points when TAb is positive.  
Baseline samples will be used to obtain a baseline total and drug-specific IgE levels in the 
event of later hypersensitivity reactions requiring additional lab work.  
To date there has been no anaphylaxis or anaphylactoid reactions in studies with BMN 190. 
However, in the event of a suspected anaphylactic reaction, serious hypersensitivity event, or 
severe hypersensitivity (defined as a hypersensitivity event of Grade 3 or higher), blood 
samples to assess C4, serum tryptase, and total IgE will be collected within 1 hour of the 
event and tested; a blood sample to assess drug-specific IgE will be collected no sooner than 
8 hours after the event, or before the next infusion. 
9.7.3 Safety Variables   
Safety will be determined from incidence, severity, and relationship to BMN 190 of 
treatment-emergent AEs/SAEs reported during the study. In addition, growth (weight, 
height), vital signs, physical examination, neurologic examination, ECG, standard clinical 
laboratory blood (chemistry panel and CBC) and urine tests, standard clinical laboratory CSF 
tests (cell count with differential, protein, glucose, and culture), and concomitant medications 
will be monitored. 
9.7.3.1 
Adverse Events 
AEs and SAEs will be recorded as defined in Section 10.1. At each visit, subjects will be 
asked about new or ongoing AEs since the previous visit. 
9.7.3.2 
Device Malfunctions 
For this study, a medical device is defined as the infusion pump and all contact parts 
(reservoir and catheter, needles, infusion line with filter, extension sets, and syringes) 
intended to be used for administration of BMN 190. Device malfunctions should be reported 

 
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following the implantation of the ICV reservoir and catheter. A device malfunction means 
the failure of a device to meet its performance specifications or otherwise perform as 
intended. All removed or replaced implantable ICV devices must be returned to BioMarin in 
order to evaluate the material integrity of the reservoir, and all other devices (as described in 
the Pharmacy Manual) except for infusion pumps, should also be returned. For reporting 
device-related AEs of special interest, please refer to Section 10.4.1. 
9.7.3.3 
Clinical Laboratory Assessment 
Blood and urine samples will be collected for routine clinical laboratory assessments (blood 
chemistries, hematology, urinalysis) and analyzed locally. Collection should precede 
infusion.   
Any abnormal test result determined clinically significant by the investigator should be 
repeated until its cause is determined, the value returns to baseline or within normal limits, or 
the investigator determines the abnormal value was no longer clinically significant. 
All abnormal clinical laboratory pages should be initialed and dated by an investigator, along 
with a comment regarding clinical significance. Each clinically significant laboratory result is 
to be recorded as medical history at Screening and as an AE subsequently. 
If known, the diagnosis associated with an abnormality in clinical laboratory results 
considered clinically significant by the investigator should be recorded on the AE CRF. 

 
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Table 9.7.3.3.1:  Clinical Laboratory Tests 
Blood Chemistry 
Hematology 
Urinalysis 
albumin  
hemoglobin  
appearance 
alkaline phosphatase  
hematocrit  
color 
ALT (SGPT) 
WBC count 
pH 
AST (SGOT) 
RBC count 
specific gravity 
direct bilirubin 
platelet count 
ketones 
total bilirubin 
differential cell count  
protein  
blood urea nitrogen 
 
glucose  
calcium 
 
bilirubin 
carbon dioxide 
 
nitrite 
chloride 
 
urobilinogen 
total cholesterol 
 
hemoglobin 
C-reactive protein 
 
 
creatinine 
 
 
creatine kinase 
 
 
glucose 
 
 
GGT 
 
 
LDH 
 
 
phosphorus 
 
 
potassium 
 
 
total protein  
 
 
sodium  
 
 
uric acid  
 
 
 
9.7.3.4 
Cerebrospinal Fluid Surveillance 
Samples of standard clinical laboratory CSF for routine surveillance (cell count with 
differential, protein, glucose, and culture) will be collected within 30 (±5) minutes before 
every infusion. A small volume of CSF will be collected from the ICV reservoir and 
analyzed locally. Collection should precede study drug infusion.   
 

 
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9.7.3.5 
Other Laboratory Assessments 
Subjects who experience an SAE possibly related to BMN 190 or other AE of concern may 
have additional blood samples drawn to assess immunogenicity or safety parameters.  
9.7.4 Pharmacokinetics Variables 
On Day 1 and Weeks 25, 49, and 97 samples of CSF and plasma for serial PK will be 
collected within 15 minutes before infusion start, and 0.25, 4, 8, 20 (±5 minutes), 72, and 
120 (±15 minutes) hours after infusion completion. The following parameters will be 
evaluated by non-compartmental analysis: 
• Area under concentration-time curve from time 0 to infinity (AUC0-∞) 
• Area under concentration-time curve from 0 to the time of last measurable 
concentration (AUC0-t) 
• Maximum observed concentration (Cmax) 
• Time to reach Cmax (Tmax) 
• Elimination half-life (t½) 
• Apparent clearance of drug (CL/F) 
• Apparent volume of distribution based on terminal phase (Vz/F) 
If a subject discontinues the study within 48 hours after an infusion completion, plasma and 
CSF samples should be drawn during the Early Termination visit. 
9.7.5 Vital Signs, Physical Examinations, and Other Observations  
9.7.5.1 
Vital Signs 
Vital signs (SBP, DBP, heart rate, respiration rate, and temperature) will be measured within 
30 (±5) minutes before infusion start (or restart), every 30 (±5) minutes during infusion, 
0.5 hours (±5 minutes), 1 hour (±5 minutes), and 4 hours (±15 minutes) after infusion end, 
and then every 4 hours (±15 minutes) for the next 16 hours. Blood pressure will be measured 
in the upper arm using an appropriately sized blood pressure cuff. If the patient’s blood 
pressure is abnormal (as compared to site-specific reference ranges), a manual blood pressure 
will be obtained by a trained healthcare professional. 
9.7.5.2 
Physical Examination 
A complete physical examination will include general appearance (head, eyes, ears, nose, and 
throat), cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, genitourinary, 
and musculoskeletal. 

 
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A brief physical examination will include general appearance, cardiovascular, respiratory, 
neurologic, and gastrointestinal assessments. 
Body weight and height will also be assessed at the timepoints indicated in Table 9.1.1.  
Use of an ICV reservoir device for intracerebroventricular drug administration requires that 
patients be monitored throughout the study for potential infections (high temperature, cough, 
rash, headache, mental status changes, swelling or drainage in the incision area) and signs of 
ICV reservoir leakage or failure (swelling of skin around reservoir site, difficulty with CSF 
extraction, erythema of the scalp, bulging of reservoir device, or extravasation of fluid on 
infusion).   
The investigator will evaluate the patency, location, and skin integrity of the reservoir at each 
study drug administration. The investigator will check for scalp edema, erythema or skin 
breakdown at the site of the reservoir prior to infusion. Patency will be assessed during 
pre-infusion sampling and again at the time of infusion. Difficulty in obtaining the required 
volume of CSF necessary for pre-infusion samples or signs of ICV reservoir leakage 
(swelling of skin around reservoir site, erythema of the scalp, bulging of reservoir device, or 
extravasation of fluid) will prompt further evaluation of the reservoir for failure prior to 
continuing with infusion. Additional surgical consultation including surgery may be required 
to fix or replace the device. Material degradation of the ICV device reservoir has occurred 
after approximately 105 perforations of the ICV device in benchtop testing, and has been 
observed in clinical trials with approximately 4 years of BMN 190 administration. Access 
device replacement should be considered prior to 4 years of regular administration of 
BMN 190; with the decision made on an individual subject level based on the medical 
judgment of the Investigator. All removed or replaced implantable ICV devices must be 
returned to BioMarin in order to evaluate the material integrity of the reservoir, and all other 
devices (as described in the Pharmacy Manual) except for infusion pumps, should also be 
returned.   
Clinically significant abnormalities will be recorded under Medical History at Screening or 
as AEs thereafter. 
9.7.5.3 
Neurological Examination 
A complete neurological examination will include level of consciousness, speech, language, 
cranial nerves, motor strength, motor tone, abnormal movements, reflexes, upper extremity 
sensation, lower extremity sensations, gait, Romberg, nystagmus, and coordination. 

