A Study of JR-171 in Patients With Mucopolysaccharidosis I

Study Overview
=================
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).

Official Title
-----------------
Phase I/II Study of JR-171 ㏌ Patients With Mucopolysaccharidosis Type I

Conditions
-----------------
Mucopolysaccharidosis I

Intervention / Treatment
-----------------
* Drug: JR-171 (lepunafusp alfa)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A patient aged 18 years or older in Part 1 or any age in Part 2, at the time of informed consent 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) need to be obtained instead of his/her consent. Even in this case, written informed consent or assent should be obtained from the patient, wherever possible A patient diagnosed with MPS I based on any one of the following criteria: Activity of IDUA enzyme below 10% of lower reference level in leucocytes or cultured skin fibroblasts, AND increased age-related urinary levels of GAGs (before enzyme replacement therapy) Activity of IDUA enzyme below 10% of 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 enzyme replacement therapy), AND presence of one pathogenic mutation in each of the alleles of the IDUA gene A patient diagnosed as having no or mild MPS I-related intellectual disability (able to report their own subjective symptoms) by the principal investigator or subinvestigator (Part 1 only) A patient who has received laronidase continuously for at least 12 weeks and has received laronidase on a stable dosage for 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) 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: A patient who received gene therapy treatment A patient who, in the opinion of the principal investigator or subinvestigator, cannot undergo lumbar puncture, including those who have a difficulty in taking a position for lumbar puncture due to joint contracture and those who are likely to develop dyspnea during lumbar puncture A patient who is pregnant or lactating 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 A patient who has received another investigational product within 12 months before enrollment in the study A patient who, in the opinion of the principal investigator or subinvestigator, is ineligible to participate in the study out of consideration for the participant safety.

Ages Eligible for Study
-----------------
Minimum Age: 0 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part1 JR-171<br>Drug: JR-171 IV infusion, dose escalation | Drug: JR-171 (lepunafusp alfa)<br>* IV infusion<br>|
| Experimental: Part2 JR-171<br>Drug: JR-171 IV infusion, dose escalation, low dose, high dose | Drug: JR-171 (lepunafusp alfa)<br>* IV infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Adverse Events | Adverse events | 13 Week | 
| Number of participants with Adverse Events | Laboratory tests (hematology, biochemistry, serum iron tests, and urinalysis) | 13 Week | 
| Number of participants with Adverse Events | Vital signs (pulse rate, body temperature, blood pressure, respiratory rate and percutaneous oxygen saturation) | 13 Week | 
| Number of participants with Adverse Events | 12-lead electrocardiogram | 13 Week | 
| Number of participants with Adverse Events | Antibodies [anti-human-α-L-iduronidase (anti-IDUA) and anti-JR-171 antibodies] | 13 Week | 
| Number of participants with Adverse Events | Infusion associated reaction (IAR) | 13 Week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of plasma drug concentration |  | Part1: 1,2,3,4 week, Part2: 1,4,12 week | 
| Assessment of pharmacokinetic parameter | Maximum Plasma Concentration[Cmax] | Part1: 1,2,3,4 week, Part2: 1, 4, 12 week | 
| Assessment of pharmacokinetic parameter | Area Under the Curve from time zero to the last blood sampling time point[AUC0-t] | Part1: 1,2,3,4 week, Part2: 1, 4, 12 week | 
| Assessment of pharmacokinetic parameter | Area Under the Curve from time zero to infinity [AUC0-∞] | Part1: 1,2,3,4 week, Part2: 1, 4, 12 week | 
| Assessment of pharmacokinetic parameter | Time to reach maximum plasma concentration [tmax] | Part1: 1,2,3,4 week, Part2: 1, 4, 12 week | 
| Assessment of pharmacokinetic parameter | Elimination half-life [t1/2] | Part1: 1,2,3,4 week, Part2: 1, 4, 12 week | 
| Assessment of pharmacokinetic parameter | Elimination rate constant [kel] | Part1: 1,2,3,4 week, Part2: 1, 4, 12 week | 
| Assessment of pharmacokinetic parameter | Mean residence time from time zero to the last blood sampling time point [MRT0-t] | Part1: 1,2,3,4 week, Part2: 1, 4, 12 week | 
| Change From Baseline Drug concentration in Cerebrospinal Fluid. |  | Part1: Baseline, 4 week Part2: Baseline, 12 week | 
| Change From Baseline in Heparan Sulfate Levels in Cerebrospinal Fluid |  | Part 1: Baseline, 4 week Part 2: Baseline, 12 week | 
| Change From Baseline in Heparan Sulfate Levels in Serum |  | Part 1: Baseline, 2,3,4,5 week Part2: Baseline, 2, 4, 6, 8, 10, 12, 13 week | 
| Change From Baseline in Heparan Sulfate Levels in Urinary |  | Part 1: Baseline, 2,3,4,5 week Part2: Baseline, 2, 4, 6, 8, 10, 12, 13 week | 
| Change From Baseline in Dermatan Sulfate Levels in Cerebrospinal Fluid |  | Part 1: Baseline, 4 week Part 2: Baseline, 12 week | 
| Change From Baseline in Dermatan Sulfate Levels in Serum |  | Part 1: Baseline, 2,3,4,5 week Part2: Baseline, 2, 4, 6, 8, 10, 12, 13 week | 
| Change From Baseline in Dermatan Sulfate Levels in Urinary |  | Part 1: Baseline, 2,3,4,5 week Part2: Baseline, 2, 4, 6, 8, 10, 12, 13 week | 
| Change From Baseline Opening pressure in Cerebrospinal Fluid |  | Part 1: Baseline, 4 week Part 2: Baseline, 12 week | 
| Change From Baseline in Liver Volume. |  | Part 1: Baseline, 5 week Part 2: Baseline, 13 week | 
| Change From Baseline in Spleen Volume. |  | Part 1: Baseline, 5 week Part 2: Baseline, 13 week | 
| Change From Baseline in Echocardiography. | left ventricular posterior wall thickness | Part 1: Baseline, 5 week Part 2: Baseline, 13 week | 
| Change From Baseline in Echocardiography. | interventricular septal thickness | Part 1: Baseline, 5 week Part 2: Baseline, 13 week | 
| Change From Baseline in Echocardiography. | left ventricular mass index | Part 1: Baseline, 5 week Part 2: Baseline, 13 week | 
| Change From Baseline in Echocardiography. | left ventricular fractional shortening | Part 1: Baseline, 5 week Part 2: Baseline, 13 week | 
| Change From Baseline in Echocardiography. | left ventricular ejection fraction | Part 1: Baseline, 5 week Part 2: Baseline, 13 week | 
| Change From Baseline in Echocardiography. | E/A ratio | Part 1: Baseline, 5 week Part 2: Baseline, 13 week | 
| Change From Baseline in 6-minute Walk Test Distance. |  | Part 2: Baseline, 13 week | 
| Change From Baseline in BVMT-R |  | Part 2: Baseline, 13 week | 
| Change From Baseline in HVLT-R |  | Part 2: Baseline, 13 week | 
| Change From Baseline in T.O.V.A. |  | Part 2: Baseline, 13 week | 
| Change From Baseline in PedsQL-FIM |  | Part 2: Baseline, 13 week |