Conditions: Mucopolysaccharidosis I
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 18
Healthy volunteers: no

Brief summary:
Phase I/II, open-label, multicenter, multinational (Japan, Brazil and US),designed to evaluate the safety, pharmacokinetics and explore the efficacy for the treatment of mucopolysaccharidosis type I (MPS I).

Detailed description:
In the JR-171-102 study, subjects will receive either 2.0 or 4.0 mg/kg/week of JR-171 intravenously at the same dosages received at Week 12 of the JR-171-101 study.

Arms:
arm 1: Drug: JR-171 IV infusion, dose escalation arm 2: Drug: JR-171 IV infusion, dose escalation, low dose, high dose

Interventions: intervention 1: JR-171 (lepunafusp alfa)
Intervention descriptions: intervention 1: IV infusion

Protocol document:
Prot_SAP_002.pdf: 
JR-171 Phase I/II study 
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Clinical Study Protocol 
Phase I/II study of JR-171 in patients with 
mucopolysaccharidosis type I 
 
Protocol Number: JR-171-101 
Version Number: ver. 6.00 
Compound: JR-171 
Study Phase: Phase I/II 
 
Sponsor: JCR Pharmaceuticals Co., Ltd. 
3-19 Kasuga-cho Ashiya, Hyogo, Japan 659-0021 
 
National Clinical Trial (NCT) Identified Number/IND Number:  
NCT04227600 
 
Approval Date: 12 November 2021 
 
Sponsor Responsible: 
 
Clinical Study Manager, Development Division 
2-4 Kasuga-cho Ashiya, Hyogo, Japan 659-0021 
 
CONFIDENTIALITY STATEMENT: This document includes information only shared with 
parties immediately involved in the study. When you publish or disclose to any third party the 
content of this document, prior consent must be obtained from JCR Pharmaceuticals Co., Ltd. 
This study will be conducted according to the principles of Good Clinical Practice as described 
in International Conference on Harmonisation guidelines, including the archiving of essential 
documents (CPMP/ICH/135/95). 


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Signature page: 
 
 
I have read Protocol JR-171-101. I agree to conduct the study as detailed in this 
protocol and in compliance with Declaration of Helsinki, International Conference on 
Harmonisation Good Clinical Practices (ICH-GCP) and all applicable regulatory 
requirements and guidelines. 
 
 
 
 
 
Principal Investigator 
 
 
Date 
 
 
 
 
 
 
As the sponsor representative, I confirm that JCR Pharmaceuticals Co., Ltd. will 
comply with all sponsor obligations as detailed in all applicable regulations and 
guidelines. I will ensure that the Principal Investigator is informed of all relevant 
information that becomes available during the conduct of this study. 
 
 
 
 
 
Clinical Study Manager 
JCR Pharmaceuticals Co., Ltd. 
 
 
Date 
 
 
 
 
 
 
Medical Monitor Name and Contact Information will be provided separately. 


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Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Date 
Ver. 1.00.000 (Original Protocol) 
8 January 2020 
Ver. 2.00.000 
20 April 2020 
Ver. 2.01.000 
18 June 2020 
Ver. 2.02.000 
20 July 2020 
Ver. 2.03.000 
31 August 2020 
Ver. 3.00 
27 November 2020 
Ver. 4.00 
5 February 2021 
Ver. 5.00 
20 August 2021 
Ver. 6.00 
12 November 2021 
 


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Table of Contents 
1. 
Protocol Summary ...................................................................................................................... 7 
1.1 
Synopsis ............................................................................................................................... 7 
1.2 
Schema ...............................................................................................................................10 
1.3 
Schedule of Activities ..........................................................................................................12 
2. 
Introduction ...............................................................................................................................16 
2.1 
Study Rationale1) ................................................................................................................16 
2.2 
Background .........................................................................................................................17 
2.3 
Benefit/Risk Assessment ....................................................................................................17 
2.3.1 
Known Potential Risks ................................................................................................17 
2.3.2 
Known Potential Benefits ............................................................................................17 
2.3.3 
Assessment of Potential Risks and Benefits ..............................................................17 
3. 
Objectives and Endpoints.........................................................................................................18 
4. 
Study Design ............................................................................................................................20 
4.1 
Overall Design ....................................................................................................................20 
4.2 
Scientific Rationale for Study Design .................................................................................21 
4.3 
Justification for Dose ..........................................................................................................22 
4.4 
End of Study Definition .......................................................................................................23 
5. 
Study Population ......................................................................................................................23 
5.1 
Inclusion Criteria .................................................................................................................23 
5.2 
Exclusion Criteria ................................................................................................................24 
5.3 
Lifestyle Considerations .....................................................................................................24 
5.4 
Screen Failures ...................................................................................................................24 
5.5 
Strategies for Recruitment and Retention ..........................................................................25 
6. 
Study Intervention ....................................................................................................................26 
6.1 
Study Interventions Administered .......................................................................................26 
6.1.1 
Composition ................................................................................................................28 
6.2 
Preparation/Handling/Storage/Accountability .....................................................................28 
6.2.1 
Acquisition and Accountability ....................................................................................28 
6.2.2 
Product Storage and Stability .....................................................................................29 
6.2.3 
Preparation .................................................................................................................29 
6.3 
Measures to Minimize Bias: Randomization and Blinding .................................................29 
6.4 
Study Intervention Compliance ..........................................................................................29 
6.5 
Concomitant Medication/Therapy .......................................................................................29 
6.5.1 
Prohibited Concomitant Medications/Therapies .........................................................29 
6.5.2 
Rescue Medicine ........................................................................................................30 
6.6 
Dosing and Administration ..................................................................................................30 
6.6.1 
Confirmation of Safety ................................................................................................30 
6.7 
Instructions for Subjects .....................................................................................................31 
6.8 
Intervention after the End of the Study ...............................................................................31 
7. 
Discontinuation of Study Intervention and Subject Discontinuation /Withdrawal ....................31 
7.1 
Discontinuation of Study Intervention .................................................................................31 
7.1.1 
Criteria for Termination or Suspension .......................................................................31 
7.2 
Subject Discontinuation/Withdrawal from the Study ..........................................................32 
7.3 
Lost to Follow-up ................................................................................................................33 


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8. 
Study Assessments and Procedures .......................................................................................33 
8.1 
Demographic and Other Baseline Characteristics .............................................................33 
8.2 
Safety Assessments ...........................................................................................................34 
8.2.1 
Pregnancy Testing (Female Subjects of Childbearing Potential Only).......................34 
8.2.2 
Administration Information ..........................................................................................35 
8.2.3 
Vital Signs ...................................................................................................................35 
8.2.4 
Laboratory Tests .........................................................................................................35 
8.2.5 
Antibodies ...................................................................................................................35 
8.2.6 
12-lead Electrocardiogram..........................................................................................36 
8.2.7 
Concomitant Medication/Therapy ...............................................................................36 
8.3 
Adverse Events and Serious Adverse Events ....................................................................36 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information .........................36 
8.3.2 
Method of Detecting AEs and SAEs ...........................................................................37 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................37 
8.3.4 
Regulatory Reporting Requirements for SAEs ...........................................................37 
8.3.5 
Pregnancy (Female Subjects and Subject’s Female Co-partners of Childbearing 
Potential Only) ............................................................................................................37 
8.3.6 
AEs of Special Interest ...............................................................................................37 
8.4 
Pharmacokinetics ...............................................................................................................39 
8.4.1 
Plasma Drug Concentration........................................................................................39 
8.5 
Efficacy Assessments .........................................................................................................39 
8.5.1 
Drug concentration in CSF .........................................................................................39 
8.5.2 
HS and DS concentrations in CSF .............................................................................39 
8.5.3 
CSF Opening Pressure ...............................................................................................40 
8.5.4 
Urinary HS and DS Concentrations ............................................................................40 
8.5.5 
Serum HS and DS Concentrations .............................................................................40 
8.5.6 
Liver and Spleen Volumes ..........................................................................................40 
8.5.7 
Cardiac Function .........................................................................................................41 
8.5.8 
6-minute Walk Test .....................................................................................................41 
8.5.9 
Other Clinical Findings Related to Neurocognitive and Behavioral Changes ............41 
8.5.10 BVMT-R and HVLT-R ..................................................................................................41 
8.5.11 T.O.V.A. .......................................................................................................................42 
8.5.12 PedsQL-FIM ................................................................................................................42 
8.5.13 Status of Cross-Reactive Immunologic Material (CRIM)............................................42 
9. 
Statistical Considerations .........................................................................................................42 
9.1 
Statistical Hypotheses ........................................................................................................42 
9.2 
Sample Size Determination ................................................................................................43 
9.3 
Populations for Analyses ....................................................................................................43 
9.4 
Statistical Analyses .............................................................................................................43 
9.4.1 
General Considerations ..............................................................................................43 
9.4.2 
Demographic and Other Baseline Characteristics .....................................................44 
9.4.3 
Safety Analyses ..........................................................................................................44 
9.4.4 
Analysis of the Pharmacokinetic endpoints ................................................................45 
9.4.5 
Analyses of the Exploratory Endpoints .......................................................................45 
9.4.6 
Subgroup Analyses .....................................................................................................46 
9.5 
Interim Analyses .................................................................................................................47 
9.6 
Independent Data Safety Monitoring Committee (IDSMC) ................................................47 


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10. Supporting Documentation and Operational Considerations ..................................................48 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .............................48 
10.1.1 Regulatory and Ethical Considerations ......................................................................48 
10.1.2 Protocol Compliance, Deviations or Changes, and Amendments .............................48 
10.1.3 Financial Payment and Insurance ..............................................................................49 
10.1.4 Financial Disclosure ....................................................................................................49 
10.1.5 Audit ............................................................................................................................49 
10.1.6 Training of Staff ...........................................................................................................50 
10.1.7 Informed Consent Process .........................................................................................50 
10.1.8 Blood and CSF Volume ..............................................................................................51 
10.1.9 Data Protection ...........................................................................................................52 
10.1.10 Future Use of Stored Specimens and Data ................................................................52 
10.1.11 Key Roles and Study Governance .............................................................................52 
10.1.12 Safety Oversight .........................................................................................................52 
10.1.13 Clinical Monitoring.......................................................................................................53 
10.1.14 Data Quality Assurance ..............................................................................................53 
10.1.15 Data Collection and Management Responsibilities ....................................................53 
10.1.16 Source Documents .....................................................................................................54 
10.1.17 Storage of Records and Other Documents ................................................................54 
10.1.18 Study and Site Start and Closure ...............................................................................55 
10.1.19 Publication Policy ........................................................................................................55 
10.1.20 Conflict of Interest Policy ............................................................................................55 
10.1.21 Additional considerations ............................................................................................55 
10.2 Appendix 2: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ...............................................................................................................56 
10.2.1 Definition of AE ...........................................................................................................56 
10.2.2 Definition of Clinically Relevant Changes in Laboratory Assessments ......................57 
10.2.3 Definition of SAE .........................................................................................................57 
10.2.4 Recording and Follow-Up of AE and/or SAE ..............................................................57 
10.2.5 Reporting of SAEs ......................................................................................................59 
10.3 Appendix 3: Abbreviations ..................................................................................................61 
10.4 Appendix 4: Protocol Amendment History ..........................................................................63 
11. References ...............................................................................................................................67 
 
 
Statement of Compliance 
The study will be carried out in accordance with the following: the Declaration of Helsinki-
Ethical Principles for Medical Research Involving Human Subjects- which was adopted by the 
18th World Medical Association General Assembly and its amendments; ICH-GCP and related 
regulations/regional requirements; this protocol. 
In the United States (US), the US Code of Federal Regulations (CFR) is applicable to clinical 
studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56 and 21 CFR Part 312).  
The protocol, informed consent form(s) (ICF(s)), and all subject materials will be submitted to 
the Institutional Review Board (IRB) for review and approval. Approval of both the protocol and 
the ICF(s) must be obtained before any subject is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study. In 
addition, all changes to the ICF will be IRB-approved; a determination will be made regarding 
whether a new consent needs to be obtained from patient or the patient’s legally acceptable 
representative. 




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 
Assessment of the other clinical findings 
related to neurocognitive and behavioral 
changes 
 
Changes in outcome of the Brief 
Visuospatial Memory Test-Revised 
(BVMT-R) and Hopkins Verbal Learning 
Test-Revised (HVLT-R) from baseline* to 
Week 13 (Part 2 only) 
 
Changes in outcome of the Test of 
Variables of Attention (T.O.V.A.) from 
baseline* to Week 13 (Part 2 only) 
 
Changes in outcome of the Pediatric 
Quality of Life Inventory Family Impact 
Module (PedsQL-FIM) from baseline* to 
Week 13 (Part 2 only) 
* Use the data determined in the screening period as the baseline data. 
Study Population:  
Male or female MPS I patients (18 years old or older in Part 1, and 2 years or older (any age 
in Japan and Brazil) in Part 2). 
 
Inclusion Criteria 
1. 
A patient aged 18 years or older in Part 1 or 2 years or older (any age in Japan and Brazil) 
in Part 2, at the time of informed consent. 
2. 
A patient from whom written informed consent can be obtained. If the patient is aged under 
18 years (20 years in case of Japan) at the time of assent or willingness to participate in 
the study cannot be confirmed due to MPS I-related intellectual disability, informed 
permission from the patient’s legally acceptable representative (e.g., his/her parents or 
guardians) needs to be obtained instead of his/her consent. Even in this case, written 
informed consent should be obtained from the patient, wherever possible. 
3. 
A patient diagnosed with MPS I based on any one of the following criteria: 
 
Activity of the IDUA enzyme below 10% of the lower reference level in leucocytes or 
cultured 
skin 
fibroblasts, 
AND 
increased 
age-related 
urinary 
levels 
of 
glycosaminoglycans (GAGs) (before enzyme replacement therapy (ERT)). 
 
Activity of the IDUA enzyme below 10% of the lower reference level in leucocytes or 
cultured skin fibroblasts, AND presence of one pathogenic mutation in each of the 
alleles of the IDUA gene. 
 
