A Phase III Study of JR-141 in Patients With Mucopolysaccharidosis II

• ClinicalTrials.gov Identifier: NCT04573023
• Recruitment Status: Recruiting
• First Posted: October 5, 2020
• Last Update Posted: April 29, 2022
• Sponsor: JCR Pharmaceuticals Co., Ltd.
• Information provided by (Responsible Party): JCR Pharmaceuticals Co., Ltd.

Study Description

Brief Summary:

A Global Phase III multicenter, randomized, assessor-blinded, active-controlled designed to evaluate safety and efficacy of study drug for the treatment of the MPS II.

Condition or disease	Intervention/treatment	Phase
Mucopolysaccharidosis II	Drug: JR-141; Drug: Idursulfase; Drug: JR-141 or Idursulfase	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase III Study of JR-141 in Patients With Mucopolysaccharidosis II
• Actual Study Start Date: February 14, 2022
• Estimated Primary Completion Date: August 31, 2024
• Estimated Study Completion Date: August 31, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: JR-141 2.0 mg/kg/week	Drug: JR-141; IV infusion, 2.0 mg/kg/week
administered as the standard of care: idursulfase (ELAPRASE®); standard of care-controlled study	Drug: Idursulfase; IV infusion
Rescue arm	Drug: JR-141 or Idursulfase; The subjects who have achieved the pre-specified criteria* are able to change the drug. *If a subject in Idursulfase group shows decline in their neurocognitive outcome, idursulfase can be switched to JR-141. If a subject in JR-141 group shows decline in their peripheral outcome, JR-141 can be switched to idursulfase.

Outcome Measures

Primary Outcome Measures :

1. Change in levels of cerebrospinal fluid heparan sulfate from baseline (Cohort A) [ Time Frame: Baseline to Week 53 ]
2. Change in the raw scores of cognitive testing measured from baseline (BSID-III) (Cohort A) [ Time Frame: Baseline to Week 105 ]

Secondary Outcome Measures :

1. Change in the growth scores of cognitive testing measured from baseline (BSID-III) (Cohort A) [ Time Frame: Baseline to Week 105 ]
2. Change in the age equivalent scores of adaptive behavior measured from baseline (VABS-II) (Cohort A) [ Time Frame: Baseline to Week 105 ]
3. Relative change in liver volume relative to body weight from baseline (Cohort A and Cohort B) [ Time Frame: Baseline to Week 53 ]
4. Relative change in spleen volume relative to body weight from baseline (Cohort A and Cohort B) [ Time Frame: Baseline to Week 53 ]
5. Relative change in distance walked using the 6-minute walk test from baseline to Week 53 (Cohort B) [ Time Frame: Baseline to Week 53 ]

Other Outcome Measures:

1. Change in levels of cerebrospinal fluid heparan sulfate from baseline. (Cohort A) [ Time Frame: Baseline to Week 26, 105 ]
2. Change in levels of cerebrospinal fluid dermatan sulfate from baseline. (Cohort A) [ Time Frame: Baseline to Week 26, 53, 105 ]
3. Change in levels of cerebrospinal fluid heparan sulfate from baseine. (Cohort B) [ Time Frame: Baseline to Week 26, 53 ]
4. Change in levels of cerebrospinal fluid dermatan sulfate from baseline. (Cohort B) [ Time Frame: Baseline to Week 26, 53 ]
5. Change in adaptive behavioral testing measured from baseline [ Time Frame: Baseline to Week 26, 53, 78, 105 ]
   Vineland Adaptive Behavior Scales (Cohort A)
6. Change in adaptive behavioral testing measured from baseline [ Time Frame: Baseline to Week 26, 53 ]
   Vineland Adaptive Behavior Scales (Cohort B)
7. Change in cognitive testing measured from baseline [ Time Frame: Baseline to Week 26, 53, 78, 105 ]
   BSID-III and KABC-II (Cohort A)
8. Change in the standard scores on omission error and variability domain measured by T.O.V.A. or composite scores on Processing speed or Working Memory measured by WISC/WAIS from baseline (Cohort B) [ Time Frame: Baseline to Week 26, 53 ]
9. Change in adaptive behavior measured by VABS-II, and intelligence scale measured by WISC/WAIS from baseline (Cohort B) [ Time Frame: Baseline to Week 26, 53 ]
10. Change in the Quality of Life by HS FOCUS from baseline. (Cohort B) [ Time Frame: Baseline to Week 26, 53 ]
11. Change in the Quality of Life by PedsQL from baseline. (Cohort A) [ Time Frame: Baseline to Week 26, 53, 78, 105 ]
12. Change in the Quality of Life by PedsQL from baseline. (Cohort B) [ Time Frame: Baseline to Week 26, 53 ]
13. Change in the Quality of Life by PedsQL-FIM from baseline. (Cohort A) [ Time Frame: Baseline to Week 26, 53, 78, 105 ]
14. Change in the Quality of Life by PedsQL-FIM from baseline. (Cohort B) [ Time Frame: Baseline to Week 26, 53 ]
15. Change in the Quality of Life by CSHQ from baseline.(Cohort A) [ Time Frame: Baseline to Week 26, 53, 78, 105 ]
16. Change in the Quality of Life by CSHQ from baseline.(Cohort B) [ Time Frame: Baseline to Week 26, 53 ]
17. Change in the global impression of severity and change by CGI from baseline. (Cohort A) [ Time Frame: Baseline to Week 26, 53, 78, 105 ]
18. Change in the global impression of severity and change by CGI from baseline. (Cohort B) [ Time Frame: Baseline to Week 26, 53 ]
19. Change in the global impression of severity and change by PGI from baseline. (Cohort A) [ Time Frame: Baseline to Week 26, 53, 78, 105 ]
20. Change in the global impression of severity and change by PGI from baseline. (Cohort B) [ Time Frame: Baseline to Week 26, 53 ]
21. Change in the Toileting Abilities Survey from baseline. (Cohort A) [ Time Frame: Baseline to Week 13, 26, 53, 78, 105 ]
22. Change in the Toileting Abilities Survey from baseline. (Cohort B) [ Time Frame: Baseline to Week 13, 26, 53 ]
23. Change in Auditory Brainstem Response. (Cohort A) [ Time Frame: Baseline to Week 26, 53, 105 ]
24. Change in Auditory Brainstem Response. (Cohort B) [ Time Frame: Baseline to Week 26, 53 ]
25. Change in cerebrospinal fluid opening pressure. (Cohort A) [ Time Frame: Baseline to Week 26, 53, 105 ]
26. Change in cerebrospinal fluid opening pressure. (Cohort B) [ Time Frame: Baseline to Week 26, 53 ]
27. Relative change in liver volume relative to body weight from baseline (Cohort A) [ Time Frame: Baseline to Week 26, 105 ]
28. Relative change in liver volume relative to body weight from baseline (Cohort B) [ Time Frame: Baseline to Week 26 ]
29. Relative change in spleen volume relative to body weight from baseline (Cohort A) [ Time Frame: Baseline to Week 26, 105 ]
30. Relative change in spleen volume relative to body weight from baseline (Cohort B) [ Time Frame: Baseline to Week 26 ]
31. Relative change in distance walked using the 6-minute walk test from baseline (Cohort B) [ Time Frame: Baseline to Week 26 ]
32. Change in Joint Range of Motion by goniometer from baseline (Cohort A) [ Time Frame: Baseline to Week 26, 53, 105 ]
33. Change in Joint Range of Motion by goniometer from baseline (Cohort B) [ Time Frame: Baseline to Week 26, 53 ]
34. Absolute change in the Forced Vital Capacity from baseline (Cohort B) [ Time Frame: Baseline to Week 26, 53 ]
35. Absolute change in the Forced Expiratory Volume from baseline (Cohort B) [ Time Frame: Baseline to Week 26, 53 ]
36. Absolute change in the percent predicted Forced Vital Capacity from baseline (Cohort B) [ Time Frame: Baseline to Week 26, 53 ]
37. Change in levels of serum heparan sulfate from baseline (Cohort A) [ Time Frame: Baseline to Week 13, 26, 53, 78, 105 ]
38. Change in levels of serum heparan sulfate from baseline (Cohort B) [ Time Frame: Baseline to Week 13, 26, 53 ]
39. Change in levels of serum dermatan sulfate from baseline (Cohort A) [ Time Frame: Baseline to Week 13, 26, 53, 78, 105 ]
40. Change in levels of serum dermatan sulfate from baseline (Cohort B) [ Time Frame: Baseline to Week 13, 26, 53 ]
41. Change in levels of the urine heparan sulfate from baseline. (Cohort A) [ Time Frame: Baseline to Week 13, 26, 53, 78, 105 ]
42. Change in levels of the urine heparan sulfate from baseline. (Cohort B) [ Time Frame: Baseline to Week 13, 26, 53 ]
43. Change in levels of the urine dermatan sulfate from baseline. (Cohort A) [ Time Frame: Baseline to Week 13, 26, 53, 78, 105 ]
44. Change in levels of the urine dermatan sulfate from baseline. (Cohort B) [ Time Frame: Baseline to Week 13, 26, 53 ]
45. Change in the left ventricular mass index (LVMI) from baseline. (Cohort A) [ Time Frame: Baseline to Week 26, 53, 105 ]
46. Change in LVMI from baseline. (Cohort B) [ Time Frame: Baseline to Week 26, 53 ]
47. Change in the interventricular septum thickness (IVST) from baseline. (Cohort A) [ Time Frame: Baseline to Week 26, 53, 105 ]
48. Change in IVST from baseline. (Cohort B) [ Time Frame: Baseline to Week 26, 53 ]
49. Change in the posterior wall thickness (PWT) from baseline. (Cohort A) [ Time Frame: Baseline to Week 26, 53, 105 ]
50. Change in PWT from baseline. (Cohort B) [ Time Frame: Baseline to Week 26, 53 ]
51. Growth velocity (Cohort A) [ Time Frame: Week 53, 105 ]
52. Growth velocity (Cohort B) [ Time Frame: Week 53 ]
53. Ongoing assessment of adverse events. [ Time Frame: Through study period ]
    adverse drug reactions (Cohort A and Cohort B)
54. Antibodies [ Time Frame: Baseline, Week 105 ]
    Plasma: Anti-IDS antibody (Cohort A)
55. Antibodies [ Time Frame: Baseline, Week 53 ]
    Plasma: Anti-IDS antibody (Cohort B)
56. Antibodies [ Time Frame: Baseline, Week 5, 13, 26, 53, 78,105 ]
    Plasma: Anti-JR-141 antibody (Cohort A)
57. Antibodies [ Time Frame: Baseline, Week 5, 13, 26, 53 ]
    Plasma: Anti-JR-141 antibody (Cohort B)
58. Antibodies [ Time Frame: Baseline, Week 26, 53, 105 ]
    Cerebrospinal fluid: Anti-JR-141 antibody (Cohort A)
59. Antibodies [ Time Frame: Baseline, Week 26, 53 ]
    Cerebrospinal fluid: Anti-JR-141 antibody (Cohort B)