 
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9.7.5.4 
Electrocardiogram 
For the first infusion of BMN 190, continuous ECG monitoring (3- or 5-lead) will be 
performed for all subjects. The ECG should begin 15 (± 5 minutes) prior to infusion start, 
continue through infusion of BMN 190, and end after infusion of flushing solution. In the 
event that the subject has already received the first infusion of BMN 190, the next infusion 
will be monitored as above. If a 12-lead ECG is required during this time, continuous 
monitoring should be interrupted in order to obtain the 12-lead ECG. 
A standard ECG (12-lead), including heart rate, rhythm, intervals, axis, conduction defects, 
and anatomic abnormalities. ECG will be performed 30 (±5) minutes after infusion end at the 
first infusion and every 24 weeks thereafter. In patients with present or past bradycardia, 
conduction disorders, or with structural heart disease, an ECG will be performed within 
30 minutes before the start of infusion (±5 minutes), at 2 hours (±15 minutes) during 
infusion, within 30 (±5) minutes after infusion end, and 12 hours (±3 hours) after infusion 
end for each study drug infusion. 
If a clinically significant abnormality is noted, the investigator or designee will evaluate 
whether study enrollment or continuation is appropriate; a clinically significant abnormality 
will be recorded under Medical History during Screening and as an AE thereafter. 
9.7.5.5 
Pregnancy Testing 
At Screening and at any time during the study, a female subject judged by the investigator to 
be of childbearing potential (as defined by onset of menses) will be tested for pregnancy with 
a urine pregnancy test; additional urine tests will be performed whenever pregnancy is in 
question. A serum pregnancy test will be performed if a urine test result is positive or 
equivocal. 

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

 
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• Is a congenital anomaly or birth defect in the child or fetus of a patient exposed to IP 
prior to conception or during pregnancy 
• Is an important medical event or reaction – that, based on medical judgment, may 
jeopardize the patient or require intervention to prevent one of the above 
consequences (e.g. anaphylaxis) 
All adverse events that do not meet any of the criteria for SAEs should be regarded as 
non-serious AEs. 
10.1.3 Adverse Events of Special Interest (AEoSI) 
The following AEoSI need to be reported to the Sponsor within 24 hours of site awareness, 
irrespective of seriousness, severity or causality, to facilitate real-time monitoring and 
assessment: 
• Status epilepticus 
• Hydrocephalus (communicating and non-communicating) 
• Meningitis 
• Unexpected rapid decline on CLN2 scale not attributable to other causes 
• Hypersensitivity 
• Temporally-related events 
• Device-related events (e.g., infection, prophylactic ICV replacement, malfunction 
with an associated AE such as leaking reservoir or a problem that ends the 
administration of study drug for that visit, etc). 
o All removed or replaced implantable ICV devices must be returned to 
BioMarin in order to evaluate the material integrity of the reservoir, and 
all other devices (as described in the protocol Pharmacy Manual) except 
for infusion pumps, should also be returned. 
• Cardiovascular events 
• ECG adverse events 
10.2 
Methods and Timing for Capturing and Assessing Safety Parameters 
10.2.1 Adverse Event Reporting Period 
The study AE/SAE/AEoSI/pregnancy reporting period is as follows: 
• After informed consent and prior to ICV access device implantation: all SAEs related 
to study-mandated procedures 

 
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• After ICV access device implantation but before first dose: all SAEs related to 
study-mandated procedures and all device-related AEs, except as defined in SAE 
Exclusion section. 
• After first dose: all AEs, SAEs, AEoSI, and pregnancies. 
AE/SAE/pregnancy reporting should continue as detailed above until the safety follow-up 
visit occurs 6 months after the last administration of study drug. The Safety Follow-up visit is 
not required if a subject enrolls in an extension study or registry or otherwise continues to 
have access to BMN 190 within 6 months of the final infusion. For subjects who enroll into 
another BioMarin-sponsored study or registry, AE/SAE reporting is as follows: 
• The 190-203 reporting period for new onset AEs/SAEs, pregnancies, and 
device related events ends when the subject receives the first dose of study drug under 
the new study or registry.   
• Ongoing AEs related to study drug will be followed until resolution under this study.   
• All ongoing SAEs, pregnancies, and device-related events will be followed until 
resolution under this study.   
Events that started in this study and worsen after first the dose of study drug in the new study 
or registry will be captured as a new event under the new study. For subjects who do not 
participate in an extension study or registry after the last dose of study drug, the 4-week 
Device Safety and 6-month Safety follow-up visit will capture information regarding 
ongoing events at the time of the last dose or new events related to study drug. 
For this study, a medical device is defined as the infusion pump and all contact parts 
(reservoir and catheter, needles, infusion line with filter, extension sets, and syringes) 
intended to be used for administration of BMN 190. Adverse events assessed by the 
investigator as related to the device, including malfunction, injury, or medication error, will 
be entered into the EDC (electronic data capture). Prophylactic replacement of the ICV must 
be reported as a device related event.  All AEs related to the device will be reported to BPV 
within 24 hours using the EDC and study specific case report form(s). The reporting period 
for device-related events begins with reservoir implantation and ends 4 weeks following the final 
removal of the implanted reservoir and catheter. 
10.2.2 Eliciting Adverse Events 
Investigators will seek information on AEs and SAEs and AEoSI at each patient contact by 
specific questioning and, as appropriate, by examination. Information on all AEs and SAEs 
and AEoSI should be recorded in the patient’s medical record and on the AE Case Report 
Form (CRF). 

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

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

 
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The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process. Regardless of the Investigator’s assessment of causality for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate (in compliance 
with applicable regulations) possible new safety findings to investigators and applicable 
regulatory authorities. 
10.3 
Procedures for Recording Adverse Events 
10.3.1 Recording Adverse Events on a eCRF 
Investigators should use precise medical terminology when recording AEs or SAEs on the 
eCRF. Avoid colloquialisms and abbreviations. 
Record only one diagnosis, sign, or symptom per event field on the AE eCRF (eg, nausea and 
vomiting should not be recorded in the same entry, but as 2 separate entries). 
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor to the 
original terms entered on the eCRF, using MedDRA (Medical Dictionary for Regulatory 
Activities) terminology. 
10.3.1.1 
Diagnosis versus Signs and Symptoms 
Using accepted medical terminology, enter a diagnosis if known.  If not known, enter sign(s) 
and/or symptom(s). If a diagnosis subsequently becomes available, then this diagnosis should 
be entered on the AE form, replacing the original entries where appropriate. 
10.3.1.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (eg, cascade events) should be identified 
by their primary cause. For example, if severe diarrhea is known to have resulted in 
dehydration, it is sufficient to record only diarrhea as an AE or SAE on the eCRF. However, 
medically important events that may be linked and/or separated in time should be recorded as 
independent events on the eCRF. For example, if severe hemorrhage leads to renal failure, 
both events should be recorded separately on the eCRF. 
10.3.1.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation time points with no change in severity. For non-serious AEs, if the severity 
changes (increases or decreases), a new AE should be entered on the AE eCRF (in which 
case it should be recorded again on the AE eCRF). AEs characterized as intermittent require 
documentation of onset and duration of each episode. 

 
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A recurrent AE is one that occurs and resolves between patient evaluation time points, but 
then subsequently recurs. Each recurrence of the AE should be recorded on the AE eCRF. 
10.3.1.4 
Abnormal Laboratory Values 
Laboratory test results will be recorded on the laboratory results pages of the eCRF, or 
appear on electronically produced laboratory reports submitted directly from the central 
laboratory, if applicable. 
Any laboratory result abnormality fulfilling the criteria for a SAE should be reported as such, 
in addition to being recorded as an AE in the eCRF. 
A clinical laboratory abnormality should be documented as AE if any 1 or more of the 
following conditions is met: 
• Accompanied by clinical symptoms 
• Leading to a change in study medication (e.g. dose modification, interruption or 
permanent discontinuation)  
• Requiring a change in concomitant therapy (e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment) 
• The laboratory abnormality persists upon repeat confirmatory testing 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management (eg, change of dose, 
discontinuation of study drug, more frequent follow-up assessments, further 
diagnostic investigation, etc.) 
This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria. 
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 
explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported.  
10.3.1.5 
Pre-existing Conditions 
A pre-existing condition is one that is present at the start of the study. Such conditions should 
be recorded as medical history on the appropriate eCRF. 