Increased age-related urinary levels of GAGs (before ERT), AND presence of one 
pathogenic mutation in each of the alleles of the IDUA gene. 
4. 
A patient diagnosed as having mild or no MPS I-related intellectual disability (able to report 
their own subjective symptoms) by the principal investigator or subinvestigator (Part 1 
only). 
5. 
A patient who has received laronidase continuously for at least 12 weeks and has received 
laronidase at a stable dosage for the 2 weeks immediately before the initial administration 
of JR-171 (except for a laronidase naïve patient or a patient who has previously been 
treated by hematopoietic stem cell transplantation (HSCT)). 
6. 
Female patient or male patient whose co-partner is of child-bearing potential agrees to 
use a medically accepted, highly effective method of contraception, such as spermatocidal 
gel plus condom, an intrauterine device or oral contraceptives until one month after the 
final administration. 
Exclusion Criteria 
1. 
A patient who has received gene therapy treatment. 
2. 
A patient who, in the opinion of the principal investigator or subinvestigator, cannot 
undergo lumbar puncture, including those who have a difficulty in taking position for lumbar 


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puncture due to joint contracture and those who are likely to develop dyspnea during 
lumbar puncture. 
3. 
A patient who is pregnant or lactating. 
4. 
A patient who has developed serious drug allergy or hypersensitivity to any drugs, in the 
opinion of the principal investigator or subinvestigator, is inappropriate for participation in 
the study. 
5. 
A patient who has received another investigational product within the 12 months prior to 
enrollment in the study. 
6. 
A patient who, in the opinion of the principal investigator or subinvestigator, is ineligible to 
participate in the study in consideration of patient’s safety. 
 
Investigational Product:  
JR-171 
 
Overall Design:  
This is a phase I/II, open-label, multicenter (six sites in total are planned), multinational (Japan, 
Brazil and the US) study for the treatment of MPS I. 
 
Disclosure Statement:  
This is an open-label, first-in-human study of JR-171 designed to evaluate the safety, PKs and 
explore the efficacy. 
 
Dosing and Administration:  
Part 1 
Subjects aged 18 years or older shall receive an initial administration of JR-171 as an 
intravenous infusion at a dose of 0.1 mg per kg of body weight. The dose level shall be then 
increased to 1.0 mg/kg for the second administration, to 2.0 mg/kg for the third administration, 
and to 4.0 mg/kg at the fourth administration. When the principal investigator or subinvestigator 
concludes that JR-171 dose increase will pose no problem based on the safety information 
collected from the administered dose to the first and second subject, JR-171 will be increased 
to the next dose upon approval of the sponsor. The start date of JR-171 administration of the 
second subject should be at least 1 week after the start date of JR-171 administration of the 
first subject. Once the two subjects complete all the four times of administrations and the safety 
of JR-171 is confirmed, then the administration for the third and subsequent subjects may be 
started. If the first or second subject is discontinued from the study during the dose-escalation 
phase (until the safety evaluation of the fourth administration), the next third subject will stay 
in the hospital and will be supervised until 21 hours after the end of each administration to 
assess safety. JR-171 is to be administered at intervals of 1 week. The total volume of infusion 
should be administered over approximately 3 hours, but may be extended to a longer period 
at the discretion of the principal investigator or subinvestigator, considering safety concerns, 
including any IARs, etc. 
 
Part 2 
The first subject aged 6-17 years and the first subject aged 2-5 years (0-5 years in Japan and 
Brazil) shall each receive an initial dose of JR-171 as an intravenous infusion at a dose of 
1.0 mg per kg of body weight. The dose level shall be then increased to 2.0 mg/kg for the 
second administration, and to 4.0 mg/kg for the third administration. From the fourth to twelfth 
administrations, JR-171 shall be administered at 4.0 mg/kg. If the first subject aged 6-17 years 
or the first subject aged 2-5 years (0-5 years in Japan and Brazil) is discontinued from the 
study during the dose-escalation phase (until the safety evaluation of the third administration), 
the next subject for the same age group shall receive JR-171 in a dose-escalation manner as 
described above (the schedule of assessments will also be the same as those for the first 
subject in each age group). 


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The first subject aged 2-5 years (0-5 years in Japan and Brazil) can receive the initial 
administration at least 1 week after the first subject aged 6-17 years receives the initial 
administration. The second subject in each age group in Part 2 could be administered with 
JR-171 after the safety evaluation of the third administration of the first subject in each age 
group. 
Subjects other than the above of aged 2 years or older (any age in Japan and Brazil) shall be 
randomly assigned to either one of 2 groups in a 1:1 ratio, and receive 2.0 or 4.0 mg of JR-171 
per kg of body weight 12 times as an intravenous infusion. JR-171 will be administered over 
approximately 3 hours every week over a 12 week period. The treatment time may be 
extended to a longer period at the discretion of the principal investigator or subinvestigator, 
considering safety concerns, including any IARs, etc. 
 
In Part 1 and Part 2, the dose of JR-171 will be calculated based on the latest body weight 
value collected at a scheduled visit. 
 
Concomitant Therapies/Medications: 
Concomitant therapies/medications can be used during this clinical study when required. 
Transfusions or maintenance transfusions for purpose of establishment an intravenous line, 
diluents for injections, bases for in-hospital preparations, disinfectants and drugs used in 
preparative treatments e.g., anesthetic (other than drugs with anticipated effects) are not 
considered as concomitant therapies/medications. 
 
Prohibited Therapies/Medications: 
Investigational products other than JR-171, laronidase, HSCT 
 
Number of Subjects 
Part 1: 4 subjects 
Part 2: Approximately 15 subjects in total.  
 
Duration of Study: 
 
Study start 
(enrollment start) Enrollment end 
Study end 
Completion of 
data analyses 
September 2020 
March 2022 
August 2022 
January 2023 
 
Part 1: 5-8 weeks (including 1-4 weeks as a screening period) 
Part 2: 13-16 weeks (including 1-4 weeks as a screening period) 
 
Independent Data Safety Monitoring Committee (IDSMC): Yes 
1.2 Schema 
Since this is a first-in-human study of JR-171, the JR-171-101 study will proceed in stages 
while confirming that safety is ensured. For the detailed procedures to confirm safety, refer to 
Section 6.6.1. 
 


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Part 
Number of subjects 
Dose 
Part 1 
4 subjects 
Initial administration 
: 0.1 mg/kg single dose 
Second administration 
: 1.0 mg/kg single dose 
Third administration 
: 2.0 mg/kg single dose 
Fourth administration 
: 4.0 mg/kg single dose 
Part 2a), b) 
At least 2 subjectsc) 
Initial administration 
: 1.0 mg/kg single dose 
Second administration 
: 2.0 mg/kg single dose 
Third administration 
: 4.0 mg/kg single dose 
After third administration : 4.0 mg/kg/week, 9 times 
Twelve administrations in total 
2.0 mg/kg/week group: 
At least 6 subjects  
 
4.0 mg/kg/week group: 
At least 6 subjects  
2.0 mg/kg/week, 12 times 
4.0 mg/kg/week, 12 times 
a) Part 2 is started only after the safety is confirmed in Part 1 by the IDSMC. Subjects participating in 
Part 1 are excluded from Part 2. 
b) Approximately 15 subjects will be enrolled in total. 
c) Starting dose of 1 mg/kg in the first subject aged 6-17 years and the first subject aged 2-5 years (0-
5 years in Japan and Brazil). 
 
Subjects who complete Part 2 of the JR-171-101 study will be eligible to participate in the 
extension study (protocol number: JR-171-102 study) and to continue receiving JR-171. 
 
Dosing Schema: 
 


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1.3 Schedule of Activities 
Part 1 
Observation/test timing 
Pre-screening 
Screening test 
Registration Baseline Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Discontinuation 
Visit window 
- 
28 days before Day 1 
(Day -28) to Day -7 
- 
Day -2 to 
Day 1 
Day 1 
Day 8 to 
Day 11 
Day 15 to 
Day 18 
Day 22 to 
Day 25 
Day 29 to 
Day 32 
Within 28 days from 
discontinuation 
JR-171 administration 
 
 
 
 
X 
X 
X 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Subject baseline characteristicsa) 
 
X 
 
 
 
 
 
 
 
 
Assessment based on 
inclusion/exclusion criteria 
 
 
X 
 
 
 
 
 
 
 
Pregnancy testing (female subjects of 
childbearing potential only) 
 
X 
 
 
 
 
 
 
 
 
Vital signsb) 
 
Xc) 
 
Xd) 
Xe) 
Xe) 
Xe) 
Xe) 
Xc), f) 
Xc) 
Laboratory testsf) 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Antibodiesf) 
 
 
 
Xg) 
 
Xh) 
 
 
Xg) 
Xg) 
Plasma drug concentrationi) 
 
 
 
 
X 
X 
X 
X 
 
 
Drug concentration in CSF 
 
 
 
Xf) 
 
 
 
Xj) 
 
Xk) 
HS and DS concentrations in CSF 
 
 
 
Xf) 
 
 
 
Xj) 
 
Xk) 
CSF opening pressure 
 
 
 
Xf) 
 
 
 
Xj) 
 
Xk) 
Urinary HS and DS concentrations 
(including measurement of creatinine for 
concentration adjustment)f) 
 
 
 
X 
 
X 
X 
X 
X 
X 
Serum HS and DS concentrationsf) 
 
 
 
X 
 
X 
X 
X 
X 
X 
Liver and spleen volumesf) 
 
 
 
X 
 
 
 
 
X 
X 
Cardiac functionf) 
 
 
 
X 
 
 
 
 
X 
X 
Other clinical findings related to 
neurocognitive and behavioral changes 
 
 
 
 
 
 
 
 
 
 
12-lead electrocardiogramf) 
 
X 
 
 
 
 
 
 
X 
X 
Cross-reactive immunologic materiall) 
 
 
 
 
 
 
 
 
 
 
AEs 
 
 
 
 
 
 
 
 
 
 
Concomitant therapies/medications 
 
 
 
 
X 
X 
X 
X 
X 
X 
a) Neurocognitive testing and adaptive behavior assessment will be performed before the first infusion 
of JR-171.  
b) Vital signs: pulse rate, body temperature, blood pressure, respiratory rate, percutaneous oxygen 
saturation and body weight. During the infusion of JR-171, it is necessary to monitor other than body 
weight (see Section 6.1 and 8.2.3). 
c) Excluding body weight 
d) Only body weight is measured. 
e) Perform before and after administration of JR-171 except for body weight. Body weight will be 
measured at either measuring point. 
f) Perform before administration of JR-171 (or before laronidase at Week 5, for subjects who will receive 
laronidase after completing the JR-171-101 study) 
g) Anti-IDUA and anti-JR-171 antibodies  
h) Anti-JR-171 antibodies 
i) Blood specimens should be collected by following the “PK sampling schedule (plasma drug 
concentration)”.  
j) Performed within 5 hours after the end of administration of JR-171 
k) Performed if deemed feasible by the principal investigator or subinvestigator 
l) Samples will be collected once in Part 1 and obtained before JR-171 administration during the visit. 


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Part 2 
Observation/test timing 
Pre-screening 
Screening test 
Registration 
Baseline 
Week 1 
Week 2 
Week 3 
Week 4 
Visit window 
- 
Day -28 to Day -7 
- 
Day -2 to Day 1 
Day 1 
Day 8 to 
Day 11a) 
Day 15 to 
Day 18a) 
Day 22±3 
Day 8±3b) 
Day 15±3b) 
JR-171 administration 
 
 
 
 
X 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
Subject baseline characteristicsc) 
 
X 
 
 
 
 
 
 
Assessment based on 
inclusion/exclusion criteria 
 
 
X 
 
 
 
 
 
Allocation for treatment group 
 
 
X 
 
 
 
 
 
Pregnancy testing (female subjects of 
childbearing potential only) 
 
X 
 
 
 
 
 
 
Vital signsd) 
 
Xe) 
 
Xf) 
Xg) 
Xg) 
Xg) 
Xg) 
Laboratory testsh) 
 
X 
 
X 
 
X 
 
X 
Antibodiesh) 
 
 
 
Xi) 
 
Xj) 
 
Xj) 
Plasma drug concentration b), k) 
 
 
 
 
X 
 
 
X 
Drug concentration in CSF 
 
 
 
Xh) 
 
 
 
 
HS and DS concentrations in CSF 
 
 
 
Xh) 
 
 
 
 
CSF opening pressure 
 
 
 
Xh) 
 
 
 
 
Urinary HS and DS concentrations 
(including measurement of creatinine for 
concentration adjustment)h) 
 
 
 
X 
 
X 
 
X 
Serum HS and DS concentrationsh) 
 
 
 
X 
 
X 
 
X 
Liver and spleen volumesh) 
 
 
 
X 
 
 
 
 
Cardiac functionh) 
 
 
 
X 
 
 
 
 
6-minute walk testm) 
 
 
 
Xh) 
 
 
 
 
Other clinical findings related to 
neurocognitive and behavioral changes 
 
 
 
 
 
 
 
 
12-lead electrocardiogramh) 
 
X 
 
 
 
 
 
 
BVMT-R and HVLT-Rm) 
 
Xp) 
 
 
 
 
 
 
T.O.V.A. m) 
 
Xp) 
 
 
 
 
 
 
PedsQL-FIMn) 
 
Xp) 
 
 
 
 
 
 
Cross-reactive immunologic materialo) 
 
 
 
 
 
 
 
 
AEs 
 
 
 
 
 
 
 
 
Concomitant therapies/medications 
 
 
 
 
X 
X 
X 
X 


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Part 2 cont. 
Observation/test timing 
Week 5 
Week 6 
Week 7 
Week 8 
Week 9 
Week 10 
Week 11 
Week 12 
Week 13 
Discontinu
ation 
Visit window 
Day 29±3 
Day 36±3 
Day 43±3 
Day 50±3 
Day 57±3 
Day 64±3 
Day 71±3 
Day 78±3 
Day 85±3 
Within 28 
days from 
discontinu
ation  
JR-171 administration 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signsd) 
Xg) 
Xg) 
Xg) 
Xg) 
Xg) 
Xg) 
Xg) 
Xg) 
Xe), h) 
Xe) 
Laboratory testsh) 
 
X 
 
X 
 
X 
 
X 
X 
X 
Antibodiesh) 
 
 
 
Xj) 
 
 
 
 
Xi) 
Xi) 
Plasma drug concentrationb), k) 
 
 
 
 
 
 
 
X 
 
 
Drug concentration in CSF 
 
 
 
 
 
 
 
Xl) 
 
Xm) 
HS and DS concentrations in CSF 
 
 
 
 
 
 
 
Xl) 
 
Xm) 
CSF opening pressure 
 
 
 
 
 
 
 
Xl) 
 
Xm) 
Urinary HS and DS concentrations 
(including measurement of creatinine 
for concentration adjustment)h) 
 
X 
 
X 
 
X 
 
X 
X 
X 
Serum HS and DS concentrationsh) 
 
X 
 
X 
 
X 
 
X 
X 
X 
Liver and spleen volumesh) 
 
 
 
 
 