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: Male
• Gender Based Eligibility: Yes
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• A patient who voluntarily signs an Institutional Review Board or Independent Ethics Committee-approved written informed consent form. If the patient is aged under 18 years (aged under 16 years in the UK) at the time of enrollment or willingness to participate in the study cannot be confirmed due to MPS II-related intellectual disability, the patient's legally acceptable representative (e.g., his parents or guardians) may sign the informed consent on behalf of the patient. Written informed assent should be obtained from the patient, wherever possible.
• Males with confirmed diagnosis of MPS II
• Naïve patients or patients who are receiving stable enzyme replacement therapy with idursulfase for more than 12 weeks before starting administration of JR-141 or idursulfase for this study.
• Male patients whose partners are of child-bearing potential agree to use a medically accepted, highly effective method of contraception being use of condoms from the time of informed consent.

<Cohort A>

• Males aged 36-42 months old: patients must have a standard score measured by the BSID-III of 85 or less at screening.
• Males aged 43-71 months old: patients must EITHER have (1) A DQ measured by BSID-III of 20 to 85 at screening OR (2) A composite standard score on NVI measured by KABC-II of 85 (only who can perform KABC-II)
• Males aged 30-35 months old at the time of randomization and who are judged as having the severe phenotype by the Expert Board.

<Cohort B>

• Males aged 6 years or older and whose IQ are 70 and higher.
• Attenuated patients with 1 SD deficiency in the omission errors or variability domains of the T.O.V.A..

Exclusion Criteria:

• Use of gene therapy or hematopoietic stem cell transplantation (HSCT), excluding those who need enzyme replacement therapy even after HSCT.
• Unable to undergo lumbar puncture.
• A patient who has received other investigational product (drug or device) within 4 months before study enrollment.
• Unable to comply with the protocol as determined by the principal investigator or subinvestigator.
• Judged by the principal investigator or subinvestigator to be ineligible to participate in the study due to a history of serious drug allergy or sensitivity including sensitivity to anesthesia or hypersensitivity to any component of JR-141.
• A patient who has a known or suspected local or general infection or is at risk of abnormal bleeding due to a medical condition or therapy.
• A patient who has documented mutation of other genes, including loci adjacent to the IDS gene that are known to be associated with developmental delay, seizures, or other significant CNS disorders.
• A patient who has documented loss of activity of sulfatases other than IDS.
• A patient who has had a ventriculoperitoneal shunt placed or any other brain surgery, or has a clinically significant ventriculoperitoneal shunt malfunction within 30 days of screening.
• full time employee of the sponsor or research site personnel directly affiliated with this study or their immediate family members.
• A patient who otherwise is judged by the principle investigator or sub-investigator to be ineligible to participate in the study.

[Only in France]

• Persons deprived of their liberty by a judicial or administrative decision, according to article L.1121-6 the Public Health Code (Code de la santé publique), adults who are the subject of a measure of legal protection or unable to express their consent according to article L. 1121-8 of the Code de la santé publique)

Contacts and Locations

Contacts

Contact: JCR Pharmaceuticals Co., Ltd.; +81-(0)797-32-8582; clinical_development@jp.jcrpharm.com

Locations

United States, California

UCSF Benioff Children's Hospital Oakland; Recruiting

Oakland, California, United States, 94609

Contact: Paul Harmatz

Contact +1-510-428-3058

United States, Illinois

Ann & Robert H. Lurie Children's Hospital of Chicago; Recruiting

Chicago, Illinois, United States, 60611

Contact: Barbara Burton

Contact 312-227-6120

Sponsors and Collaborators

JCR Pharmaceuticals Co., Ltd.

More Information

• Responsible Party: JCR Pharmaceuticals Co., Ltd.
• ClinicalTrials.gov Identifier: NCT04573023
• Other Study ID Numbers: JR-141-GS31
• First Posted: October 5, 2020
• Last Update Posted: April 29, 2022
• Last Verified: April 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Mucopolysaccharidosis II; Mucopolysaccharidoses; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Metabolic Diseases; Mental Retardation, X-Linked; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, X-Linked; Heredodegenerative Disorders, Nervous System