 
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A pre-existing condition should be recorded as an AE or SAE during the study only if the 
frequency, intensity, or character of the condition worsens during the study period. It is 
important to convey the concept that a pre-existing condition has changed by including 
applicable language in the verbatim description of the event (eg, more frequent headaches). 
10.3.1.6 
Seizure Reporting 
Seizures that occur during the subject’s enrollment in the study and have not changed in 
severity, frequency, duration or type from the seizure activity characterized at baseline do not 
require reporting as an AE/SAE. 
AE/SAE Seizure reporting for this study is required for the following situations:  
• New onset seizures  
• Seizures that have worsened in frequency, severity and/or duration  
• Onset new type of seizure 
If a subject has more than 1 type of seizure reported at baseline (absence and clonic/tonic), it 
is important to identify which type of seizure has changed (e.g. more frequent absence 
seizures, or worsening clonic/tonic seizures). If more than one seizure type is involved, an 
AE/SAE report form is required for each type that has changed (e.g. worsening drop attacks 
and new onset clonic/tonic seizure). 
Please note for these events, if the seizure returns to baseline seizure activity level then the 
event would be resolved. If another event of worsening in seizure activity, it would be 
reported as a new event. If a subject’s seizure activity does not return to baseline, but 
stabilizes so that the new type, frequency or duration is considered the subject’s new 
threshold seizure activity, then the event would considered recovered/resolved with sequelae. 
Any worsening from this new threshold would then be considered a new event and should be 
reported as such. 
Cluster type seizures do not require reporting of each individualized seizure. Cluster type 
seizures should be reported using a consistent time frame. For example, if the subject’s 
cluster seizure pattern is 8 to 12 drop attacks a day every 3 days, then this is the baseline time 
frame for this subject’s seizure pattern. If a subject has one clonic/tonic seizure /week, then 
this is the baseline time frame for this seizure pattern. 
Seizures that occur within 24 hours of the start of the BMN 190 infusion should be as an 
AEoSI and in addition to providing the required assessments, the investigator should indicate 
if the seizure is consistent with the subject’s baseline seizure activity. 

 
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10.3.1.7 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition (refer to Section 10.3.1.5). During the study, any new clinically significant findings 
and/or abnormalities discovered on physical examination that meet the definition of an AE 
(or an SAE) must be recorded and document as an AE or SAE on the AE eCRF. 
10.3.1.8 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol (refer to 
Section 10.1.2). 
There are some hospitalization scenarios that do not require reporting as an SAE when there 
is no occurrence of an AE. These scenarios include planned hospitalizations or prolonged 
hospitalizations to: 
• Perform a protocol-mandated procedure (excluding prophylactic ICV replacement) 
• Undergo a diagnostic or elective surgical procedure, which was planned prior to study 
enrollment, for a pre-existing medical condition. 
• Receive scheduled therapy (study drug or otherwise) for the study indication 
10.3.1.9 
Deaths 
All deaths that occur during the AE reporting period (refer to Section 10.2.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the Sponsor (in 
compliance with applicable regulations) as an SAE. 
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF. If the cause of death 
is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the eCRF. If the death is attributed to progression of the 
disease or condition being studied, record “progressive CLN2 disease” as the SAE term on 
the eCRF. 
10.3.1.10 Pregnancy 
Although not an AE per se, pregnancy in either a patient or the partner of a patient taking 
trial medication should be expeditiously reported to BPV in compliance with applicable 
regulations to facilitate outcome monitoring by the Sponsor. Refer to Section 10.2.1 for 
pregnancies reporting period. 

 
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Pregnancy in a patient or partner should be reported within 24 hours of the site becoming 
aware of the pregnancy by completing the Pregnancy eCRF and submitting to BPV. In 
addition, pregnancy in a patient is also reported on the End of Study eCRF. The Investigator 
must make every effort to follow the patient through resolution of the pregnancy (delivery or 
termination) and to report the resolution on the Pregnancy Follow-up Form eCRF. In the 
event of pregnancy in the partner of a study patient, the Investigator should make every 
reasonable attempt to obtain the woman’s consent for release of protected health information. 
Abortion, whether therapeutic or spontaneous, should always be classified as an SAE (as the 
Sponsor considers these to be medically significant), recorded on the AE eCRF, and 
expeditiously reported to the Sponsor as an SAE in compliance with applicable regulations. 
10.4 
Reporting Requirements 
10.4.1 Expedited Reporting Requirements 
All SAEs, AEoSI, and pregnancies that occur during the course of the AE Reporting Period 
(refer to Section 10.2.1), whether or not considered related to study drug, must be reported 
via eCRF to BioMarin Pharmacovigilance (BPV) within 24 hours of the site becoming aware 
of the event. If the eCRF system is not available, the SAE must be reported on the 
study-specific SAE report form and entered into eCRF when possible. If the AE/SAE is 
assessed as related to the device (or any of its components), in addition to the eCRF entry, 
the study-specific device report form must be completed and submitted via email/fax within 
24 hours of the site becoming aware of the event. Investigators should not wait to collect 
information that fully documents the event before notifying BPV of an SAE. BioMarin may 
be required to report certain SAEs to regulatory authorities within 7 calendar days of being 
notified about the event; therefore, it is important that Investigators submit any information 
requested by BioMarin as soon as it becomes available. 
The reporting period for SAEs begins after informed consent is obtained and continues until 
6 months following either the last administration of study drug or study 
discontinuation/termination, whichever is longer (also see Section 10.2.1). The reporting 
period for device-related events begins with reservoir implantation and ends 4 weeks following 
removal of the implanted reservoir and catheter. 
10.4.2 IRB/IEC Reporting Requirements 
Reporting of SAEs to the IRB/IEC will be done in compliance with the standard operating 
procedures and policies of the IRB/IEC and with applicable regulatory requirements. 
Adequate documentation must be obtained by BioMarin showing that the IRB/IEC was 
properly and promptly notified as required. 

 
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10.5 
Follow-up of Patients after Adverse Events 
The Investigator should follow all unresolved AEs/ SAEs until the events are resolved or 
have stabilized, the patient is lost to follow-up, or it has been determined that the study 
treatment or participation is not the cause of the AE/SAE. Outcome of AEs and resolution of 
SAEs (with dates) should be documented on the AE eCRF and in the patient’s medical 
record to facilitate source data verification. 
For some SAEs, the Sponsor may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details (eg, hospital discharge summary, consultant 
report, or autopsy report) deemed necessary to appropriately evaluate the SAE report. 
10.6 
Post-Study Adverse Events 
At the last scheduled visit, the Investigator should instruct each patient to report, to the 
Investigator and/or to BPV directly, any subsequent SAEs that the patient’s personal 
physician(s) believes might be related to prior study treatment. 
The Investigator should notify the study Sponsor of any death or SAE occurring at any time 
after a patient has discontinued or terminated study participation, if the Investigator believes 
that the death or SAE may have been related to prior study treatment. The Sponsor should 
also be notified if the Investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a patient that participated in this 
study.  
10.7 
Urgent Safety Measures 
The regulations governing clinical trials state that the sponsor and Investigator are required to 
take appropriate urgent safety measures to protect patients against any immediate hazards 
that may affect the safety of patients, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
patients, the sponsor and the Investigator shall take appropriate urgent safety measures to 
protect the patients against any immediate hazard. The sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
IRB/EC/REC is notified at the same time.”  
The Sponsor is responsible for identifying, preparing and reporting all suspected, unexpected 
serious adverse reactions (SUSARs) to the relevant competent authorities, ethics committees 

 
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and investigators in accordance with the requirements identified in the Clinical Trials 
Regulations. 
The reporting period for these events which may require the implementation of urgent safety 
measures is the period from the time of signing of the ICF through the completion of the last 
study visit or at the Early Termination Visit (ETV). Investigators are required to report any 
events which may require the implementation of urgent safety measures to BioMarin within 
24 hours. 
Examples of situations that may require urgent safety measures include discovery of the 
following: 
• Immediate need to revise the IP administration (eg, modified dose amount or 
frequency not defined in protocol) 
• Lack of study scientific value, or detrimental study conduct or management 
• Discovery that the quality or safety of the IP does not meet established safety 
requirements 
10.8 
BioMarin Pharmacovigilance Contact Information 
Contact information for BioMarin Pharmacovigilance is as follows: 
BioMarin Pharmaceutical Inc. 
Address 
105 Digital Drive 
 
 
Novato, CA 94949 
Phone:  
Fax: 
 
E-mail: 
The Investigator is encouraged to discuss with the medical monitor any AEs for which the 
issue of seriousness is unclear or questioned. Contact information for the medical monitor is 
as follows: 
Name:  
 
Address: 
105 Digital Drive 
 
 
Novato, CA 94949 USA 
Phone:  
 
E-mail: 
 