 
 
 
X 
X 
Cardiac functionh) 
 
 
 
 
 
 
 
 
X 
X 
6-minute walk testm) 
 
 
 
 
 
 
 
 
X 
X 
Other clinical findings related to 
neurocognitive and behavioral 
changes 
 
 
 
 
 
 
 
 
 
 
12-lead electrocardiogramh) 
 
 
 
 
 
 
 
 
X 
X 
BVMT-R and HVLT-Rm) 
 
 
 
 
 
 
 
 
Xq) 
 
T.O.V.A.m) 
 
 
 
 
 
 
 
 
Xq) 
 
PedsQL-FIMn) 
 
 
 
 
 
 
 
 
Xq) 
 
Cross-reactive immunologic materialo) 
 
 
 
 
 
 
 
 
 
 
AEs 
 
 
 
 
 
 
 
 
 
 
Concomitant therapies/medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a) The first subject aged 6-17 years and the first subject aged 2-5 years (0-5 years in Japan and 
Brazil) 
b) Excluding the first subject aged 6-17 years and the first subject aged 2-5 years (0-5 years in 
Japan and Brazil) 
c) Neurocognitive testing and adaptive behavior assessment will be performed before the first 
infusion of JR-171. 
d) Vital signs: pulse rate, body temperature, blood pressure, respiratory rate, percutaneous 
oxygen saturation and body weight. During the infusion of JR-171, it is necessary to monitor 
other than body weight (see Section 6.1 and 8.2.3). 
e) Excluding body weight 
f) Only body weight is measured. 
g) Perform before and after administration of JR-171 except for body weight. Body weight will be 
measured at either measuring point. 
h) Perform before administration of JR-171 (or before laronidase at Week 13, for subjects who 
will receive laronidase after completing the JR-171-101 study) 
i) Anti-IDUA and anti-JR-171 antibodies 
j) Anti-JR-171 antibodies 
k) Blood specimens should be collected by following the “PK sampling schedule (plasma drug 
concentration)”. 
l) Performed within 5 hours after the end of administration of JR-171 
m) Performed if deemed feasible by the principal investigator or subinvestigator 
n) Only for subjects accompanied by their family, caregiver or equivalent thereof. 
o) Samples will be collected once in Part 2 and obtained before JR-171 administration during the 
visit. 
p) Should be performed before the first infusion of JR-171. 
q) Visit window: ±10 days


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PK sampling schedule (plasma drug concentration) 
Test timing 
Part 1: Week 1, Week 2, Week 3 and Week 4 
Part 2: Week 1, Week 4 and Week 12 
Elapsed time 
Before administration 1 hour after the start of 
administration 
At the end of 
administration 
3 hours after the end 
of administration 
6 hours after the end 
of administration 
21 hours after the end 
of administration 
Time window (min) 
-60 to 0 
±15 
+10 
±15 
±15 
±60 
 


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2. Introduction 
2.1 Study Rationale1) 
MPS I is an autosomal recessive disorder caused by a deficiency of IDUA, a lysosomal enzyme 
involved in the breakdown of GAGs, which results in systemic accumulation of GAGs, 
particularly DS and HS. The accumulation of GAGs causes various symptoms, including 
deafness, otitis media, bone or joint deformity, joint contracture, obstructive respiratory disorder, 
apnea syndrome, cardiac valvulopathy, and CNS symptoms. MPS I is classified into three 
forms based on age of onset, clinical manifestation, severity, and degree of disease 
progression: Hurler syndrome, which is the most severe form, and Hurler-Scheie syndrome 
and Scheie syndrome, which are milder than Hurler syndrome. The most severe form, Hurler 
syndrome, clinically manifests in early childhood and progresses rapidly. It has been reported 
that approximately 75% of naïve patients with Hurler syndrome die before 10 years of age due 
to obstructive respiratory disorder, respiratory infection, cardiac complications, etc. On the 
other hand, the mildest form Scheie syndrome initially manifests as heart valve disease, 
corneal opacity, joint contracture, hernia, carpal tunnel syndrome, etc., but these symptoms 
are mild or associated with other diseases, often leaving Scheie syndrome undiagnosed until 
adulthood. Patients with Hurler syndrome have CNS symptoms, whereas Scheie syndrome 
involves no CNS symptoms. Hurler-Scheie syndrome is of intermediate severity and involves 
only mild CNS symptoms or none at all. 
MPS I is a very rare disease, with an estimated prevalence of 0.11-3.62 per 100000 live births. 
In particular, the prevalence in Japan, the US, and Brazil is estimated to be 0.23, 0.34, and 
0.24 per 100000 live births, respectively.2) A study of 987 patients with MPS I registered in the 
Global MPS I Registry reported that Hurler syndrome, Hurler-Scheie syndrome, and Scheie 
syndrome accounted for 60.9%, 23.0%, and 12.9% of patients, respectively (unknown in 3.2% 
cases).3) 
MPS I is usually treated with HSCT or ERT. HSCT is a treatment option for the severe form 
involving CNS symptoms. After HSCT, uptake of the enzyme secreted from the transplanted 
cells by the patient’s cells results in a reduction in accumulated GAGs and improvement of 
clinical symptoms (e.g., hepatosplenomegaly, joint contracture, respiratory symptoms), and 
these effects are permanently maintained after successful engraftment. It has been reported 
that early HSCT preserves intellectual development. The management and treatment 
guidelines for MPS I recommend to select the therapy based on the risk/benefit ratio for HSCT 
versus ERT individually for each patient with MPS I.4) HSCT is recommended for patients 
<2 years of age who are cognitively intact, and for the other patients, ERT is the more 
reasonable option for palliative therapy. A European consensus panel recommends HSCT for 
Hurler syndrome diagnosed before 2.5 years of age.5) However, HSCT may cause fatal 
complications such as graft-versus-host disease and infection. In 258 patients with Hurler 
syndrome who underwent HSCT in 1995 to 2007, the post-transplant 5-year survival rate was 
reportedly 74%.6) Due to the aforementioned risks and the necessity of human leukocyte 
antigen-compatible donors, HSCT is not indicated for every patient. 
On the other hand, ERT is exogenous enzyme supplementation using cellular uptake of the 
enzyme via the cation-independent mannose-6-phosphate receptor (M6PR). Laronidase 
(laronidase solution for intravenous infusion; brand name: Aldurazyme), the first enzyme 
preparation approved in the US and the European Union (EU) in 2003, is indicated for patients 
with Hurler and Hurler-Scheie forms of MPS I and for patients with the Scheie form who have 
moderate to severe symptoms. Based on clinical study results and post-marketing experience 
over more than 10 years, laronidase is known to improve cardiopulmonary function, ability to 
walk, hepatosplenic volume, cardiac function, joint function, visual acuity, quality of life, etc. 
However, laronidase, which does not penetrate the blood-brain barrier, is not effective for CNS 
symptoms.7) 
 
In conclusion, early HSCT is effective for CNS symptoms of MPS I, but there are risks and an 
upper age limit for treatment. ERT is shown to be effective for systemic symptoms, but not for 
CNS symptoms. Therefore, it is desirable to establish a safe and effective treatment for MPS I 


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that also addresses the CNS symptoms. 
2.2 Background 
JR-171 is a fusion protein genetically modified to penetrate the blood-brain barrier and consists 
of IDUA and the Fab fragment of a humanized antibody that specifically recognizes human 
transferrin receptor 1 (hTfR). 
JR-171, which binds to hTfR and M6PR, may be transported to the cerebral parenchyma via 
hTfR on the cerebrovascular endothelium and to peripheral organ cells via M6PR and hTfR. 
In a repeated dose study where human transferrin receptor 1 knock-in/α-L-iduronidase knock-
out mice (hTfR KI/Idua KO mice), an animal model of MPS I, received JR-171 once a week for 
4 or 12 weeks, GAG concentrations in the brain and peripheral organs decreased to almost 
the normal range. Therefore, JR-171 is expected to decrease intracellularly accumulated 
GAGs and inhibit the progression of CNS and systemic symptoms. In addition, no safety 
concerns have been raised in nonclinical studies. 
 
Therefore, based on the conclusion that it is scientifically and ethically appropriate to conduct 
a clinical study of JR-171, which is an innovative treatment for MPS I of high clinical 
significance, the sponsor is planning a phase I/II study in patients with MPS I. 
2.3 Benefit/Risk Assessment 
2.3.1 Known Potential Risks 
As JR-171 contains anti-hTfR antibody, the ordinary iron transport system (binding of 
transferrin to the transferrin receptor) might be inhibited, which may lead to the development 
of adverse drug reactions (anemia, etc.). JR-171 is also considered to cross the blood-brain 
barrier, and adverse drug reactions (vomiting, headache, etc.) may therefore occur. 
Furthermore, the enzyme portion of JR-171 is similar to laronidase, and similar adverse drug 
reactions reported with use of laronidase may occur, including those potential risks, 
anaphylactic shock, and IARs as well as anti-JR-171 antibody and anti-IDUA antibody 
production. 
2.3.2 Known Potential Benefits 
JR-171 is expected to be effective for CNS symptoms of MPS I. JR-171 is also expected to be 
as effective as laronidase for systemic symptoms. 
2.3.3 Assessment of Potential Risks and Benefits 
Given its current battery of nonclinical studies results, JR-171 is expected to suppress central 
nervous and systemic symptoms of MPS I by being transported to the cerebral parenchyma 
via hTfR and to peripheral organ cells via M6PR and hTfR to decrease intracellularly 
accumulated GAGs. In addition, no safety concerns have been raised in the nonclinical 
studies that have been conducted to date. 






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4. Study Design 
4.1 Overall Design 
A Phase I/II, open-label, multicenter (six sites in total are planned), multinational (Japan, Brazil 
and the US), designed to evaluate the safety, PKs and explore the efficacy for the treatment 
of MPS I. 
 
The JR-171-101 study will consist of Part 1 and Part 2.  
In Part 1, subjects aged 18 years or older shall receive administration of JR-171 as an 
intravenous infusion in a dose-escalation manner. When the principal investigator or 
subinvestigator concludes that JR-171 dose increase will pose no problem based on the safety 
information collected from the administered dose to the first and second subject, JR-171 will 
be increased to the next dose upon approval of the sponsor. The start date of JR-171 
administration of the second subject should be at least 1 week after the start date of JR-171 
administration of the first subject. Once the two subjects complete all the four times of 
administrations and the safety of JR-171 is confirmed, then the administration for the third and 
subsequent subjects may be started. If the first or second subject is discontinued from the 
study during the dose-escalation phase (until the safety evaluation of the fourth administration), 
the next third subject will stay in the hospital and will be supervised until 21 hours after the end 
of each administration to assess safety. 
In part 2, the first subject aged 6-17 years and the first subject aged 2-5 years (0-5 years in 
Japan and Brazil) shall each receive an initial dose of JR-171 as an intravenous infusion at a 
dose of 1.0 mg per kg of body weight. The dose level shall be then increased to 2.0 mg/kg for 
the second administration, and to 4.0 mg/kg for the third administration. From the fourth to 
twelfth administrations, JR-171 shall be administered at 4.0 mg/kg. If the first subject aged 6-
17 years or the first subject aged 2-5 years (0-5 years in Japan and Brazil) is discontinued from 
the study during the dose-escalation phase (until the safety evaluation of the third 
administration), the next subject for the same age group shall receive JR-171 in a dose-
escalation manner as described above (the schedule of assessments will also be the same as 
those for the first subject in each age group). 
The first subject aged 2-5 years (0-5 years in Japan and Brazil) can receive the initial 
administration at least 1 week after the first subject aged 6-17 years receives the initial 
administration. The second subject in each age group in Part 2 could be administered with 
JR-171 after the safety evaluation of the third administration of the first subject in each age 
group. 
Subjects other than above of 2 years or older (any age in Japan and Brazil) shall be randomly 
assigned to one of either 2 groups in a 1:1 ratio and receive 2.0 or 4.0 mg/kg of JR-171. 
Since this is a first-in-human study of JR-171, the JR-171-101 study will proceed in stages 
while confirming that safety is ensured. For the detailed procedures to confirm safety, refer to 
Section 6.6.1. 
Subjects who complete Part 2 of the JR-171-101 study will be able to participate in the 
extension study (protocol number: JR-171-102 study) and continue receiving JR-171. 
 


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Part 
Number of subjects 
Dose 
Part 1 
4 subjects 
Initial administration 
: 0.1 mg/kg single dose 
Second administration 
: 1.0 mg/kg single dose 
Third administration 
: 2.0 mg/kg single dose 
Fourth administration 
: 4.0 mg/kg single dose 
Part 2a), b) 
At least 2 subjectsc) 
Initial administration 
: 1.0 mg/kg single dose 
Second administration 
: 2.0 mg/kg single dose 
Third administration 
: 4.0 mg/kg single dose 
After third administration : 4.0 mg/kg/week, 9 times 
Twelve administrations in total 
2.0 mg/kg/week group: 
At least 6 subjects  
 
4.0 mg/kg/week group: 
At least 6 subjects  
2.0 mg/kg/week, 12 times 
4.0 mg/kg/week, 12 times 
a) Part 2 is started only after the safety is confirmed in Part 1 by the IDSMC. Subjects participating in 
Part 1 are excluded from Part 2. 
b) Approximately 15 subjects will be enrolled in total. 
c) Starting dose of 1 mg/kg in the first subject aged 6-17 years and the first subject aged 2-5 years (0-
5 years in Japan and Brazil). 
 