 
PI
PI
PI
PI

 
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11 
APPROPRIATENESS OF MEASUREMENTS 
11.1 
Natural History Studies 
Two ongoing prospective natural history studies of CLN2 disease (Weill Cornell Medical 
Center and University Medical Center, Hamburg, Germany) continue to provide evidence 
that rating scale scores change in a predictable manner with increasing disease duration 
(Steinfeld, 2002); (Worgall, 2007).  
The Weill Cornell database comprises approximately 45 patients with genetically diagnosed 
CLN2 disease and includes Weill Cornell Scale scores, some Hamburg Scale scores, and 
MRI data, which have been shared with BioMarin (Crystal, 2004), Approximately half the 
patients have two assessments 2 weeks to 16 months apart. 
The Hamburg registry includes both retrospective and prospective data from approximately 
30 patients with CLN2 disease with scoring of 6-month periods from birth to 8-10 years of 
age. All participants are genetically diagnosed; data include Hamburg Scale scores, 
neurologic and cardiologic examinations, ophthalmology testing, routine clinical pathology, 
volumetric MRI, EEG, ECG, and echocardiogram. Although clinical data have accrued for 
up to 10 years, MRI data collection started in 2009 and these data have been shared with 
BioMarin (A Schulz and A Kohlschütter, Hamburg).   
The Hamburg registry is a subset of Dem-CHILD, a multi-center clinical database of CLN 
disorders that currently has 72 CLN2 patients. This database continues to add sites and 
patients, collection of clinical and research information is ongoing. 
The natural history data will be used to (1) better understand the properties of the CLN2 
disease scale, (2) evaluate correlations between the scale and potential surrogate markers 
such as neuroimaging, (3) generate the comparison group that will be matched to the study 
population of this clinical study. 
11.2 
CLN2 Clinical Rating Scale 
Disease severity will be evaluated by the CLN2 clinical rating scale (Steinfeld, 2002); 
(Worgall, 2008). This consists of 4 domains (Appendix 1), each of which has intrinsic high 
content validity. Within each domain, a score from 0 to 3 is assigned and overall scores are 
calculated by summing the 4 domain scores for a final rating of 0 (severely impaired) to 
12 (normal).  
A clinical rating scale, the Hamburg Scale, was developed to document retrospectively the 
natural history of CLN2 disease (Steinfeld, 2002). A modified form of that scale, the 
Modified Hamburg Scale, demonstrated statistically significant slowing of neurologic decline 

 
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in subjects receiving gene therapy intervention when compared with decline among control 
subjects (Worgall, 2008). A second CLN2 disease rating scale, the Weill Cornell Scale 
(Dyke, 2012); (Worgall, 2007), has also been used to evaluate CLN2 disease severity with 
highly comparable results. 
Although all 4 domains of the Hamburg rating scale will be completed (Appendix 1), the 
motor and language domains are expected to be most useful for this study. Since these 
2 domains are most relevant to CLN2 disease progression, they will be used to assess study 
eligibility and efficacy. To be eligible for study participation, motor and language domains of 
the Hamburg CLN2 rating scale administered during Screening must document 
asymptomatic to moderate CLN2 disease progression with a 2-domain score of 3-6 for these 
2 domains, as defined in the Ratings Assessment Guidelines. The planned patient enrollment 
of at least 10 patients is to include at least 5 patients with a combined ML score ≥ 5 points 
(mild or asymptomatic disease) and at least 5 patients with a ML score < 5 points (moderate 
disease) to ensure that an equal number of patients with mild and moderate disease are 
enrolled. 
The remaining 2 domains (Appendix 1) are less likely to be informative for this study. 
Greater detail in the seizure and movement disorders associated with CLN2 disease are 
captured using a modified UBDRS inventory for involuntary movements and seizures.  
Because of practical (limited number of available patients) and ethical (neurosurgery in 
children with fatal neurologic disease) concerns, this study design cannot involve 
contemporaneous, matched, randomized, blinded, or untreated control subjects  
(Arkin, 2005); (Crystal, 2004). Therefore, changes in CLN2 disease scale scores will be 
compared with historical data from the registry at the University Medical Center in Hamburg, 
Germany and with data from siblings with CLN2 disease, when available.  
11.3 
Magnetic Resonance Imaging 
As patients progress from mild to severe CLN2 disease, MRI has indicated progressive loss 
of cortical volume and ventricular enlargement (Worgall, 2007). By late CLN2 disease 
stages, despite their young age, these patients exhibit substantial atrophy predominantly in 
the cortical grey matter, comparable to that in elderly people with severe Alzheimer’s 
disease. MRS in patients with CLN2 disease has demonstrated reduced neuronal N-acetyl-
aspartate (NAA), reduced NAA/creatine metabolite ratios, and increased 
myoinositol/creatine ratios when compared with healthy individuals (Seitz, 1998). 
Of all 10 MRI measurements examined to quantitate CLN2 disease progression 
(Worgall, 2007), ventricular volume or percentage ventricular volume correlated most 

 
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strongly with age (r2=0.67-0.87), duration of disease (r2=0.71-0.79), and severity on clinical 
rating scales (r2=0.56-0.76), suggesting that the measurement of ventricular volumes may be 
the most relevant and sensitive MRI measurement of disease progression. Based on these 
data, MRI measures of atrophy are more strongly correlated with disease progression than are 
MRS measures of neuronal viability. 
In nonclinical CLN2 disease studies with TPP1-null dachshunds, MRI measurement of 
ventricular volume enlargement was reduced with BMN 190 treatment. Therefore, this 
clinical study of CLN2 disease will include MRI measurement of ventricular volume.  

 
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12 
STUDY PROCEDURES 
12.1 
Screening 
After the nature of the study has been explained, written informed consent by parent or 
authorized legal guardian must be obtained prior to any research-related procedures. Within 
21 days prior to hospital admission to implant the ICV access device, the following 
procedures will be performed: 
• Informed consent 
• Confirm diagnosis of CLN2 disease determined by TPP1 enzyme activity (dried 
blood spot) in the fibroblasts and leukocytes.  
• Blood for TPP1 enzyme activity and CLN2 gene analysis 
• Hamburg CLN2 disease rating scale (motor, language, vision, and seizure subscales) 
with videotaping. Documentation of extent of disease progression with total score of 
3-6 for motor/gait and language domains, as defined in the Ratings Assessment 
Guidelines, is required for study entry.  
• Verify criteria for study entry 
• Cranial MRI 
• Complete physical examination, including medical history 
• CLN2-specific QoL Questionnaire  
• Pregnancy testing (in females of childbearing potential) 
• After informed consent, assessment of SAEs related to protocol-imposed 
interventions and seizure history 
• Concomitant medications, including anti-epileptic treatments  
In order to ensure appropriate patients are enrolled in the study (including those with the 
necessary CLN2 ML scores at Screening), a confirmation of patient study eligibility will be 
provided to the Investigator by BioMarin. Surgery should not be performed until this 
approval is obtained. Information that must be provided for Sponsor approval includes (but is 
not limited to) patient age, results of TPP1 enzyme activity, results of CLN2 genotype testing 
(if available) and Screening ML score. 
12.2 
Surgery Visit 
Following confirmation of patient eligibility and enrollment, study patients will be admitted 
to the hospital for surgical implantation of an ICV access device to the right lateral ventricle. 
An MRI will be performed prior to surgery to ensure proper planning and placement of the 
ICV access device. At minimum, subjects will be observed in a nursing-intensive 

 
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environment for 48 hours post-ICV device placement and after the start of the first drug 
infusion. The following procedures will also be performed: 
• AE assessment, including ongoing seizure history 
• Concomitant medication, including anti-epileptic treatments 
Following ICV access device placement, subjects and their caregivers will be given written 
instructions providing details on signs and symptoms of concern for device complications 
and instruction on when to return to the site for device evaluation. An additional follow-up 
phone call will be conducted within 48 hours of inpatient discharge. 
12.3 
Baseline Visit and First Infusion 
12.3.1  Baseline Visit 
The following baseline values will be recorded within 2 days before the first infusion (which 
will occur at least 14 days from surgery and no more than 28 days after surgery): 
• Height and body weight assessment 
• Hamburg CLN2 disease rating scale (motor, language, vision, and seizure subscales) 
with videotaping 
• ECG (12-lead) (heart rate, rhythm, intervals, axis, conduction defects, and anatomic 
abnormalities) 
• EEG (standard awake) 
• Cranial MRI 
• CSF (TAb and NAb in all subjects) and serum (TAb, NAb, total IgE and 
drug-specific IgE in all subjects) for immunogenicity  
• Complete physical examination 
• Neurological examination 
• Clinical laboratory testing (hematology, blood chemistry, and urinalysis) 
• Modified Unified Batten Disease Rating Scale Involuntary Movement Scale 
(mUBDRS-Movement) 
• Modified Unified Batten Disease Rating Scale Seizure Inventory (mUBDRS-Seizure)  
• Optical coherence tomography 
• PedsQL 
• Denver II Developmental Scale 
• CLN2-specific QoL Questionnaire  