 
4.2 Scientific Rationale for Study Design 
JR-171 is expected to provide clinical benefit to MPS I patients especially those who show 
CNS manifestations. Since many patients with MPS I are receiving ERT8) or/and have received 
an HSCT,5) and it is very difficult to enroll naïve patients, the JR-171-101 study is designed to 
target MPS I patients with or without previous HSCT treatment and to mainly focus on the 
switch in treatment from laronidase to JR-171. Laronidase will be totally eliminated from the 
subject’s body within 1 week because its mean t1/2 ranges from 1.5 to 3.6 hours. Moreover, 


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given that there is no evidence of accumulation of laronidase,7) no extended washout period 
prior to switching from laronidase is included to evaluate the safety and exploratory efficacy of 
JR-171. Since interruption of ERT for MPS I over a certain period of time may result in 
irreversible progression of the disease, no placebo control group is included from an ethical 
perspective. The JR-171-101 study will be conducted, in part, to evaluate the safety of JR-171 
and to explore its efficacy. 
Since this is a first-in-human study of JR-171, in Part 1, four MPS I patients aged 18 years or 
older will receive 4 times JR-171 administration in a weekly dose-escalation manner. When it 
is concluded that there are no safety issues in Part 1 and JR-171 can be shown to potentially 
penetrate the blood-brain barrier in humans, treatment in Part 2 will be started in approximately 
15 subjects with MPS I. 
Since no accumulation of HS and DS is observed in non-MPS patients,9), 10) and there are risks 
that the administration of protein drug to healthy volunteers, in terms of neutralizing antibody 
production, this phase I/II study is conducted in subjects with MPS I to assess the relationship 
between PKs and pharmacodynamics. 
The nonclinical safety of JR-171 was demonstrated in a repeated intravenous dose toxicity 
study where male and female cynomolgus monkeys received JR-171 at a dosage of 40 mg/kg 
once a week for 4 weeks. Furthermore, a 13-week toxicity study will be completed before this 
phase I/II recruits subjects. Given a decrease in accumulated GAGs in the brain and other 
peripheral organs in a repeated intravenous dose study where hTfR KI/Idua KO mice received 
JR-171 once every week or once every 2 weeks for 12 weeks, the duration of the present study 
is considered to be appropriate to evaluate the efficacy in an exploratory manner. 
4.3 Justification for Dose 
Given a no-observed-adverse-effect-level (NOAEL) of 40 mg/kg in a nonclinical toxicity study 
in male and female cynomolgus monkeys, dose equivalence in human is calculated to be 
approximately 1.0 mg/kg with safety margin of 10. In this first-in-human study of JR-171 one-
tenth of the aforementioned dose is selected as the initial dose level in Part 1 for safety 
considerations, and the dose level is increased each week. 
In a repeated dose study where hTfR KI/Idua KO mice received JR-171 once every week or 
once every 2 weeks for 12 weeks, the drug at dosages of 2.0 and 4.0 mg/kg/every 2 weeks 
was shown to be as effective for systemic symptoms as laronidase at dosage of 
0.58 mg/kg/week. In addition, unlike laronidase, JR-171 also decreased HS and DS 
concentrations in the brain and CSF at all doses. However, slightly greater reductions in the 
HS and DS levels in some tissues were observed in treatment groups receiving every week 
regimen than the treatment groups receiving every 2 weeks dosing regimen. Furthermore, 
based on the results of nonclinical pharmacology, ADME, and toxicology studies, it is 
considered that there are no serious safety concerns in intravenous administration of JR-171 
to MPS I patients at the dose levels up to 4.0 mg/kg, which is the planned maximum dose in 
Phase I/II study. 
Based on these findings, 2.0 and 4.0 mg/kg were selected as doses to be administered every 
week in Part 2 of the JR-171-101 study. 
Part 2 is started only after the safety is confirmed in Part 1 by the IDSMC, and all subjects 
aged 18 years or older will have received 2.0 or 4.0 mg/kg for weekly administration. 
Considering the safety for subjects under 18 years, the first subject aged 6-17 years and the 
first subject aged 2-5 years (0-5 years in Japan and Brazil) in Part 2 will each receive the 
administration of JR-171 by dose-escalation manner, and its initial dose of JR-171 shall start 
from 1.0 mg/kg. A previous report indicated that concentration of soluble transferrin receptor 
gradually decreases from the neonatal period to adolescence, and then reduces further to the 
adult level after which the concentration remains stable.11) However, no marked reduction of 
the soluble transferrin receptor was found in adults, indicating that effect of JR-171 is not 
expected to vary with the subject’s age. Therefore, the initial dose of JR-171 shall start from 
1.0 mg/kg as part of dose-escalation, and 2 years (0 years in Japan and Brazil) or older 
patients, including naïve ones, can also be enrolled in consideration of ethical perspective 
because it is desirable to start treatment earlier in order to suppress progressive 
neurodegeneration. Second and subsequent subjects under 18 years in each age group will 


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receive 2.0 or 4.0 mg/kg for weekly administration, after the safety evaluation of the third 
administration of the first subject. 
4.4 End of Study Definition 
A subject is considered to have completed the study if he/she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities, 
Section 1.3. 
 
The end of the study is defined that the point of when all subjects complete all procedures 
relating to the JR-171-101 study. 
5. Study Population 
In order to be eligible to participate in the JR-171-101 study, a patient must meet all of the 
inclusion criteria, and none of the exclusion criteria. 
5.1 Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria apply: 
 
1. 
A patient aged 18 years or older in Part 1, or 2 years or older (any age in Japan and Brazil) 
in Part 2, at the time of informed consent. 
2. 
A patient from whom written informed consent can be obtained. If the patient is aged under 
18 years (20 years in case of Japan) at the time of assent or willingness to participate in 
the study cannot be confirmed due to MPS I-related intellectual disability, informed 
permission from the patient’s legally acceptable representative (e.g., his/her parents or 
guardians) needs to be obtained instead of his/her consent. Even in this case, written 
informed consent should be obtained from the patient, wherever possible. 
3. 
A patient diagnosed with MPS I based on any one of the following criteria: 
 
Activity of the IDUA enzyme below 10% of the lower reference level in leucocytes or 
cultured skin fibroblasts, AND increased age-related urinary levels of GAGs (before 
ERT). 
 
Activity of the IDUA enzyme below 10% of the lower reference level in leucocytes or 
cultured skin fibroblasts, AND presence of one pathogenic mutation in each of the 
alleles of the IDUA gene. 
 
Increased age-related urinary levels of GAGs (before ERT), AND presence of one 
pathogenic mutation in each of the alleles of the IDUA gene. 
4. 
A patient diagnosed as having mild or no MPS I-related intellectual disability (able to report 
their own subjective symptoms) by the principal investigator or subinvestigator (Part 1 
only). 
5. 
A patient who has received laronidase continuously for at least 12 weeks and has received 
laronidase at a stable dosage for the 2 weeks immediately before the initial administration 
of JR-171 (except for a laronidase naïve patient or a patient who has previously been 
treated by HSCT). 
6. 
Female patient or male patient whose co-partner is of child-bearing potential agrees to 
use a medically accepted, highly effective method of contraception, such as spermatocidal 
gel plus condom, an intrauterine device or oral contraceptives until one month after the 
final administration. 
Rationale for the Inclusion Criteria:  
1. In this first in human study of JR-171, the minimum age of 18 years was defined in Part 1 
for safety considerations. In Part 2, pediatric patients will be also eligible to participate 
since treatment of MPS I often starts in childhood. 
2. Signed informed consent (i.e., written consent) is necessary for the study registration. 
3. This criterion was defined to enroll only patients with MPS I in the study. 


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4. Since JR-171 is administered to patients for the first time in Part 1, only patients who will 
be able to report their own subjective symptoms are eligible to participate to collect and 
evaluate safety information carefully. 
5. The result of the phase I/II study for laronidase showed that urinary GAG concentrations 
was 60 to 80% below the baseline after 8 to 12 weeks of intravenous administration of 
Aldurazyme.12) Based on these results, we set the duration of laronidase administration 
before the initial administration of JR-171 as at least 12 weeks for a patient who does not 
have a history of HSCT. 
6. This criterion was defined because the safety of reproductive and developmental toxicity 
and genotoxic have not been proven when JR-171 is administered to patients with MPS I. 
5.2 Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in the 
JR-171-101 study: 
 
1. A patient who has received gene therapy treatment. 
2. A patient who, in the opinion of the principal investigator or subinvestigator, cannot 
undergo lumbar puncture, including those who have a difficulty in taking position for lumbar 
puncture due to joint contracture and those who are likely to develop dyspnea during 
lumbar puncture. 
3. A patient who is pregnant or lactating. 
4. A patient who has developed serious drug allergy or hypersensitivity to any drugs, in the 
opinion of the principal investigator or subinvestigator, is inappropriate for participation in 
the study. 
5. A patient who has received another investigational product within the 12 months prior to 
enrollment in the study. 
6. A patient who, in the opinion of the principal investigator or subinvestigator, is ineligible to 
participate in the study in consideration of patient’s safety. 
Rationale for the Exclusion Criteria: 
1. CNS and systemic symptoms could have been alleviated in patients responsive to gene 
therapy treatment. This criterion was defined to explore the efficacy of JR-171 for CNS 
and systemic symptoms. 
2. This criterion was defined due to the necessity of collecting CSF by lumbar puncture to 
evaluate the efficacy of JR-171 for CNS symptoms. 
3. This criterion was defined because the safety of reproductive and developmental toxicity 
as well as genotoxicity have not been proven at the point that JR-171 is administered to 
patients with MPS I. 
4. This criterion was defined in consideration of the patient’s safety. 
5. This criterion was defined in consideration of the patient’s safety. 
6. This criterion was defined in consideration of the patient’s safety. 
5.3 Lifestyle Considerations 
It is not applicable for the JR-171-101 study. 
5.4 Screen Failures 
Screening failures are defined as subjects for whom consent to participate in the clinical study 
is given but who are not registered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure subjects, to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details 
and eligibility criteria. 


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5.5 Strategies for Recruitment and Retention 
 
Target: Male or female MPS I patients 
 
Target sample size:  
Part 1: 4 subjects (18 years or older) 
Part 2: Approximately 15 in total 
 
Description of sites/facilities enrolling subjects: 6 sites (Japan, Brazil and the US) are 
planned. 
 
For compensation or any incentives that subjects may receive, please refer to the informed 
consent documents. 


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6. Study Intervention 
Study intervention is defined as any investigational interventions intended to be administered 
to a study subject according to the study protocol. 
6.1 Study Interventions Administered 
Intervention Name 
 
Investigational product name (Code): JR-171 
 
Generic name:  
Applications under preparation for International 
Nonproprietary Names (INN) and application under 
preparation for Japanese Accepted Names for 
Pharmaceuticals (JAN) 
Dosing and 
administration 
Part 1 
Subjects aged 18 years or older shall receive an initial 
administration of JR-171 as an intravenous infusion at a dose of 
0.1 mg per kg of body weight. The dose level shall be then 
increased to 1.0 mg/kg for the second administration, to 2.0 mg/kg 
for the third administration, and to 4.0 mg/kg at the fourth 
administration. When the principal investigator or subinvestigator 
concludes that JR-171 dose increase will pose no problem based 
on the safety information collected from the administered dose to 
the first and second subject, JR-171 will be increased to the next 
dose upon approval of the sponsor. The start date of JR-171 
administration of the second subject should be at least 1 week 
after the start date of JR-171 administration of the first subject. 
Once the two subjects complete all the four times of 
administrations and the safety of JR-171 is confirmed, then the 
administration for the third and subsequent subjects may be 
started. If the first or second subject is discontinued from the 
study during the dose-escalation phase (until the safety evaluation 
of the fourth administration), the next third subject will stay in the 
hospital and will be supervised until 21 hours after the end of each 
administration to assess safety. JR-171 is to be administered at 
intervals of 1 week. The total volume of infusion should be 
administered over approximately 3 hours, but may be extended to 
a longer period at the discretion of the principal investigator or 
subinvestigator, considering safety concerns, including any IARs, 
etc. 
Part 2 
The first subject aged 6-17 years and the first subject aged 2-
5 years (0-5 years in Japan and Brazil) shall each receive an 
initial dose of JR-171 as an intravenous infusion at a dose of 
1.0 mg per kg of body weight. The dose level shall be then 
increased to 2.0 mg/kg for the second administration, and to 
4.0 mg/kg for the third administration. From the fourth to twelfth 
administrations, JR-171 shall be administered at 4.0 mg/kg. If the 
first subject aged 6-17 years or the first subject aged 2-5 years (0-
5 years in Japan and Brazil) is discontinued from the study during 
the dose-escalation phase (until the safety evaluation of the third 
administration), the next subject for the same age group shall 
receive JR-171 in a dose-escalation manner as described above 
(the schedule of assessments will also be the same as those for 
the first subject in each age group). 
The first subject aged 2-5 years (0-5 years in Japan and Brazil) 
can receive the initial administration at least 1 week after the first 
subject aged 6-17 years receives the initial administration. The 
second subject in each age group in Part 2 could be administered 
with JR-171 after the safety evaluation of the third administration 
of the first subject in each age group is completed. 
 








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6.5.2 Rescue Medicine 
Appropriate medication will be immediately provided to the subject when a principal 
investigator or subinvestigator deems this to be necessary. 
6.6 Dosing and Administration 
6.6.1 Confirmation of Safety 
Part 1: Doses in Part 1 are 0.1, 1.0, 2.0, 4.0 mg/kg and will be administered to a subject at 
intervals of 1 week. Considering that this is a first-in-human study of JR-171, the safety 
of JR-171 will be initially evaluated in four adult MPS I patients aged 18 years or older 
in Part 1. In Part 1, each subject will stay in the hospital and will be supervised until 
21 hours after the end of each administration to assess safety. When the principal 
investigator or subinvestigator concludes that JR-171 dose increase will pose no 
problem based on the safety information collected from the administered dose to the 
first and second subject, JR-171 will be increased to the next dose upon approval of 
the sponsor. 
The sponsor will establish an IDSMC. If any IARs with Common Terminology Criteria 
for Adverse Events (CTCAE) grade ≥ III occur up to 24 hours after the end of each 
administration in the first and second subjects, the sponsor will consult with the IDSMC 
to ask their opinion about the appropriateness of the JR-171 dose increase. The dose 
increase determination will be made according to the same procedures for each 
dosage. The start date of JR-171 administration of the second subject should be at 
least 1 week after the start date of JR-171 administration of the first subject. Once the 
two subjects complete all the four times of administrations and the safety of JR-171 is 
confirmed, then the administration for the third and subsequent subjects may be 
started. If the first or second subject is discontinued from the study during the dose-
escalation phase (until the safety evaluation of the fourth administration), the next third 
subject will stay in the hospital and will be supervised until 21 hours after the end of 
each administration to assess safety. 
After completing the clinical study for all subjects who participated in Part 1, the 
sponsor will convene the IDSMC and ask their opinion about the appropriateness of 
the initiation of Part 2 based on all safety data collected from the start of administration 
to Week 5. After taking into consideration the opinion of the IDSMC, when the sponsor 
concludes, that initiation of Part 2 will pose no problem, from ethical, scientific, and 
medical perspective, then Part 2 may be initiated.  
 
Part 2: The first subject aged 6-17 years and the first subject aged 2-5 years (0-5 years in 
Japan and Brazil) shall each receive an initial dose of JR-171 as an intravenous 
infusion at a dose of 1.0 mg per kg of body weight. The dose level shall be then 
increased to 2.0 mg/kg for the second administration, and to 4.0 mg/kg for the third 
administration. From the fourth to twelfth administrations, JR-171 shall be 
administered at 4.0 mg/kg. If the first subject aged 6-17 years or the first subject aged 
2-5 years (0-5 years in Japan and Brazil) is discontinued from the study during the 
dose-escalation phase (until the safety evaluation of the third administration), the next 
subject for the same age group shall receive JR-171 in a dose-escalation manner as 
described above (the schedule of assessments will also be the same as those for the 
first subject in each age group). 
The first subject aged 2-5 years (0-5 years in Japan and Brazil) can receive the initial 
administration at least 1 week after the first subject aged 6-17 years receives the initial 
administration. 
Subjects other than the above of aged 2 years or older (any age in Japan and Brazil) 
shall be allocated to receive either 2.0 or 4.0 mg/kg/week JR-171 group. The safety 
evaluation in Part 2 will be conducted in subjects aged 2-17 years (0-17 years in Japan 
and Brazil). The first subject aged 6-17 years will stay in the hospital and will be 
supervised until 21 hours after the end of each administration at Week 1, Week 2 and 
Week 3 to assess safety. When the principal investigator or subinvestigator, and the 


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sponsor confirm the safety in the first subject aged 6-17 years after the end of third 
administration, the second and subsequent subjects aged 6-17 years can be assigned 
to either 2.0 or 4.0 mg/kg/week JR-171 group. If any IARs with CTCAE grade ≥ III 
occur up to 24 hours after completion of the administration among the dose-escalating 
infusions in the first subject aged 6-17 years, the sponsor should convene the IDSMC 
and ask their opinion about the appropriateness of the JR-171 dose increase. 
The first subject aged 2-5 years (0-5 years in Japan and Brazil) can receive the initial 
administration at least 1 week after the first subject aged 6-17 years receives the initial 
administration. The first subject aged 2-5 years (0-5 years in Japan and Brazil) will 
stay in the hospital and will be supervised until 21 hours after the end of administration 
at Week 1, Week 2 and Week 3 to assess safety. When the principal investigator or 
subinvestigator, and the sponsor confirm the safety in the first subject aged 2-5 years 
(0-5 years in Japan and Brazil) after the end of third administration, the second and 
subsequent subjects aged 2-5 years (0-5 years in Japan and Brazil) can be assigned 
to either of 2.0 or 4.0 mg/kg/week JR-171 group. If any IARs with CTCAE grade ≥ III 
occur up to 24 hours after completion of the administration among the dose-escalating 
infusions in the first subject aged 2-5 years (0-5 years in Japan and Brazil), the 
sponsor should convene the IDSMC and ask their opinion about the appropriateness 
of the JR-171 dose increase. 
 
The sponsor’s Safety Evaluation Manual in a separate document will be followed for the 
confirmation of safety procedure. 
6.7 Instructions for Subjects 
The principal investigator or subinvestigator must fully inform the subjects about the purpose 
and significance regarding the clinical study, and must instruct subjects according to the 
following items.  
 
1. 
Female subject or male subject whose co-partner is of childbearing potential is required 
to refrain from conception during the study period and/or to use an adequate method of 
contraception. The subject or co-partner should contact the principal investigator or 
subinvestigator immediately if they suspect that they might be pregnant. 
2. 
The subject and co-partner must be willing to use a medically accepted, highly effective 
method of contraception, such as spermatocidal gel plus condom, an intrauterine device 
or oral contraceptives. 
3. 
The subject or co-partner must use an adequate method of contraception until one month 
after the final administration. 
6.8 Intervention after the End of the Study 
The sponsor is planning an extension study of the Study JR-171-101 of over 5 years’ duration 
to confirm the long-term safety and efficacy of JR-171. 
7. Discontinuation of Study Intervention and Subject Discontinuation 
/Withdrawal 
7.1 Discontinuation of Study Intervention 
7.1.1 Criteria for Termination or Suspension 
The sponsor will consider the discontinuation/cessation of the whole or part of the clinical study 
in any situation described in the information below. In this case, all principal investigators will 
be immediately informed by the sponsor. 
1. 
Occurrence of a serious adverse event (SAE) with CTCAE grade ≥ IV 
2. 
Occurrence of serious adverse drug reactions coded to same preferred term (PT) in 2 or 
more subjects 
3. 
A research report that suggests the tendency of occurrence of adverse drug reactions, 


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such as the number of reactions that occur, the frequency of occurrence, and occurrence 
conditions, have significantly changed 
4. 
A research report that shows the clinical study may cause serious diseases including 
cancer, disabilities, or death 
5. 
When the clinical study suggests that there is no efficacy of JR-171 in this population 
6. 
A research report that demonstrates that there is no efficacy or effectiveness for the 
disease that the clinical study aims to treat 
7. 
When either the sponsor, the study institution, or the principal investigator has committed 
a grave breach of ICH-GCP, the protocol, or the contract, leading to a situation where the 
proper continuation of the clinical study is considered problematic 
8. 
When the continuation of the clinical study is considered difficult due to changes of the 
structure or environment for conducting the clinical study (e.g., a transfer of the principal 
investigator) 
9. 
Other cases in which the continuation of the clinical study is considered inappropriate due 
to new information or a change in the situation identified during the clinical study 
 
When the clinical study is discontinued the following examinations/observations described 
below are to be performed as much as possible, if the subject agrees, after final administration 
of the investigational product. The details should be recorded in the eCRF listed below except 
for items 3, 4, 5, 7 and 9, it is not necessary to record measurements in the eCRF. The date of 
discontinuation and the reason for discontinuation will also be recorded in the eCRF. 
1. 
Vital signs (pulse rate, body temperature, blood pressure, respiratory rate and 
percutaneous oxygen saturation) 
2. 
Laboratory tests (hematologic test, blood biochemical test, determination of serum iron 
levels, and urinalysis) 
3. 
Antibody tests (anti-IDUA and anti-JR-171 antibodies) 
4. 
Drug concentration in CSF 
5. 
HS and DS concentrations in CSF 
6. 
CSF opening pressure 
7. 
Urinary HS and DS concentrations 
8. 
Urinary creatinine 
9. 
Serum HS and DS concentrations 
10. Liver and spleen volumes 
11. Cardiac function 
12. 6-minute walk test (Part 2 only) 
13. Other clinical findings related to neurocognitive and behavioral changes 
14. 12-lead electrocardiogram 
15. AEs 
16. Concomitant medications/therapies 
 
Note that the items below are very invasive tests and will be conducted only when the principal 
investigator or subinvestigator deems them possible by considering matters including the 
condition of a subject and the frequency of lumbar puncture. For items 1 and 2, it is not 
necessary to record measurements in the eCRF. For the reporting of the results, data should 
be reported by the laboratory. 
1. 
Drug concentration in CSF 
2. 
HS and DS concentrations in CSF 
3. 
CSF opening pressure 
 
After completion of examinations/observations at discontinuation, the principal investigator or 
subinvestigator should consider the necessity of (re)starting of laronidase in consideration of 
the subject’s status (e.g., progression to underlying disease or a significant worsening of their 
clinical parameters including serum and urinary HS and DS concentrations). 
7.2 Subject Discontinuation/Withdrawal from the Study 
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to the principal investigator. Subjects who are prematurely withdrawn from the study will not 
be replaced. 
A principal investigator or subinvestigator may discontinue or withdraw a subject from the study 
for the following reasons: 
1. 
When a subject or his/her legal representative wishes to discontinue the clinical study 
2. 
When the continuation of the study became impossible for reasons including a transfer to 
another hospital/change of address during the clinical study 
3. 
When a subject was found to be ineligible after the start of the clinical study such that 
continued participation would compromise safety of the subject or integrity of the study 
4. 
When the continuation of the clinical study becomes impossible for reasons including the 
occurrence of an AE* 
5. 
When a subject experiences anaphylactic shock 
6. 
Other cases in which the principal investigator or subinvestigator deems it necessary to 
discontinue the clinical study because compliance with the protocol has become difficult 
 
*When the occurrence of an SAE with CTCAE grade ≥ IV, the principal investigator or 
subinvestigator should consider the discontinuation/temporary cessation of the study. If the 
principal investigator or subinvestigator can rule out a causal relationship with JR-171 based 
on the additional information and CTCAE grade improved to III or less, administration could be 
resumed, but otherwise subjects must be discontinued. 
 
For examinations/observations at the time of the subject discontinuation from the study, see 
Section 7.1.1. 
7.3 Lost to Follow-up 
For subjects who do not visit the hospital, the principal investigator or subinvestigator will 
inquire into reasons and their subsequent progress and record the information in the eCRF. 
 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(see Section 10.1.18). 
8. Study Assessments and Procedures 
 
Study procedures and their timing are summarized in the Schedule of Activities. 
Protocol waivers are not allowed. 
 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue 
study intervention. 
 
Adherence to the study design requirements, including those specified in the 
Schedule of Activities, is essential and required for study conduct. 
 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The principal investigator will maintain a screening 
log to record details of all subjects screened and to confirm eligibility or record reasons 
for screening failure, as applicable. 
 
Procedures conducted as part of the subject’s routine clinical management (e.g., 
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in the Schedule of Activities. 
8.1 Demographic and Other Baseline Characteristics 
The following will be investigated and recorded in the eCRF: 
 
Date of written consent obtained from the subject and, if applicable, written permission 
from his/her legally acceptable representative 
 
Age at the time of informed consent 
 
Date of diagnosis of MPS I 
 
Presence or absence of use of laronidase, and start date (if applicable) 




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menopausal for more than 1 year prior to the time of informed consent or surgically sterile). In 
the eCRF, whether or not a measurement has been performed as well as the sample collection 
date and results of measurement, if performed, should be recorded. 
8.2.2 Administration Information 
For each dose of JR-171, the status of administration should be recorded in the eCRF: whether 
or not JR-171 has been administered, date of administration, start time of administration, 
ending time of administration, start time of interruption if applicable, time of administration 
resumed if applicable, applied dose, whether or not administration 
has been 
discontinued/interrupted, whether or not the infusion rate has been reduced. 
8.2.3 Vital Signs 
Pulse rate, body temperature, blood pressure (systolic and diastolic blood pressure) 
respiratory rate, and percutaneous oxygen saturation will be measured before and after 
administration of JR-171 or laronidase. Body weight will be measured only once at each 
measurement point. In principle, blood pressure will be measured in the same posture 
throughout the JR-171-101 study. In the eCRF, whether or not a measurement has been 
performed as well as the date and time and results of measurement, if performed, should be 
recorded. When JR-171 is administered, vital signs will be also measured at the end of 
administration, and the time of measurement as well as the results of pulse rate, body 
temperature and blood pressure should be recorded in the eCRF. 
During infusion of JR-171, the principal investigator or subinvestigator ensure vital signs are 
taken in a timely manner. Especially, vital signs are recommended to be obtained when infusion 
rate is increased, and to be obtained at least every 30 minutes while the infusion rate does not 
change. The measurements during infusion of JR-171 do not have to be recorded in the eCRF, 
but if AEs occur, the detail of the AEs should be recorded in the eCRF. 
8.2.4 Laboratory Tests 
Blood and urine will be collected before administration of JR-171 or laronidase to measure the 
parameters listed below. In the eCRF, whether or not a measurement has been performed as 
well as the sample collection date and results of measurement, if performed, should be 
recorded. 
8.2.4.1 
Hematology 
White blood cell count, differential leukocyte count, red blood cell count, hemoglobin, 
hematocrit, platelet count, mean corpuscular volume (MCV), mean corpuscular hemoglobin 
(MCH), mean corpuscular hemoglobin concentration (MCHC), reticulocyte ratio, prothrombin 
time, and activated partial thromboplastin time (APTT). 
8.2.4.2 
Biochemistry 
Total protein, albumin, albumin/globulin ratio, haptoglobin, CK, total bilirubin, aspartate 
aminotransferase (AST [GOT]), alanine transaminase (ALT [GPT]), γ-GT (γ-GTP), alkaline 
phosphatase (ALP), total cholesterol, triglycerides, creatinine (enzymatic method), Na, K, Cl, 
Ca, and P. 
8.2.4.3 
Serum Iron Tests 
Serum iron, unsaturated iron binding capacity (UIBC), total iron binding capacity (TIBC), ferritin, 
and transferrin saturation (TSAT). 
8.2.4.4 
Urinalysis 
Determination of glucose, protein, and occult blood. 
8.2.5 Antibodies 
Antibodies will be measured centrally by the laboratory under contract with the sponsor. If the 
test results of anti-JR-171 antibodies are positive, then neutralizing activity against M6PR 
binding and hTfR binding of JR-171 will be measured. 


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Venous blood will be collected from each subject before administration of JR-171 or laronidase 
to measure anti-IDUA and anti-JR-171 antibodies. In the eCRF, whether or not a measurement 
has been performed and, if applicable, the sample collection date should be recorded. Data 
should be reported by the laboratory. 
8.2.6 12-lead Electrocardiogram 
Electrocardiography will be performed before administration of JR-171 or laronidase. In the 
eCRF, whether or not a measurement has been performed as well as the date of measurement 
and the presence or absence of abnormal finding, including its details and whether or not it will 
be considered an AE, should be recorded. 
8.2.7 Concomitant Medication/Therapy 
All concomitant medications/therapies taken by the subjects will be collected from the Week 1 
dose to the last visit (Week 5 in Part 1/Week 13 in Part 2, or discontinuation). In the eCRF, 
presence or absence of usage of concomitant medication/therapy, and if applicable, its details 
(see Section 6.5) should be recorded. 
Rationale for the Safety Assessments 
For the safety evaluation, systemic endpoints, that is, AEs (see Section 8.3), laboratory tests, 
vital signs, and 12-lead electrocardiogram were selected. Serum iron tests were included 
based on the involvement of TfR, which is responsible for iron transport, in the mechanism of 
cellular uptake of JR-171. 
8.3 Adverse Events and Serious Adverse Events 
In the event of AEs, the safety of subjects is ensured by providing appropriate medical care to 
subjects. 
AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject’s legally authorized representative). 
The principal investigator and any qualified designees are responsible for detecting, 
documenting, and recording events that meet the definition of an AE or SAE (Appendix 2 (see 
Section 10.2.1 and 10.2.3)) and remain responsible for following up on AEs that are serious, 
considered related to the study intervention or study procedures, or that caused the subject to 
discontinue the study (see Section 7). 
If an AE occurs, the name, severity, seriousness, day of onset, presence or absence of 
treatment for study treatment, outcome of the AE (including date of assessment), relationship 
between the AE and investigational product, comments as appropriate, and whether or not 
with IAR should be recorded in the eCRF. 
8.3.1 Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the time of informed consent until the last visit (Week 5 
in Part 1/Week 13 in Part 2, or discontinuation) at the time points specified in the Schedule of 
Activities (see Section 1.3). Events occurring within 28 days after the time of observation at 
Week 5 in Part 1/Week 13 in Part 2 or discontinuation that are considered related to the 
investigational product will be collected as adverse drug reactions in the JR-171-101 study, 
except for events that are occurred during the extension study of the JR-171-101 study (JR-
171-102). In the eCRF, presence or absence of AEs and, if applicable, its details (Appendix 2 
(see Section 10.2.4)) should be recorded. 
Data of MPS I-related medical occurrences that begin before obtaining informed consent will 
be recorded in the Medical History/Current Medical Conditions section of the case report form 
not in the AE section. 
All SAEs will be recorded and reported to the sponsor immediately and under no circumstance 
should exceed 24 hours, as indicated in Appendix 2 (see Section 10.2). The principal 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
Principal investigators are not obligated to actively seek AEs or SAEs after conclusion of the 
study participation. However, if the principal investigator learns of any SAE, including a death, 


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at any time after a subject has been discharged from the study, and he/she considers the event 
to be reasonably related to the study intervention or study participation, the principal 
investigator must promptly notify the sponsor. 
8.3.2 Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2 (see 
Section 10.2.4). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences. 
8.3.3 Follow-up of AEs and SAEs 
After the initial AE/SAE report, the principal investigator is required to proactively follow each 
subject at subsequent visits/contacts. All AEs, and AEs of special interest (see Section 8.3.6), 
will be followed until resolution, stabilization, or the event is otherwise explained. Further 
information on follow-up procedures is provided in Appendix 2 (see Section 10.2.4). 
8.3.4 Regulatory Reporting Requirements for SAEs 
 
Prompt notification by the principal investigator to the sponsor of an SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of subjects and 
the safety of a study intervention under clinical investigation are met. 
 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/Independent Ethics 
Committees (IEC), and principal investigators. 
 