 
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• Ophthalmologic assessments 
• Visual acuity testing 
o All subjects will undergo Preferential Looking Testing. In addition, for 
those children who retain the cognitive function to adhere to testing, the 
Lea Vision Test or E Hook (or Tumbling E) Vision Test should also be 
performed during the same assessment. The subject must not be sedated at 
the time of visual acuity testing.  
• AE assessment, including ongoing seizure history 
• Concomitant medications, including anti-epileptic treatments 
12.3.2 First Infusion 
If done on the same day, assessments of function and QOL should be completed before MRI 
and blood sampling, which should precede infusion; blood samples may be collected when 
subjects are sedated for MRI. 
12.3.2.1 
First Infusion: Day 1 
The following procedures will be performed on Day 1 of the first infusion: 
• Continuous ECG monitoring (3- or 5-lead) will be performed for all subjects. 
The ECG should begin 15 (± 5 minutes) prior to infusion start, continue through 
infusion of BMN 190, and end after infusion of flushing solution. In the event that the 
subject has already received the first infusion of BMN 190, the next infusion will be 
monitored as above.  
• ECG (12-lead) (heart rate, rhythm, intervals, axis, conduction defects, and anatomic 
abnormalities) 30 (±5) minutes after infusion end at the first infusion. In patients with 
present or past bradycardia, conduction disorders, or with structural heart disease, an 
ECG will be performed within 30 minutes before the start of infusion (±5 minutes), at 
2 hours (±15 minutes) during infusion, 30 (±5) minutes after infusion end, and 
12 hours (±3 hours) after infusion end. 
• CSF surveillance (cell count, protein, glucose, and culture) 
• Device patency/infection 
• Study drug infusion 
• CSF and blood for disease-related biomarkers 
• CSF and plasma for PK 
• Vital signs (SBP, DBP, heart rate, oral body temperature, and respiration rate) 
• Brief physical examination 

 
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• AE assessment (investigator may collect additional blood samples for safety or 
immunogenicity testing for any AE of concern) and ongoing seizure history 
• Concomitant medication assessment, including anti-epileptic treatments 
• Post-infusion monitoring in an appropriate inpatient setting for a minimum of 
24 hours 
12.3.2.2 
First Infusion: Days 2-6 
The following procedures will be performed on Days 2-6 following the first infusion: 
• Clinical laboratory testing (hematology, blood chemistry, and urinalysis) (Day 2) 
• CSF surveillance (cell count, protein, glucose, and culture) (Day 6) 
• Brief physical examination (Day 6) 
• Device patency/infection (Day 6) 
• AE assessment (investigator may collect additional blood samples for safety or 
immunogenicity testing for any AE of concern) (each day) and ongoing seizure 
history 
• Concomitant medication assessment (each day), including anti-epileptic treatments 
Following inpatient discharge from the first infusion, a follow-up telephone call will be 
placed to parent/guardian within 48 hours. 
12.4 
Every 2 Weeks 
The following assessments and procedures should be performed every 2 weeks (14 days) 
during the study. All study visits should occur every 2 weeks (14 days) from the date of the 
first infusion (±3 days). All assessments and procedures should be completed before study 
drug infusion unless specified otherwise. If done on the same day, QOL should be completed 
before MRI and blood sampling; blood samples may be collected when subjects are sedated 
for MRI. 
For all visits, if no safety issues are observed, a subject may be discharged after 24 hours if 
medically stable. A follow-up phone call to the parent or legal guardian will be conducted 
~48 hours after discharge to determine health status.  
• Brief physical examination 
• CSF surveillance (cell count with differential, protein, glucose, and culture) 
• CSF for disease-related biomarker assays (Weeks 1-71) 
• Device patency/infection assessment 
• Study drug administration 

 
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• Vital signs (SBP, DBP, heart rate, oral body temperature, and respiration rate) 
• ECG (12-lead) (heart rate, rhythm, intervals, axis, conduction defects, and anatomic 
abnormalities) 30 (±5) minutes after infusion end at the first infusion. In patients with 
present or past bradycardia, conduction disorders, or with structural heart disease, an 
ECG will be performed within 30 minutes before the start of infusion (±5 minutes), at 
2 hours (±15 minutes) during infusion, 30 (±5) minutes after infusion end, and 
12 hours (±3 hours) after infusion end. 
• AE assessment (investigator may collect additional blood samples for safety or 
immunogenicity testing for any AE of concern) and ongoing seizure history 
• Concomitant medication assessment, including anti-epileptic treatments 
• Telephone call to parent/guardian within 48 hours after visit 
12.5 
Every 4 Weeks 
The following assessments and procedures should be performed every 4 weeks during the 
study. Where applicable, blood sampling may occur during sedation for MRI. 
• Routine clinical laboratory tests (hematology, blood chemistry, and urinalysis) (first 
2 assessments only [Weeks 1-9]) 
• Hamburg CLN2 disease rating scale (motor, language, vision, and seizure subscales) 
12.6 
Every 8 weeks 
The following assessments and procedures should be performed every 8 weeks during the 
study. Where applicable, blood sampling may occur during sedation for MRI. 
• Routine clinical laboratory tests (hematology, blood chemistry, and urinalysis) (for 
5 assessments only [Weeks 17 to 49]) 
• CSF for disease-related biomarker assays (Weeks 79-145) 
• Blood for disease-related biomarker assays (Weeks 1-49) 
12.7 
Every 12 Weeks 
The following assessments and procedures should be performed every 12 weeks during the 
study. All assessments and procedures should be completed before study drug infusion unless 
specified otherwise. If done on the same day, assessments of function and QOL should be 
completed before MRI and blood sampling; blood samples may be collected when subjects 
are sedated for MRI. 

 
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• Routine clinical laboratory tests (hematology, blood chemistry, and urinalysis) 
(starting at Week 61-145) 
• Blood for disease-related biomarker assays (Weeks 61-145) 
• Videotaping to accompany administration of the Hamburg CLN2 disease rating scale 
(motor, language, vision, and seizure subscales), which will be administered every 
4 weeks. 
o Change in seizure activity (clinical [0 to 3 point Hamburg CLN2 rating 
scale seizure subscale]) 
o Visual acuity testing 
o All subjects will undergo Preferential Looking Testing every 12 weeks. In 
addition, for those children who retain the cognitive function to adhere to 
testing, the Lea Vision Test or E Hook (or Tumbling E) Vision Test 
should also be performed during the same assessment. Visual acuity 
testing can be performed either before or after the infusion (± 3 days), but 
should be performed at a time (relative to infusion) that can be repeated 
consistently between study visits. The subject must not be sedated at the 
time of visual acuity testing.  
• Neurological examination 
• CSF and serum sampling for immunogenicity  
• mUBDRS-Movement 
• mUBDRS-Seizure  
• PedsQL 
• Denver II Developmental scale  
• CLN2-specific QoL Questionnaire 
12.8 
Every 24 Weeks 
The following assessments and procedures should be performed every 24 weeks during the 
study:   
• Height and body weight assessment 
• ECG (12-lead) (heart rate, rhythm, intervals, axis, conduction defects, and anatomic 
abnormalities)  
• Cranial MRI 
• EEG (standard awake) 
• Optical coherence tomography 
• CSF and plasma for PK (Weeks 25, 49, and 97).  