For all studies except those utilizing medical devices principal investigator safety 
reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to principal investigators as necessary. 
 
A principal investigator who receives a principal investigator safety report describing 
an SAE or other specific safety information (e.g., summary or listing of SAEs) from 
the sponsor will review and then file it along with the Investigator’s Brochure and will 
notify the IRB/IEC, if appropriate according to local requirements. 
8.3.5 Pregnancy (Female Subjects and Subject’s Female Co-partners of 
Childbearing Potential Only) 
 
For female subjects, details of all pregnancies in childbearing potential (female 
subjects of non-childbearing potential are confirmed by being either post-menopausal 
for more than 1 year prior to the time of informed consent or surgically sterile) will be 
collected after the start of study intervention and until a miscarriage, an abortion or 1 
month after the delivery. The follow-up for infants will be about one month after the 
birth. 
 
If a pregnancy is confirmed in a female subject or subject’s female co-partner of 
childbearing potential, the principal investigator should inform the sponsor within 
24 hours of learning of the pregnancy using the designated form. 
 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
 
For female subjects, whether or not a measurement of pregnancy testing has been 
performed as well as the sample collection date and results of measurement, if 
performed, should be recorded in the eCRF. 
8.3.6 AEs of Special Interest 
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described below occur, they will be defined as significant AEs and evaluated.  
 
 
Anaphylaxis, anaphylactic shock 
Cutaneous symptoms including urticaria, digestive symptoms including abdominal 
pain and vomiting, respiratory symptoms including a feeling of dyspnea, and shock 
symptoms including sudden pallor and clouding of consciousness are called 
anaphylaxis. When the principal investigator or subinvestigator diagnoses the 
anaphylaxis, refer to criteria described below.16) A condition in which a sharp drop in 
blood pressure occurs and symptoms like disturbance of consciousness are seen is 
specifically called anaphylactic shock. 
 
When any 1 of the 3 criteria are fulfilled, regard the event as an anaphylaxis. 
1. 
Acute onset of an illness (minutes to hours) with involvement of Skin/mucosal 
tissue (e.g., hives, generalized itch/flush, swollen lips/tongue/uvula) 
AND 
Compromised airway (e.g., dyspnea, wheeze/bronchospasm, stridor, reduced 
peak expiratory flow) 
OR 
Reduced blood pressure or associated symptoms (e.g., hypotonia, syncope) 
2. 
Two or more of the following after exposure to known allergen for that patient 
(minutes to hours) 
History of severe allergic reaction 
Skin/mucosal tissue symptoms (e.g., hives, generalized itch/flush, swollen 
lips/tongue/uvula) 
Compromise airways (e.g., dyspnea, wheeze/bronchospasm, stridor, reduced 
peak expiratory flow) 
Reduced blood pressure or associated symptoms (e.g., hypotonia, syncope) 
In suspected food allergy: gastrointestinal symptoms (e.g., crampy abdominal 
pain, vomiting) 
3. 
Hypotension after exposure to known allergen for that patient (minutes to hours) 
Infants and children: low systolic blood pressure (age-specific) or >30% drop in 
systolic blood pressure* 
Adults: systolic blood pressure, <100 mm Hg or >30% drop from the last 
measurement 
Caution: These criteria describe so-called classic cases of anaphylaxis. Other 
presentations may also indicate anaphylaxis (e.g., early presentation, 
generalized flushing; isolated presentation, sudden hypotension only in a 
patient without evidence of allergen exposure; classic presentation but with 
a non-allergenic cause, such as exercise). Conversely, clinicians need to 
remember the potential for false-positive symptoms or signs (e.g., difficulty 
breathing from panic, faintness from vasovagal episode). 
*Low systolic blood pressure for children is defined as <70 mm Hg from 1 month to 
1 year; less than (70 mm Hg + (2 × age)) from 1 to 10 years; and <90 mm Hg from 
age 11 to 17 years. 
 
 
IAR17) 
Reactions harmful to the living body that are caused by administration of the infusion, 
occurring during or within 24 hours after completion of the infusion (e.g., chill, fever, a 
feeling of body temperature fluctuation, nausea, high blood pressure). 
 
Also, in addition to reported SAEs, all the events that have significantly abnormal laboratory 
values or require such action as the discontinuation, temporary cessation, or addition of 
important combination therapy with respect to the investigational product should be evaluated 
as significant AEs. 


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8.4 Pharmacokinetics 
8.4.1 Plasma Drug Concentration 
Plasma drug concentration is designated as a centrally measured parameter and will be 
measured by the laboratory under contract with the sponsor. 
Venous blood will be collected from each subject to measure plasma drug concentration. In 
Part 1, each subject will stay in the hospital and will be supervised until 21 hours after the end 
of each administration to collect the venous blood sample. In Part 2, each subject randomized 
to one of the 2 treatment groups (2.0 or 4.0 mg/kg/week JR-171 group) will stay at hospital 
and will be supervised until 21 hours after the end of each administration at Week 1, Week 4 
and Week 12 to collect the venous blood sample. 
In the eCRF, whether or not a measurement has been performed and, if applicable, the sample 
collection date and time should be recorded. For the reporting of results, data should be 
reported by the laboratory. 
Rationale for the Pharmacokinetics Assessments 
The PK endpoints were selected to determine the PKs of and exposure to JR-171 after 
continuous intravenous infusion in patients with MPS I by calculating parameters from plasma 
drug concentration. In a nonclinical PK study in cynomolgus monkeys, measured plasma 
JR-171 concentrations showed that the plasma exposure to JR-171 up to 24 hours after the 
start of administration (AUC0-24) accounted for almost 100% of the plasma exposure from the 
start of administration to infinity (AUC0-∞). It was therefore decided to measure drug 
concentration up to 21 hours after the end of administration (the last blood sampling time point) 
in order to calculate PK parameters. 
8.5 Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the Schedule of Activities. 
8.5.1 Drug concentration in CSF 
Drug concentration in CSF is designated as a centrally measured parameter and measured by 
the laboratory under contract with the sponsor. 
CSF will be collected from each subject once before administration of JR-171 at the initial 
administration and within 5 hours of the end of administration of JR-171 at Week 4 in Part 1 or 
Week 12 in Part 2 to measure drug concentration in the CSF. In the case of discontinuation, 
the measurement will be performed if deemed feasible by the principal investigator or 
subinvestigator. In the eCRF, whether or not a measurement has been performed and, if 
applicable, the sample collection date and time should be recorded. For the reporting of results, 
data should be reported by the laboratory. 
Rationale for this Exploratory Assessment 
This assessment was selected to confirm the penetration of JR-171 into the CNS. 
8.5.2 HS and DS concentrations in CSF 
HS and DS concentrations in CSF is designated as a centrally measured parameter and 
measured by the laboratory under contract with the sponsor. 
Care is to be taken not to contaminate the sample with blood, heparin or heparin-like 
compounds when collecting samples. In the eCRF, whether or not a measurement has been 
performed as well as the sample collection date, if performed, should be recorded. For the 
reporting of results, the measurement results should be reported by the laboratory. 
Subjects will undergo lumbar puncture under sedation or general anesthesia to obtain CSF. 
Fluoroscopy with anesthesia may be needed in subjects with difficult access to CSF. 
To minimize the risks associated with lumbar puncture procedures in the subjects with MPS I, 
the principal investigator or subinvestigator should consider the following: 
- Intravenous or oral administration of sedatives prior to the procedure should be considered 
when subject’s discomfort, anxiety or agitations are such that they affect the safe and smooth 


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conduct of the procedure. 
- Subjects during the sedation should be closely monitored with respect to potential 
complications, in particular respiratory inhibition, so that appropriate measures can be taken 
whenever these complications occur. 
Rationale for this Exploratory Assessment 
Given accumulation of HS and DS in patients with MPS I, this assessment was selected to 
explore the efficacy of JR-171 on CNS symptoms. 
8.5.3 CSF Opening Pressure 
Before the CSF sample collection, the CSF opening pressure will be measured once a needle 
is in position. End-tidal carbon dioxide pressure will be monitored and maintained during the 
measurement from 35 to 40 mm Hg to ensure the opening pressure accuracy. In the eCRF, 
whether or not a measurement has been performed, the date of measurement and the result 
should be recorded. 
Rationale for this Exploratory Assessment 
This assessment was selected to explore the efficacy of JR-171 on CNS abnormalities. 
8.5.4 Urinary HS and DS Concentrations 
Urinary HS and DS concentrations are designated as a centrally measured parameter and 
measured by the laboratory under contract with the sponsor. Urinary creatinine concentration 
will be measured to enable urinary HS and DS concentrations to be calculated and will be 
measured by an in-house laboratory. 
Urine will be collected from each subject before administration of JR-171 or laronidase to 
measure urinary HS and DS concentrations. Care is to be taken not to contaminate the sample 
with heparin or heparin-like compounds when collecting samples. In the eCRF, whether or not 
a measurement has been performed and the sample collection date and urinary creatinine 
concentration should be recorded. For urinary HS and DS concentrations, the measurement 
results should be reported by the laboratory. 
Rationale for this Exploratory Assessment 
Given increased urinary excretion of HS and DS in patients with MPS I, this assessment was 
selected to explore the efficacy of JR-171 on systemic symptoms. 
8.5.5 Serum HS and DS Concentrations 
Serum HS and DS concentrations are designated as centrally measured parameters and will 
be measured by the laboratory under contract with the sponsor. 
Venous blood will be collected from each subject before administration of JR-171 or laronidase 
to measure serum HS and DS concentrations. Care is to be taken not to contaminate the 
sample with heparin or heparin-like compounds when collecting samples. In the eCRF, whether 
or not a measurement has been performed and, if applicable, the sample collection date should 
be recorded. The measurement results should be reported by the laboratory. 
Rationale for this Exploratory Assessment 
Given systemic accumulation of HS and DS in patients with MPS I, this assessment was 
selected to explore the efficacy of JR-171 on systemic symptoms. 
8.5.6 Liver and Spleen Volumes  
Computed tomography (CT) or magnetic resonance imaging (MRI) will be performed before 
administration of JR-171 or laronidase to measure liver and spleen volumes. The same 
modality (CT or MRI) should be used throughout the study for the same subject. When 
selecting CT or MRI, the principal investigator or subinvestigator should pay attention to the 
subject’s condition, treatment status or radiation exposure doses, including conduct of other 
imaging tests in order to protect the subject’s safety. In the eCRF, whether or not a 
measurement has been performed as well as the date and results of measurement should be 




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HVLT-R, refer to the separate sponsor manual. 
Rationale for this Exploratory Assessment 
The BVMT-R will be used to measure the visuospatial memory, and the HVLT-R will be used 
to assess the verbal learning and memory. 
8.5.11 T.O.V.A. 
The T.O.V.A., version 9 (T.O.V.A.) (visual test) will be measured in Part 2, and will be performed 
only in subjects at least 4 years of age and able to comply with the testing procedures. Testing 
should be performed after adequate sleep to avoid interference resulting from patient fatigue, 
and conditions should be the same at each testing. 
In the eCRF, whether or not an assessment has been performed as well as the date and results 
should be recorded. 
For the detailed procedures of T.O.V.A., refer to the separate sponsor manual. 
Rationale for this Exploratory Assessment 
This assessment was selected to evaluate the attention deficits. 
8.5.12 PedsQL-FIM 
The PedsQL-FIM, standard version will be tested in Part 2, and will be performed only for 
subjects accompanied by their family, caregiver or equivalent thereof. The PedsQL-FIM will be 
performed to assess specifically caregiver’s and family’s burden. In the eCRF, whether or not 
a test has been performed as well as the date and results of the test should be recorded. 
 
Rationale for this Exploratory Assessment 
This assessment was selected to explore how the QoL has changed, because it is known that 
burden of caregiver and family of patients with MPS I is high and gathering data of QoL is 
important. 
8.5.13 Status of Cross-Reactive Immunologic Material (CRIM) 
A blood specimen and fibroblasts will be collected once in the JR-171-101 study from subjects 
who agreed to the sample collection to determine the CRIM status, and the samples will be 
obtained before the JR-171 administration during the visit. The sample collection date should 
be recorded in the eCRF. The assay for the CRIM status will be performed by the laboratory 
under contract with the sponsor. 
Rationale for this Exploratory Assessment 
This assessment was selected to evaluate the impact of the CRIM status on the PKs, 
pharmacodynamics, safety and efficacy endpoints. 
9. Statistical Considerations 
9.1 Statistical Hypotheses 
For the exploratory endpoint analyses, a paired sample t-test will be conducted on HS and DS 
concentrations in CSF. The quantity of interest is the mean change from baseline. The null 
hypothesis for comparison (H0) with threshold value of delta (Δ) and the alternative hypothesis 
of effect of JR-171 (H1) are defined as follow, where μ denotes mean change from baseline in 
HS or DS concentrations in CSF and Δ = 0. 
H0: μ = Δ 
H1: μ > Δ or μ < Δ. 
 
No hypothesis testing is planned for the other exploratory endpoints, safety and PK 
assessments. 


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9.2 Sample Size Determination 
Part 1: 4 subjects (18 years or older) 
Part 2: Approximately 15 subjects in total 
Rationale for the Target Sample Size 
In this first-in-human study of JR-171, adult patients (18 years old or older) with mild MPS I 
who can report their own subjective symptoms are deemed appropriate to confirm the safety 
of JR-171 in Part 1. MPS I is an extremely rare disease, which is estimated to have the birth 
prevalence of approximately 0.11 to 3.62 per 100000 live births.2) In addition, 60.9% of the 
patients are reported to have severe disease manifestations with intellectual disability,3) 
indicating that there may be very few adult patients with mild MPS I who have little or no 
intellectual disability. Based on these considerations and the target sample size of 4 subjects 
was selected for Part 1 in view of feasibility. 
 
In Part 2, pediatric patients will be able to participate since treatment of MPS I often starts in 
childhood. It is assumed that only a small number of patients could undergo lumbar puncture. 
Furthermore, it is reported that 54.9% of severe MPS I patients have a history of HSCT.8) 
Therefore, it is assumed only a very limited number of patients would be eligible to participate 
in the study. Based on these considerations and in view of feasibility, the target sample size of 
approximately 15 subjects was selected to evaluate the safety and efficacy of JR-171. 
9.3 Populations for Analyses 
The following populations are defined: 
 
Population 
Description 
Safety set (SS) 
All subjects who sign the ICF. 
Pharmacokinetic set (PKS) 
Subjects assigned to study intervention and have 
data for plasma drug concentration after 
administration of JR-171. 
Full analysis set (FAS) 
Subjects assigned to study intervention and have 
data for at least one exploratory endpoint after 
administration of JR-171 
9.4 Statistical Analyses 
The statistical analysis plan will be finalized prior to First Patient First Visit, and it will include a 
more technical and detailed description of the statistical analyses as well as the handling of 
subjects and individual data determined in consultation with the medical and statistical experts 
as appropriate. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints. 
9.4.1 General Considerations 
9.4.1.1 
Significance Level and Confidence Interval 
Unless otherwise specified, all statistical tests will be 2-sided hypothesis tests performed at 
the 5% level of significance and all confidence intervals will be 2-sided 95% confidence 
intervals. All statistical tests and confidence intervals will be parametric assuming normally 
distributed sample means. 
9.4.1.2 
Definitions of Baseline 
Unless otherwise specified, the baseline value will be defined as the measurement prior to and 
closest to the date of the first dose of JR-171.  
9.4.1.3 
Definitions of Study Period 
Data for regular scheduled visits will be summarized as below. 
 




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or shift tables will be created for each subject. 
For vital signs, summary statistics of measured values at each time point as well as changes 
from baseline will be calculated for Part 1 and each group in Part 2, and time courses will be 
created. 
For 12-lead electrocardiogram, the presence or absence of abnormality will be tabulated. 
For antibody tests, shift tables will be created with respect to the presence or absence of 
antibody development at each time point. 
9.4.4 Analysis of the Pharmacokinetic endpoints 
This section outlines the planned analyses of the PK endpoints of the JR-171-101 study.  
PK analyses will be performed on the PKS. 
 
Part 1 
For the plasma drug concentration at each time point, summary statistics, geometric mean, 
and geometric coefficient of variation (CV) will be calculated for each dose. In addition, time 
courses of mean and standard deviation (SD) will be created for each dose, and a listing and 
time courses will be created for each subject. 
The following PK parameters will be calculated for each subject using a non-compartment 
model analysis, and summary statistics, geometric mean, and geometric CV will be calculated 
for each dose. In estimating the parameters, the plasma drug concentration calculated by the 
plasma drug concentration at baseline, and the actual blood collection time will be used. 
 
Part 2 
For the plasma drug concentration at each time point, summary statistics, geometric mean, 
and geometric CV will be calculated for each group. In addition, time courses of mean and SD 
will be created for each group, and a listing and time courses will be created for each subject. 
The following PK parameters will be calculated for each subject using a non-compartment 
model analysis, and summary statistics, geometric mean, and geometric CV will be calculated 
for each group. In estimating the parameters, the plasma drug concentration will be calculated 
using the plasma drug concentration at baseline, and the actual blood collection time will be 
used. 
 
[PK Parameters] 
 
AUC0-t 
 
Cmax 
 
AUC0-∞ 
 
tmax 
 
kel 
 
t1/2 
 
MRT0-t 
9.4.5 Analyses of the Exploratory Endpoints 
The following section outlines the planned analyses of the exploratory endpoints of the 
JR-171-101 study. Analyses will be performed on the FAS, unless otherwise specified. 
9.4.5.1 
Drug Concentration in CSF 
For drug concentration in CSF, summary statistics of measured values will be calculated by 
each period and dose group (2.0 or 4.0 mg/kg). 
9.4.5.2 
HS and DS Concentrations in CSF 
For HS and DS concentrations in CSF, summary statistics of measured values at each time 
point will be calculated, and time courses will be created for Part 1 and each group in Part 2. 
In addition, difference from baseline, ratio to baseline and relative change from baseline at 
Week 4 in Part 1 or Week 12 in Part 2 and corresponding 2-sided 95% confidence interval will 
be calculated. 
 




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. 
9.5 Interim Analyses 
No interim analyses will be performed in the JR-171-101 study. 
9.6 Independent Data Safety Monitoring Committee (IDSMC) 
For the purpose of consistent and objective safety assessment, the sponsor will establish an 
IDSMC completely independent from the sponsor. 
The sponsor will immediately set up the IDSMC. The IDSMC will evaluate safety and report 
the results to the sponsor. 
Detailed procedures for the IDSMC are provided in the Safety Evaluation Manual which is 
created by the sponsor as a separate document. 


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10. Supporting Documentation and Operational Considerations
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1 Regulatory and Ethical Considerations
The study will be conducted in accordance with the guidelines in ICH-GCP, the 18th World 
Medical Association’s Declaration of Helsinki, applicable regulatory/regional requirements and 
this protocol.
The appropriate IRB/IEC must approve the protocol, patient information sheet and informed 
consent document, and where appropriate, agree to monitor the conduct of the study and 
agree to review periodically. The principal investigator will provide the sponsor with 
documentation that the IRB/IEC has approved the study before the study may begin.
In addition, the principal investigator must provide the sponsor with the IRB/IEC approval of 
any revisions to the patient information sheet and informed consent document or amendments 
to the protocol.
Details of the IRB/IEC’s composition including names of their members, their qualifications and 
what function they perform in the committee (e.g., chairman, specialist, lay-member) will be 
made available to conform to regulations governing the conduct of clinical studies within each 
country. The constitution of the IRB/IEC must be supplied to the sponsor.
10.1.2 Protocol Compliance, Deviations or Changes, and Amendments
Compliance with Protocol
The principal investigator shall fully discuss the ethical and scientific validity of the conduct of 
the clinical trial with the sponsor based on the data and information provided, such as the 
protocol and the latest Investigator’s Brochure, and agree on the content and compliance with 
the protocol. The principal investigator and the sponsor will sign to the Agreement Form and 
date it in order to confirm the above agreement.
Protocol Deviations or Changes
The principal investigator or subinvestigator must not make a deviation from or change to the 
protocol without obtaining prior written agreement from the sponsor and a review-based written 
approval from the IRB/IEC in advance (except in medically unavoidable circumstances such 
as to avoid the immediate danger to a subject, or cases in which changes are related only to 
the administrative matters of the clinical study).
In medically unavoidable circumstances, such as avoiding an immediate danger to a subject, 
the principal investigator must submit, as promptly as possible, the details of and reasons for 
deviations or changes to the sponsor, as well as to the head of medical institution (in countries 
where applicable) and to the IRB/IEC of the study institution to obtain approval for such 
deviations or changes. In addition, the principal investigator will submit, without delay, a report 
of any change of the clinical study that can have a significant impact on the conduct of the 
clinical study or increase a danger to a subject, to the sponsor as well as to the head of medical 
institution (in countries where applicable) and to the IRB/IEC of the study institution.
Note that the principal investigator or subinvestigator will record in source documents all 
deviations from the protocol.
Of all the deviations from the protocol, the sponsor will define the five items below as critical 
deviations and will collect and evaluate information regarding them.
1.
A deviation in which a subject had been enrolled in the clinical study without meeting the
entry criteria
2.
A deviation in which a subject fell under the discontinuation criteria during the clinical study
period but had not been withdrawn
3.
A deviation in which a subject violated the assigned dosage (administration requirements)
4.
A deviation in which a subject received a concomitant medication/therapy that is prohibited
5.
Other critical deviations


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Protocol Amendment 
If the sponsor finds it necessary to amend the protocol, the sponsor shall provide the principal 
investigator with the necessary documents and information, including the protocol and the 
latest Investigator’s Brochure. 
Based on the revised protocol and the latest Investigator’s Brochure, the principal investigator 
should fully discuss with the sponsor the information and agree on the content and compliance 
with the protocol. The principal investigator and the sponsor will sign to the Agreement Form 
and date it in order to confirm the above agreement. 
Submit the revised protocol to the head of the medical institution (in countries where 
applicable). 
In addition, when changes are made in administrative matters, etc. that are not related to the 
nature of the clinical trial plan, the revised edition should be reported to the principal 
investigator and the head of the medical institution (in countries where applicable) at any time. 
10.1.3 Financial Payment and Insurance 
With respect to any liability directly or indirectly caused by the investigational products in 
connection with this clinical trial, the sponsor assumes liability by law on behalf of the principal 
investigator(s) and his/her assistants, only in cases that meet all of the following; the principal 
investigator(s) and his/her assistants have followed the instructions of the sponsor in 
accordance with this protocol and any amendments; the investigational products administered 
to the subject in this clinical trial have been supplied by the sponsor; the principal investigator 
and his/her assistants have performed this clinical study in accordance with current medical 
and scientific practice. 
A letter of indemnity will be signed between the sponsor and the principal investigator(s) 
(between the sponsor and the head of the medical institution in countries where applicable), 
and the sponsor will insure according to local requirements. 
Compensation for health damages 
When the causal relationship between the JR-171 administration and the health damage 
cannot be reasonably ruled out, the sponsor compensates for the health damage unless it is 
caused for any reason attributable to the medical institution or subject. 
Medical cost 
In the event of study-related health damage, the patient’s out-of-pocket expenses excluding 
benefits from health insurance, etc. shall be reimbursed by the sponsor. 
Compensation claim 
In the event that a request for compensation from a subject has been filed or a matter subject 
to compensation is suspected, the participating medical organization should immediately 
contact the sponsor. The sponsor will respond promptly in accordance with the SOP for health 
damage compensation for test subjects in-house. 
Insurance 
The sponsor will purchase insurance to ensure the performance of these procedures. 
10.1.4 Financial Disclosure 
Principal investigators and subinvestigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Principal investigators are responsible for providing information on financial interests during 
the course of the study and for one year after completion of the study. 
10.1.5 Audit 
Authorized representatives of the sponsor and/or a national regulatory authority may visit the 
center to perform audits or inspections, including source data verification. The purpose of a 
the sponsor audit or inspection is to systematically and independently examine all study related 


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activities and documents to determine whether these activities were conducted and data were 
recorded, analyzed, and accurately reported according to the protocol, ICH-GCP guidelines 
and any applicable regulatory requirements. The principal investigators should contact the 
sponsor immediately if contacted by a regulatory agency about an inspection at their center. 
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
inspection by local and regulatory authorities. 
10.1.6 Training of Staff 
The principal investigator at each participating study site will maintain a record, “authorized 
representative signature sheet”, of all individuals involved in the study (medical, nursing and 
other staff). In collaboration with the sponsor, the principal investigator will ensure that 
appropriate training relevant to the study and/or study procedures is given to all of these staff, 
and that any new information of relevance to the performance of the JR-171-101 study is 
forwarded to the staff involved. 
10.1.7 Informed Consent Process 
The principal investigator is to review and submit to the IRB/IEC for approval of the ICF for the 
patients and written permission form for patient’s legally acceptable representative as well as 
written information for them modified from the master sponsor ICF to comply with each 
country’s applicable regulations. 
 
The ICF and written information should include explanations of the elements as described in 
points 1 to 21 below:  
1. 
That the study involves research; 
2. 
The purpose of the study; 
3. 
Principal investigator’s name, job title and contact information; 
4. 
Methods of study (including the experimental aspects of the study, subject inclusion criteria, 
and the probability for random assignment (if applicable) to each treatment); 
5. 
The reasonably expected clinical benefits and risks or inconveniences (When there is no 
intended clinical benefit to the subject, the subject should be made aware of this);  
6. 
If a patient is to be a subject, whether or not there is any alternative procedure(s) or 
course(s) of treatment that may be available to the patient, and their important potential 
benefits and risks; 
7. 
The expected duration of the subject’s participation in the study; 
8. 
That the subject’s participation in the study is voluntary and that the patient or the subject’s 
legally acceptable representative may refuse to participate or withdraw from the study, at 
any point of time, without penalty or loss of benefits to which the subject is otherwise 
entitled if not participating in the study; 
9. 
That the monitor(s), the auditor(s), the IRBs, and the regulatory authority(ies) will be able 
to access the subject’s original medical records, without violating the confidentiality of the 
subject, and that, by signing a written ICF, the patient or the subject’s legally acceptable 
representative is authorizing such access; 
10. That the subject’s identity will remain confidential even if the results of the study are 
published; 
11. The point of contact at the study institution to make an inquiry to, or make a contact with, 
for further information regarding the study and the rights of study subjects, and in the event 
of study-related injury; 
12. The compensation and treatment available to the subject in the event of study-related 
injury; 
13. The number of subjects to be involved in the study; 
14. That the subject or the subject’s legally acceptable representative will be informed as soon 
as possible if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study; 
15. The circumstances or reasons under which the subject’s participation in the study may be 
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16. The anticipated expenses, if any, to the subject for participating in the study; 
17. Details of reimbursement to be made to the subject for participating in the study 
(agreements on how the amount is determined, etc.); 
18. The rules the subject should comply with; 
19. The type of the IRB that examines or discusses whether or not the study is appropriate, 
matters that are to be examined or discussed by individual IRBs, and other matters 
associated with IRBs that directly concern the study (including the name of the organizer 
of an individual institutional review committee and its location, and information concerning 
such an organizer that is available to view); 
20. That the written SOP for the IRB is made available to view by the public on the website or 
at the office of the study institution, etc. and that the subject should come forward if he/she 
wishes to view these documents; 
21. That the data used in applying for an approval may be used by the regulatory agency in 
each country for research purposes. 
 