 
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12.9 
Every 48 Weeks 
The following assessments and procedures should be performed every 48 weeks during the 
study:   
• Complete physical examination 
• Ophthalmologic assessments 
 
12.10 Study Completion or Early Termination Visit 
At Study Completion or Early Termination, subjects will return to the study site within 
3 days. The following procedures will be completed: 
• Hamburg CLN2 disease rating scale (motor, language, vision, and seizure subscales) 
with videotaping  
• ECG (12-lead) (heart rate, rhythm, intervals, axis, conduction defects, and anatomic 
abnormalities)  
• EEG (standard awake) 
• Cranial MRI 
• CSF surveillance (cell count, protein, glucose, and culture) 
• CSF and blood for disease-related biomarker assays 
• CSF and plasma for PK 
• CSF and serum sampling for immunogenicity 
• Vital signs (SBP, DBP, heart rate, oral body temperature, and respiration rate) 
• Complete physical examination 
• Height and body weight assessment 
• Neurological examination 
• Routine clinical laboratory tests (hematology, blood chemistry, and urinalysis) 
• Denver II Developmental scale 
• Optical coherence tomography 
• PedsQL 
• Pregnancy testing (in females of childbearing potential) 
• CLN2-specific QoL Questionnaire 

 
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• Visual acuity testing 
o All subjects will undergo Preferential Looking Testing. In addition, for 
those children who retain the cognitive function to adhere to testing, the 
Lea Vision Test or E Hook (or Tumbling E) Vision Test should also be 
performed during the same assessment. The subject must not be sedated at 
the time of visual acuity testing.  
• Ophthalmologic assessments 
• AE assessment (investigator may collect additional blood samples for safety or 
immunogenicity testing for any AE of concern) and ongoing seizure history 
• Concomitant medication assessment, including anti-epileptic treatments 
Following the Study Completion Visit or Early Termination Visit, subjects who will not be 
continuing to receive BMN 190 in another setting (e.g., commercial use, participation in a 
registry, participation in another BMN 190 clinical study, etc.) should have their ICV access 
device removed. Removal of the device should occur no more than 4 weeks after the Study 
Completion Visit or ETV. All removed or replaced implantable ICV devices must be 
returned to BioMarin in order to evaluate the material integrity of the reservoir, and all other 
devices (as described in the Pharmacy Manual) except for infusion pumps, should also be 
returned.   
12.11 Device Safety Follow-Up 
Subjects will return to the study site 4 weeks (±3 days) after removal of the ICV access 
device, when the following procedures will be completed: 
• Hamburg CLN2 disease rating scale (motor, language, vision, and seizure subscales) 
(videotaping not required) 
• Vital signs (SBP, DBP, heart rate, oral body temperature, and respiration rate) 
• Brief physical examination (including close examination of the former device site to 
check for signs of infection, etc.) 
• Serum sampling for immunogenicity 
• Neurological examination 
• Routine clinical laboratory tests (hematology, blood chemistry, and urinalysis) 
• AE assessment (investigator may collect additional blood samples for safety or 
immunogenicity testing for any AE of concern), including ongoing events at the time 
of the last dose or new events related to study drug. 
• Concomitant medication assessment, including anti-epileptic treatments 

 
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Upon study completion or early termination, all patients will be given the opportunity to 
participate in a postmarketing registry that will assess long-term safety and efficacy of 
BMN 190 for patients receiving commercial drug. 
The 4-week Device Safety Follow-Up Visit will be waived for subjects who do not undergo 
device removal because they will be continuing to receive BMN 190 in another setting 
(e.g., commercial use, participation in a registry, participation in another BMN 190 clinical 
study, etc.).  
12.12 Safety Follow-Up 
The Safety Follow-up visit is not required if a subject enrolls in an extension study or registry 
or otherwise continues to have access to BMN 190 within 6 months of the final infusion. 
For subjects who do not participate in an extension study or registry after the last dose of 
study drug, the 6 month safety follow visit will capture information regarding ongoing events 
at the time of the last dose or new events related to study drug.  If required, subjects will 
return to the study site 6 months after the last study treatment, when the following procedures 
will be completed: 
• Hamburg CLN2 disease rating scale (motor, language, vision, and seizure subscales) 
(videotaping not required) 
• ECG (12-lead) (heart rate, rhythm, intervals, axis, conduction defects, and anatomic 
abnormalities)  
• Serum sampling for immunogenicity  
• Vital signs (SBP, DBP, heart rate, oral body temperature, and respiration rate) 
• Complete physical examination 
• Height and body weight assessment 
• Routine clinical laboratory tests (hematology, blood chemistry, and urinalysis) 
• AE assessment (investigator may collect additional blood samples for safety or 
immunogenicity testing for any AE of concern), including ongoing events at the time 
of the last dose or new events related to study drug, and ongoing seizure history 
• Concomitant medication assessment, including anti-epileptic treatments 

 
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12.13 Study Termination 
The study will end after the last subject completes the last Safety Follow-Up visit. BioMarin 
reserves the right to discontinue the study any time for clinical or administrative reasons and 
to discontinue participation of an individual investigator or site for clinical or administrative 
reasons, including, but not limited to, poor enrollment or noncompliance with procedures of 
the protocol or GCP. In addition, the study may be terminated if, in the opinion of BioMarin, 
the safety of the study subjects may be compromised. 
Upon study completion or early termination, all patients will be given the opportunity to 
participate in a postmarketing registry that will assess long-term safety and efficacy of 
BMN 190 for patients receiving commercial drug. 

 
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13 
DATA QUALITY ASSURANCE 
BioMarin personnel or designees will visit the study site prior to initiation of the study to 
review with site personnel information about the study drug, protocol and other regulatory 
document requirements, any applicable randomization procedures, source document 
requirements, CRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs.  
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on CRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records.  
The designated clinical data management group will enter or transfer CRF data into a study 
database. 
Data quality control and analysis will be performed by BioMarin or a designee, based on a 
predefined analysis plan. 

 
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14 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
Because the completeness of the data affects the integrity and accuracy of the final study 
analysis, every effort should be made to ensure complete, accurate, and timely data 
collection. 
14.1 
Statistical Analysis Plan 
A Statistical Analysis Plan (SAP) will be written prior to final database lock that will provide 
details on the planned statistical analysis. If discrepancies exist between the statistical 
analysis as described in the protocol and the final SAP, the SAP will prevail. 
14.1.1 Interim Analyses 
No formal interim analyses are planned. As a single-arm, open-label study, study data will be 
available for review on an ongoing basis. 
There will be no Data Monitoring Committee. However, BioMarin will convene a Data 
Review Board of internal and external experts to assist the Medical Monitor in assessing 
data. 
Early stopping will be considered based on clinical judgment; no inferential stopping rules 
will be employed. 
14.2 
Primary Efficacy Analysis 
The primary efficacy endpoint is the 0 to 6-point ML score on the Hamburg CLN2 rating 
scale. The primary measure of efficacy is the rate of CLN2 decline. This analysis will include 
patients with a baseline ML score < 6 points and patients with a ML score < 6 points 
post-baseline.  
CLN2 disease rating scale scores will be evaluated relative to natural history data in 
untreated historical controls (data from a CLN2 disease patient registry and data from 
siblings with CLN2 disease, when available). 
14.2.1 Secondary Efficacy Analyses 
Time to disease manifestation will be assessed for asymptomatic patients. For all patients, an 
analysis of interest is time to first confirmed decline, defined as 2 consecutive CLN2 
assessments (i.e., approximately 4 weeks apart) with scores less than the baseline CLN2 
score. 
The time to first confirmed decline is defined by the earlier of the 2 CLN assessments. 

 
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The 0-to-9 point Hamburg CLN2 scores (incorporating the motor, language, and vision 
domains) and the total 0-to-12 point Hamburg CLN2 scores (motor, language, vision, and 
seizure), will be presented descriptively. 
The following variables obtained by MRI of the brain will be presented descriptively: 
• Volume of CSF 
• Volume of cortical gray matter 
• Volume of white matter 
• Whole brain apparent diffusion coefficient 
Endpoints may be compared to natural history data in untreated historical controls (data from 
a CLN2 disease patient registry and data from siblings with CLN2 disease, when available). 
14.2.2 Exploratory Analyses   
The following domains/assessment instruments will be presented descriptively: 
• mUBDRS-Movement 
• mUBDRS-Seizure 
• Seizure activity (clinical [0 to 3 point Hamburg CLN2 rating scale seizure subscale]) 
• Anti-epileptic treatment 
• Retinal anatomy, as determined by optical coherence tomography 
• PedsQL 
• CLN2 health-related QoL 
• Denver II Developmental scale 
• EEG, standard awake 
• Preferential Looking Test; Optional Lea Vision Test or E Hook (or Tumbling E) 
Vision Test 
• CSF/ blood biomarkers 
 
14.2.3 Immunogenicity Analysis 
Immunogenicity tests will be performed using validated immunogenicity assays. Routine 
immunogenicity tests will include total antibody (TAb) and neutralizing antibody (NAb) in 
the serum and CSF. NAb testing will not be performed if the TAb is negative. Incidence and 
titer summary statistics will be provided for serum TAb, CSF TAb, serum Nab, and CSF 
NAb in table format and will include mean, median, standard deviation, and 

 
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minimum/maximum titer values at each study visit. Potential impact of anti-drug antibodies 
on efficacy and safety will be explored.  
In the event of serious or severe (≥Grade 3) hypersensitivity AE, blood samples will be 
collected within 1 hour of the event to assess C4, serum tryptase, and total IgE. A second 
blood sample will be collected no sooner than 8 hours after the event (or before the next 
infusion) for drug-specific IgE testing. Potential associations between immunogenicity 
results and hypersensitivity adverse events will be analyzed. 
14.3 
Pharmacokinetic Analysis 
The following parameters will be evaluated by non-compartmental analysis: 
• Area under concentration-time curve from time 0 to infinity (AUC0-∞) 
• Area under concentration-time curve from 0 to the time of last measurable 
concentration (AUC0-t) 
• Maximum observed concentration (Cmax) 
• Time to reach Cmax (Tmax) 
• Elimination half-life (t½) 
• Apparent clearance of drug (CL/F) 
• Apparent volume of distribution based on terminal phase (Vz/F) 
14.4 
Safety Analysis  
Safety analysis will be descriptive.   
All AEs will be coded by BioMarin using the current version of MedDRA to assign system 
organ class and preferred term classification to events and diseases, based on the original 
terms entered on the CRF. The incidence of AEs will be summarized by system organ class, 
preferred term, relationship to study treatment, and severity.  
Concomitant medications will be coded using World Health Organization Drug Dictionary 
and summarized. 