The principal investigator or subinvestigator will provide each patient with an explanation on 
any and all activities associated with the study before it is performed and written consent from 
each patient will be obtained. In the case of a patient who is under the age of 18 (20 years in 
Japan) at the time of informed consent process, or if it is not possible to obtain consent from 
the patient him/herself due to his/her intellectual disabilities associated with MPS I, the 
principal investigator or subinvestigator will perform the following procedures for the patient’s 
legally acceptable representative and written consent should be obtained from the patient 
him/herself too, wherever possible. 
The principal investigator or subinvestigator at each center will ensure that the patient is given 
full and adequate oral and written information about the nature, purpose, possible risks and 
benefits of the study. Patients must also be notified that they are free to discontinue from the 
study at any point in time. The patient should be given the opportunity to ask questions and be 
allowed time to consider the information provided. 
The patient’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The signed and dated ICFs will be kept by the principal 
investigator and will be available for inspection by the sponsor and the authorities. A copy of 
the signed written ICF must be given to the patient. 
The global ICF will be approved by the sponsor if modifications are made according to local 
requirements; the new version has to be approved by both the sponsor and the IRB/IECs. 
The written ICF will explain that the study data will remain confidential in accordance with 
national data legislation. The subject ID code will only identify subjects in the database. The 
written ICF will also explain that for data verification purposes, authorized representatives of 
the sponsor, regulatory authority, and IRB/IEC require direct access to parts of the hospital 
records relevant to the study, including the subject’s medical history. 
The ICF may need to be revised during the study, should important new information become 
available that may be relevant to the safety of the subject. In this instance, the IRB/IEC should 
always give approval; if applicable, existing subjects should be informed of the changes, and 
signed consent obtained for the new changes. 
The principal investigator should, with the consent of the subject, inform the subject’s primary 
physician about their participation in the clinical study. 
As used in this protocol, the term “informed consent” includes all consent given by patients or 
their legal representatives. 
10.1.8 Blood and CSF Volume 
Blood and CSF volumes that will be collected in this study are described below. Additonal 
testing that accompanies blood sampling will be performed as deemed necessary by the 
principal investigator or subinvestigator. 
 




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review by the IRB/IEC as to whether continuing the clinical study is appropriate, according to 
each institution’s SOP. 
1. 
When the sponsor notifies the principal investigator of new information, including safety 
information (when the sponsor notifies the study Institution Head of new information in 
countries where applicable). 
2. 
When the principal investigator notifies the study Institution Head of a SAE (when the 
principal investigator becomes aware of a SAE in countries where applicable). 
3. 
When the principal investigator revises the ICF and reports to that effect to the study 
Institution Head (when the principal investigator revises the ICF in countries where 
applicable). 
10.1.13 Clinical Monitoring 
Clinical site monitoring will be conducted by the sponsor representative to ensure that the 
rights and well-being of study subjects are protected, that the reported study data are accurate, 
complete, and verifiable, and that the conduct of the study is in compliance with the currently 
approved 
protocol/amendment(s), 
with 
ICH-GCP, 
and 
with 
applicable 
regulatory 
requirement(s). 
 
Before the study begins, a monitor representing the sponsor will visit the investigational site to 
determine the adequacy of the facilities and to discuss with the principal investigator(s) and 
other personnel involved in the study their responsibilities with regard to protocol adherence, 
and the responsibilities of the sponsor or its representatives. 
During the study, a monitor representing the sponsor will have regular contact with the 
investigational site, including visits to: 
 
provide information and support to the principal investigator(s) 
 
confirm that facilities remain acceptable 
 
confirm that the investigational team is adhering to the protocol 
 
confirm that data are being accurately recorded in the eCRF 
 
confirm that the study is conducted according to the ICH-GCP 
 
confirm that an update of the screening log is performed, and that investigational 
product accountability checks are being performed 
 
Perform source data verification (a comparison of the data in the eCRFs with the 
subject’s records at the hospital or practice, and other records relevant to the study.) 
This will require direct access to all original records for each subject (e.g., clinic charts). 
The monitor, medical monitor or the sponsor representatives will be available between visits if 
the principal investigator(s) or other staff at the investigational site need information and advice. 
10.1.14 Data Quality Assurance 
In order to verify the proper conduct of the clinical study, which is compliant with this protocol 
as well as ICH-GCP and related notifications, and data reliability, the sponsor will perform 
quality control according to the SOP that are defined separately. 
In order to ensure the conduct of the clinical study, as well as the creation, recording, and 
reporting of data are compliant with this protocol as well as ICH-GCP and related notifications, 
the sponsor will conduct audits that are performed by a controller of audit/auditor, who is 
independent of the department involved in the clinical study, in the company and the study 
institution or an outsourcing contractor as needed, according to the SOP that are defined 
separately. 
 
At the request of a monitor, controller of audit/auditor, the IRB/IEC, or the regulatory authority, 
the principal investigator/the study institution head will provide direct access to all the records 
related to the clinical study, including source documents. 
10.1.15 Data Collection and Management Responsibilities 
The management of data and each specific data point will be determined before data are 
locked, through discussion(s) with medical specialists and statisticians, as needed. 


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Data collection is the responsibility of the clinical study staff at the site under the supervision 
of the principal investigator. The principal investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
recording of data in the eCRF. 
Data recorded in the eCRF derived from source documents should be consistent with the data 
recorded on the source documents. 
Clinical data (including AEs and concomitant medications) will be entered into an eCRF, a 
21 CFR Part 11-compliant data capture system. The data system includes password 
protection and internal quality checks to identify data that appear to be inconsistent, incomplete, 
or inaccurate. Clinical data will be entered directly into the eCRF from the source documents. 
For completion/correction of the eCRF, refer to the separate sponsor manual. 
10.1.16 Source Documents 
JCR Pharmaceuticals Co., Ltd. is the sponsor for the JR-171-101 study. Subject data will be 
registered at the study site. The sponsor will supply the study site with all necessary material 
and eCRF at the initiation of the study. Each eCRF and the subject’s medical records will be 
verified carefully by monitors representing the sponsor to ensure full protocol compliance with 
the planned procedures with to regard to data completion and follow-up. The sponsor provides 
project oversight at all times. A project representative from the sponsor will be available to the 
study sites by telephone and/or by visit. 
The principal investigator is responsible for completing the eCRF forms and including all 
relevant data. The eCRF forms will be monitored by representatives of the sponsor who will 
contact the principal investigator should the need arise for further clarification. Data lists will 
be generated from the database enabling a direct comparison between the original case report 
forms and the database. This will facilitate the clarification of any errors. These corrected 
documents, and other study documents, will be retained as the final study documentation. 
The principal investigator must arrange for the retention of the ID codes of subjects (i.e., 
hospital/unit code, study ID code and study number) for as long as the sponsor requests after 
completion or discontinuation of the clinical study. Other source documents, such as subject 
files and clinic case notes, must be retained for the maximum period of time permitted by the 
hospital, institution or private practice and if this is less than the sponsor requires after the 
completion or discontinuation of the clinical study, then the sponsor must be notified to arrange 
record retention. 
If the principal investigator relocates or retires, or otherwise withdraws his/her responsibility for 
maintaining the study documentation, the sponsor must be notified in writing so that adequate 
provision can be made with regard to the ID codes of subjects, copies of the study 
documentation (e.g., copies of eCRFs) and other source data (if available). This responsibility 
may be transferred to the sponsor, who will make arrangements to store the data. An inventory 
of stored data will be held by the principal investigator and a copy by the sponsor. 
Data without a written or electronic record will be identified before study start and should be 
recorded directly on the eCRF, which will be documented clearly as being the source data. 
10.1.17 Storage of Records and Other Documents 
The principal investigator/institute shall store the essential documents and records related to 
the clinical trial for either of the following periods, 1 or 2, whichever comes later. 
1. 
The sponsor specific essential documents should be retained until at least 2 years after 
the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region. These documents should be 
retained for a longer period however if required by the applicable regulatory requirement(s) 
or if needed by the sponsor. 
2. 
If the sponsor discontinues the clinical development of an investigational product (i.e., for 
any or all indications, routes of administration, or dosage forms), the sponsor should 
maintain all sponsor-specific essential documents for at least 2 years after formal 
discontinuation or in conformance with the applicable regulatory requirement(s). 
Principal investigators/institutes take measures to ensure that these records are stored 


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appropriately during this storage period and that they can be retrieved on request. No records 
will be destroyed without the written consent of the sponsor. 
10.1.18 Study and Site Start and Closure 
The first act of recruitment will be after the first site open. 
 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed by the sponsor. 
The principal investigator may initiate study-site closure at any time, provided there is 
reasonable cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or principal investigator may 
include but are not limited to: 
 
Failure of the principal investigator to comply with the protocol, the requirements of 
the IRB/IEC or local health authorities, the sponsor’s procedures, or ICH-GCP 
guidelines 
 
Inadequate recruitment of subjects by the principal investigator 
 
Discontinuation of further study intervention development 
 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
Principal Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The principal investigator shall promptly inform the 
subject and should assure appropriate subject therapy and/or follow-up. 
10.1.19 Publication Policy 
When publishing an academic paper or making a presentation at a conference in relation to 
this clinical study, the principal investigator will obtain prior written approval from the sponsor. 
Note that a patent, manufacturing method, and pharmaceutical formulation related to this 
investigational product will not be disclosed without approval of the sponsor. 
The sponsor has the right to use the result of this clinical study to promote sales after obtaining 
approval. 
10.1.20 Conflict of Interest Policy 
Any actual conflict of interest of the principal investigator, subinvestigator or persons who have 
a role in the design, conduct, analysis, publication, or any aspects of this clinical study will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will 
be required to have such conflicts managed in a way that is appropriate to their participation 
in the study. 
10.1.21 Additional considerations 
It is not applicable for the JR-171-101 study. 
 
























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11. References 
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Set), Mucopolysaccharidosis type I: Clinical features, biochemistry, diagnosis, genetics, 
and treatment. Nova science publishers. 2018; Chapter 9: p. 143-64. 
2) Khan SA, Peracha H, Ballhausen D, Wiesbauer A, Rohrbach M, Gautschi M, et al. 
Epidemiology of mucopolysaccharidoses. Mol Genet Metab. 2017; 121(3): 227-40. 
3) Beck M, Arn P, Giugliani R, Muenzer J, Okuyama T, Taylor J, et al. The natural history 
of MPS I: global perspectives from the MPS I Registry. Genetics in Medicine. 2014; 
16(10): 759-65. 
4) Muenzer J, Wraith JE, Clarke LA, and the International Consensus Panel on 
Management and Treatment of Mucopolysaccharidosis I. Mucopolysaccharidosis I: 
management and treatment guidelines. Pediatrics. 2009; 123(1): 19-29. 
5) de Ru MH, Boelens JJ, Das AM, Jones SA, van der Lee JH, Mahlaoui N, et al. Enzyme 
replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in 
patients with mucopolysaccharidosis type I: results of a European consensus procedure. 
Orphanet J Rare Dis. 2011; 6(55). 
6) Boelens JJ, Aldenhoven M, Purtill D, Ruggeri A, Defor T, Wynn R, et al. Outcomes of 
transplantation using various hematopoietic cell sources in children with Hurler 
syndrome after myeloablative conditioning. Blood. 2013; 121(19): 3981-87. 
7) Aldurazyme (Generic Name: Laronidase), HIGHLIGHTS OF PRESCRIBING 
INFORMATION. Revised April 2013. 
8) D'Aco K, Underhill L, Rangachari L, Arn P, Cox GF, Giugliani R, et al. Diagnosis and 
treatment trends in mucopolysaccharidosis I: findings from the MPS I Registry. 
European Journal of Pediatrics. 2012; 171(6): 911-9. 
9) Forni G, Malvagia S, Funghini S, Scolamiero E, Mura M, Della Bona M, et al. LC-MS/MS 
method for simultaneous quantification of heparan sulfate and dermatan sulfate in urine 
by butanolysis derivatization. Clin Chim Acta. 2019; 488: 98-103. 
10) Giugliani R, Giugliani L, de Oliveira Poswar F, Donis KC, Corte AD, Schmidt M, et al. 
Neurocognitive and somatic stabilization in pediatric patients with severe 
Mucopolysaccharidosis Type I after 52 weeks of intravenous brain-penetrating insulin 
receptor antibody-iduronidase fusion protein (valanafusp alpha): an open label phase 1-
2 trial. Orphanet Journal of Rare Diseases 2018; 13(1). 
11) Suominen P, Virtanen A, Lehtonen-Veromaa M, Heinonen OJ, Salmi TT, Alanen M, et 
al., Regression-based reference limits for serum transferrin receptor in children 6 
months to 16 years of age. Clin Chem. 2001; 47(5): 935-7. 
12) Kakkis ED, Muenzer J, Tiller GE, Waber L, Belmont J, Passage M, et al. Enzyme-
replacement therapy in mucopolysaccharidosis I. N Engl J Med. 2001; 344(3): 182-8. 
13) 
National institutes for Quantum and Radiological Science and Technology [Internet]. 
Available 
from: 
https://www.qst.go.jp/site/qms/1889.html 
(Japanese) 
and 
https://www.innervision.co.jp/01inner/2010/201006bougo/046-049.pdf (Japanese) 
14) Smith-Bindman R, Wang Y, Chu P, Chung R, Einstein AJ, Balcombe J, et al. International 
variation in radiation dose for computed tomography examinations: prospective cohort 
study. BMJ. 2019; 364. 
15) Japan Radiological Society, Japanese Society of Radiological Technology and 
Japanese Society of Pediatric Radiology. Pediatric CT guideline.(Japanese) 2005. 
16) Sampson HA, Muñoz-Furlong A, Bock SA, Schmitt C, Bass R, Chowdhury BA, et al. 
Symposium on the definition and management of anaphylaxis: summary report. J 
Allergy Clin Immunol. 2005; 115(3): 584-91. 


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17) Doessegger L, Banholzer ML. Clinical development methodology for infusion-related 
reactions with monoclonal antibodies. Clin Transl Immunology. 2015; 4(7):e39.