 
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Clinical laboratory data will be summarized in terms of observed values and changes from 
Baseline.  Lab data will also be summarized relative to categorical reference ranges (e.g., lab 
normal ranges and/or CTCAE grade). 
Vital signs will be summarized in terms of observed values and changes from Baseline. 
ECGs will be summarized in terms of investigator overall interpretation, abnormal findings, 
and quantitative intervals (QTcF, etc.). 
14.5 
Determination of Sample Size 
Sample size was determined on the basis of clinical judgment.  Statistical power was not a 
consideration. 
14.6 
Changes in the Conduct of the Study or Planned Analyses 
Only BioMarin may modify the protocol. Any change in study conduct considered necessary 
by the investigator will be made only after consultation with BioMarin, who will then issue a 
formal protocol amendment to implement the change. The only exception is when an 
investigator considers a subject’s safety compromised without immediate action. In these 
circumstances, immediate approval of the chairman of the IRB/IEC/REC must be sought, and 
the Investigator should inform BioMarin and the full IRB/IEC/REC within two (2) working 
days after the emergency occurs.  
With the exception of minor administrative or typographical changes, the IRB/IEC/REC 
must review and approve all protocol amendments. Protocol amendments that have an impact 
on subject risk or the study objectives, or require revision of the ICF, must receive approval 
from the IRB/IEC/REC prior to their implementation. 
When a protocol amendment substantially alters the study design or the potential risks or 
burden to subjects, the ICF will be amended and approved by BioMarin and the 
IRB/IEC/REC, and all active subjects must again provide informed consent. 

 
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15 
DATA REVIEW BOARD 
There will be no formal DMC for this study, however a safety and efficacy evaluation board 
(the Data Review Board [DRB]) will be established. 
The DRB will review safety and efficacy on an ongoing basis. The DRB will meet to assess 
available patient safety and efficacy data and make recommendations with regards to the 
conduct of study. Should a safety signal arise, including one which may warrant a halt of 
study enrollment, the DRB will promptly convene for further assessment of patient safety. 
Notification of all DRB meetings and meeting outcomes will be sent to participating sites. 
The DRB will consist of 3 members: the BioMarin medical monitor, a representative from 
BPV, and one study investigator. The DRB will meet on a quarterly basis, for the first year of 
the study and ad hoc thereafter. The DRB will be provided with statistical support and may 
access external clinical opinion. 

 
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16 
COMPENSATION, INSURANCE, AND SUBJECT INJURY 
There will be no monetary compensation provided to subjects for their participation in this 
study. BioMarin is responsible for all study participation expenses, including tests, 
procedures, and treatments. In addition, BioMarin may reimburse the cost of travel for 
study-related visits after ethics committee approval. BioMarin will not pay for any 
hospitalization, tests, or treatments for medical problems not part of this protocol regardless 
of their relationship to the subject’s disease. Costs associated with hospitalization, tests, and 
treatments should be billed and collected in the way that such costs would be customarily 
billed and collected. 
The investigator should contact BioMarin immediately upon notification that a study subject 
has an injury related to the study treatment or to the procedures or assessments performed as 
part of the study. Any subject who experiences a study-related injury should be instructed by 
the investigator to seek medical treatment at a pre-specified medical institution (if possible) 
or at the closest medical treatment facility (if necessary). The subject should be given the 
contact information if they require further information about or assistance with treatment for 
study-related injuries. The treating physician should bill the subject’s health insurance 
company or other third party payer for the cost of this medical treatment. If the subject has 
followed the investigator’s instructions, BioMarin will pay for reasonable and necessary 
medical services to treat the injuries caused by the study treatment or study assessments or 
procedures if these costs are not covered by health insurance or another third party that 
customarily would pay these costs. In some jurisdictions, BioMarin is obligated by law to 
pay for study-related injuries without prior recourse to third party payer billing. If this is the 
case, BioMarin will comply. 

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

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

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

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

 
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20 
USE OF INFORMATION AND PUBLICATION 
BioMarin recognizes the importance of communicating medical study data and, therefore, 
encourages publication of these data in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, manuscripts, 
and presentations based on data from this study will be described in the Clinical Trial 
Agreement between BioMarin and the investigator and/or institution. Consideration for 
authorship of all publications will be based on compliance with the Uniform Requirements 
for Manuscripts Submitted to Biomedical Journals (“Uniform Requirements”) of the 
International Committee of Medical Journal Editors 
(http://www.icmje.org/ethical_1author.html) and good publication practices (GPP). 

 
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21 
REFERENCES 
Arkin, LM, Sondhi, D, Worgall, S, Suh, LH et. al. Confronting the issues of therapeutic misconception, 
enrollment decisions, and personal motives in genetic medicine-based clinical research studies for fatal 
disorders. Hum Gene Ther 16[9], 1028-1036. 2005.  
Awano, T, Katz, ML, O'Brien, DP, Sohar, I et. al. A frame shift mutation in canine TPP1 (the ortholog of 
human CLN2) in a juvenile Dachshund with neuronal ceroid lipofuscinosis. Mol Genet Metab 89[3], 254-260. 
2006.  
Brooks R.  EuroQol: the current state of play.  Health Policy 37[1], 53-72.  1996. 
Chang, M. CLN2. The Nueronal Ceroid Lipofuscinoses. New York: Oxford Univ Press, 2011: 80-109. 
Crystal, RG, Sondhi, D, Hackett, NR, Kaminsky, SM et. al. Clinical protocol. Administration of a replication-
deficient adeno-associated virus gene transfer vector expressing the human CLN2 cDNA to the brain of 
children with late infantile neuronal ceroid lipofuscinosis. Hum Gene Ther 15[11], 1131-1154. 2004.  
Dekaban AS, Sadowski D. Changes in brain weights during the span of human life: relation of brain weights to 
body heights and body weights. Ann Neurol 1978 Oct; 4(4): 345–356. 
Dierenfeld, AD, McEntee, MF, Vogler, CA, Vite, CH et. al. Replacing the enzyme alpha-L-iduronidase at birth 
ameliorates symptoms in the brain and periphery of dogs with mucopolysaccharidosis type I. Sci Transl Med 
2[60], 60ra89. 2010.  
Dyke, JP, Sondhi, D, Voss, HU, Shungu, DC et. al. Assessment of Disease Severity in Late Infantile Neuronal 
Ceroid Lipofuscinosis Using Multiparametric MR Imaging. AJNR Am J Neuroradiol . 2012.  
EuroQol Group.  EuroQol - a new facility for the measurement of health-related quality of life.  Health Policy 
16[3], 199-208.  1990. 
Giedd, JN, Snell, JW, Lange, N, Rajapakse, JC et. al. Quantitative magnetic resonance imaging of human brain 
development: ages 4-18. Cereb Cortex 6[4], 551-560. 1996.  
Karavelis A, Foroglou G, Selviaridis P et al.  Intraventricular administration of morphine for control for 
intractable cancer pain in 90 patients.  Neurosurgery 39[1], 57-62.  1996. 
Kronenberg MF, Laimer I, Rifici C et al.  Epileptic seizure associated with intracerebroventricular and 
intrathecal morphine bolus.  Pain 75[2], 383-387.  1998. 
Kurachi, Y, Oka, A, Mizuguchi, M, Ohkoshi, Y et. al. Rapid immunologic diagnosis of classic late infantile 
neuronal ceroid lipofuscinosis. Neurology 54[8], 1676-1680. 2000.  
Kwon JM, Adams H, Rothberg PG, et al.  Quantifying physical decline in juvenile neuronal ceroid 
lipofuscinosis (Batten disease).  Neurology 77[20], 1801-1807.  2011. 
Lishner M, Perrin RG, Feld R et al.  Complications Associated with Ommaya Reservoirs in Patients with 
Cancer: The Princess Margaret Hospital Experience and a Review of the Literature.  Arch Intern Med 150[1], 
173-176.  1990. 
Msall ME.  Measuring functional skills in preschool children at risk for neurodevelopmental disabilities.  Ment. 
Retard. Dev. Disabil. Res. Rev. 11, 263-273.  2005. 

 
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Pappenheimer JR, Heisey SR, Jordon EF, Downer JC. Perfusion of the cerebral ventricular system in 
unanesthetized goats. Am. J. Physiol. 203[5], 763-774.  1962 
Schulz, A, Ajayi, T, Specchio, N, de Los Reyes, E, et al. Study of Intraventricular Cerliponase Alfa for CLN2 
Disease. N Engl J Med 2018; 378[20]:1898-1907.  
Seitz, D, Grodd, W, Schwab, A, Seeger, U et. al. MR imaging and localized proton MR spectroscopy in late 
infantile neuronal ceroid lipofuscinosis. AJNR Am J Neuroradiol 19[7], 1373-1377. 1998.  
Sleat, DE, El-Banna, M, Sohar, I, Kim, KH et. al. Residual levels of tripeptidyl-peptidase I activity dramatically 
ameliorate disease in late-infantile neuronal ceroid lipofuscinosis. Mol Genet Metab . 2008.  
Sleat, DE, Wiseman, JA, El-Banna, M, Kim, KH et. al. A mouse model of classical late-infantile neuronal 
ceroid lipofuscinosis based on targeted disruption of the CLN2 gene results in a loss of tripeptidyl-peptidase I 
activity and progressive neurodegeneration. J Neurosci 24[41], 9117-9126. 2004.  
Steinfeld, R, Heim, P, von Gregory, H, Meyer, K et. al. Late infantile neuronal ceroid lipofuscinosis: 
quantitative description of the clinical course in patients with CLN2 mutations. Am J Med Genet 112[4], 347-
354. 2002.  
Vuillemenot, BR, Katz, ML, Coates, JR, Kennedy, D et. al. Intrathecal tripeptidyl-peptidase 1 reduces 
lysosomal storage in a canine model of late infantile neuronal ceroid lipofuscinosis. Mol Genet Metab 104[3], 
325-337. 2011.  
Vuillemenot, BR, Kennedy, D, Reed, RP, Boyd, RB, et. al. Recombinant human tripeptidyl peptidase-1 infusion 
to the monkey CNS: safety, pharmacokinetics, and distribution. Toxicol Appl Pharmacol 277[1], 49-57. 2014. 
Worgall, S, Kekatpure, MV, Heier, L, Ballon, D et. al. Neurological deterioration in late infantile neuronal 
ceroid lipofuscinosis. Neurology 69[6], 521-535. 2007.  
Worgall, S, Sondhi, D, Hackett, NR, Kosofsky, B et. al. Treatment of late infantile neuronal ceroid 
lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. Hum 
Gene Ther 19[5], 463-474. 2008.  
Xu, S, Wang, L, El-Banna, M, Sohar, I et. al. Large-volume intrathecal enzyme delivery increases survival of a 
mouse model of late infantile neuronal ceroid lipofuscinosis. Mol Ther 19[10], 1842-1848. 2011.  
 
Yasuda, T, Tomita, T, McLone, DG, Donovan, M. Measurement of Cerebrospinal Fluid Output through 
External Ventricular Drainage in One Hundred Infants and Children: Correlation with Cerebrospinal Fluid 
Production. Pediatr Neurosurg 36, 22–28. 2002.  

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

 
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SIGNATURE PAGE 
Protocol Title: A Phase 2, Open-Label, Multicenter Study to Evaluate Safety, Tolerability, 
and Efficacy of Intracerebroventricular BMN 190 in Pediatric Patients < 18 years of age with 
CLN2 Disease 
Protocol Number: 190-203 Amendment 6 
 
I have read the forgoing protocol amendment and agree to conduct this study as outlined. 
I agree to conduct the study in compliance with all applicable regulations and guidelines, 
including E6 ICH, as stated in the protocol, and other information supplied to me. 
 
 
 
 
Investigator Signature 
Date 
 
Printed Name: 
 
 
Accepted for the Sponsor: 
 
 
 
 
Medical Monitor Signature 
Date 
 
Printed Name:  
 
 
 
 
 
PI

 
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APPENDICES 
Appendix 1: Adapted CLN2 Disease Rating Scale 
Hamburg LINCL Scale (Steinfeld, 2002),  
adapted for multicenter use 
Weill Cornell LINCL Scale (Dyke, 2012), 
adapted for multicenter use 
Motor / Gait 
3 
Grossly normal gait. No prominent ataxia, no pathologic falls 
 
2 
Independent gait, as defined by ability to walk without support for 10 steps. Will have obvious instability, and may have 
intermittent falls. 
 
1 
Requires external assistance to walk, or can crawl only. 
 
0 
Can no longer walk or crawl. 
Language 
3 
Apparently normal language. Intelligible and grossly age-appropriate. No decline noted yet. 
 
2 
Language has become recognizably abnormal: some intelligible words, may form short sentences to convey concepts, 
requests, or needs. This score signifies a decline from a previous level of ability (from the individual maximum reached by 
the child). 
 
1 
Hardly understandable. Few intelligible words 
 
0 
No intelligible words or vocalizations 
Vision 
3 
Grossly normal. Appears to recognize multiple 
objects and reacts appropriately (reaches for a 
toy, etc.) 
Myoclonus 
3 
No myoclonus, involuntary movements. Babinski 
not present 
 
2 
Apparent difficulty seeing some objects. May 
be able to discern large objects, moving objects, 
but vision is clearly impaired. This score 
signifies a decline from a previous level of 
ability. 
 
2 
One finding: (myoclonus) (chorea, dystonia, 
tremor, athetosis) (Babinski present) 
 
1 
Reacts only to light 
 
1 
Two findings: (myoclonus) (chorea, dystonia, 
tremor, athetosis) (Babinski present)  
 
0 
No reaction to light 
 
0 
Myoclonus, involuntary movements, and Babinski 
present 

 
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Seizures 
(grand mal) 
3 
No seizures in 12-week period 
Feeding 
3 
No swallowing dysfunction 
 
2 
1 to 2 seizures in 12-week period 
 
2 
Mild swallowing dysfunction but tolerates most 
food / drinks 
 
1 
3 seizures in 12-week period (1 per 4 weeks) 
 
1 
Moderate swallowing dysfunction: difficulty with 
many foods 
 
0 
> 3 seizures in 12-week period (> 1 per 4 
weeks) 
 
0 
Gastrostomy tube dependent 

 
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PROTOCOL AMENDMENT TEXT REVISIONS  
The following is a detailed summary of significant protocol revisions corresponding with the rationale for changes (Page 2-5); added text is 
underlined and deleted text is struck. Additional administrative changes have been made for consistency and clarity throughout this 
amendment and are reflected in the protocol body.  
Section  
Revision 
Rationale for 
Change 
Table 9.1.1/SOE 
• 
Restored row for Ophthalmologic Assessments that was inadvertently removed in Protocol 
Amendment 5. 
 
 
Assessments and 
Events 
Screeninga 
 
Baseline/ First Infusion 
(≤ 2 days prior to first dose) 
Treatment 
Period 
Weeks 1 to 
144 
Study 
Completion/ 
Early 
Termination 
Device 
Safety 
Follow-
Up 
Safety 
Follow-
Up 
Ophthalmologic 
assessments 
 
 
X 
 
Q48W 
X 
 
 
Visual acuity testingu 
 
 
X 
 
Q12W 
X 
 
 
1 
12.3.1/ Baseline Visit 
• 
Ophthalmologic assessments 
• 
Visual acuity testing 
o 
All subjects will undergo Preferential Looking Testing. In addition, for those children 
who retain the cognitive function to adhere to testing, the Lea Vision Test or E Hook 
(or Tumbling E) Vision Test should also be performed during the same assessment. 
The subject must not be sedated at the time of visual acuity testing.  
 
1 
12.9/ Every 48 Weeks 
• 
Complete physical examination 
• 
Ophthalmologic assessments 
1 
12.10/ Study Completion 
or Early Termination 
Visit 
• 
Visual acuity testing 
o 
All subjects will undergo Preferential Looking Testing. In addition, for those children 
1 

 
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who retain the cognitive function to adhere to testing, the Lea Vision Test or E Hook 
(or Tumbling E) Vision Test should also be performed during the same assessment. 
The subject must not be sedated at the time of visual acuity testing.  
• 
Ophthalmologic assessments