PABINAFUSP ALFA for Mucopolysaccharidosis type II | Hunter Syndrome

Inclusion criteria

• {"criterion_text":"- A patient who voluntarily signs an IRB or Independent Ethics Committee (IEC)-approved written ICF. 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 or her parents or guardians) may sign the informed consent on behalf of the patient. Written informed assent should be obtained from the patient, wherever possible.\n- Patients with confirmed diagnosis of MPS II, based on all of the following criteria: 1) Deficient activity of IDS in leucocytes, plasma or fibroblasts defined by 10% or less of the lower limit of the measuring laboratory normal range unless the hospital or laboratory has established different criteria 2) Documented mutation identified in the IDS gene 3) Increased levels of urinary glycosaminoglycans (GAGs) (or uronic acid) or clinical symptoms and signs consistent with MPS II (such as dysostosis multiplex, coarse facies, cardiac valve disease, developmental delay, chronic pulmonary disease, hernias, kyphosis, joint contractures, carpal tunnel syndrome, etc)\n- Naïve patients or patients who are receiving stable enzyme replacement therapy (ERT) with idursulfase for more than 12 weeks before starting administration of JR-141 or idursulfase for this study.\n- Cohort A - Patients aged 36-42 months of age at the time of ICF signing: patients must have a standard score on the cognitive domain measured by the BSID-III of 85 or less at screening - Patients aged 43-71 months old at the time of ICF signing: patients must EITHER have 1. A development quotient (DQ) on the cognitive domain measured by the BSID-III between 20 and 85 at screening 2. A composite standard score on Nonverbal Index (NVI) measured by the KABC-II of 85 or less at screening for only who are able to perform the KABC-II - Patients aged 30-35 months of age at the time of randomization and who are judged as having the severe phenotype by the Expert Board based on presence of one of the following mutations in the IDS gene and other information such as high CSF HS concentrations: 1) Large deletion or rearrangement 2) Small insertions or deletions that are out of frame 3) Missense mutations, nonsense mutations, in frame inserts or deletions that involve neuronopathic disease in other documented neuronopathic or other cases within the patient's family.\n- Cohort B - Patients 6 years of age or older at the time of ICF signing. - Intelligence quotient (IQ) measured by the Wechsler test (WISC-V, or WAIS-IV) is 70 or higher at screening. - Enrollment of subjects in Cohort B is contingent on the availability in that country of a validated country-specific version of the test (either WISC-V, WIAS-IV, or T.O.V.A.). - Patients with 1SD deficiency in the omission errors or variability domains of the T.O.V.A. test or Processing Speed or Working memory on the Wechsler tests at screening\n- Patients or patients whose female partners are of child-bearing potential i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile, agree to use a medically accepted, highly effective method of contraception as described in Section 10.4 of protocol, from the time of informed consent. The method of contraception must be used during the study until 90 days for male subjects, and 30 days for female subjects after the final study intervention administration.\n- For subjects with hearing impairment requiring hearing aid(s), every effort has been made to encourage compliance with the use of functioning hearing aid(s) before baseline neurocognitive assessments, and parent/legally acceptable representative or subject agrees to encourage wearing them during the study and on neurocognitive testing days."}

Exclusion criteria

• {"criterion_text":"- A patient with a history of engrafted hematopoietic stem cell transplantation (HSCT), with successful engraftment.\n- [Only in France] Persons deprived of their liberty by a judicial or administrative decision, according to article L. 1121-6 of the Public Health Code (Code de la santé publique, CSP), 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 CSP.\n- A patient who has had a ventriculoperitoneal (VP) shunt placed or any other brain surgery, or has a clinically significant VP shunt malfunction within 30 days of screening (Patients may be rescreened after the 30-day waiting period has elapsed).\n- A patient who is full time employee of the Sponsor or research site personnel directly affiliated with this study or their immediate family members, defined as a spouse, parent, child, or sibling, whether biological or legally adopted.\n- A patient who otherwise is judged by the principal investigator or sub-investigator to be ineligible to participate in the study.\n- The subject has a positive pregnancy test or is breastfeeding at screening or randomization.\n- A patient who has received gene therapy treatment at any point.\n- A patient who is judged by the principal investigator or sub-investigator as being unable to undergo lumbar puncture, including those who have difficulties in taking position for lumbar puncture due to joint contracture or those who are likely to experience breathing difficulties during the lumbar puncture process.\n- A patient who is enrolled in another clinical study that involves clinical investigations or use of any investigational product (drug or device) within 4 months before obtaining informed consent\n- A patient who is unable to comply with the protocol (e.g., is unable to return for safety evaluations or is otherwise unlikely to complete the study) as determined by the principal investigator or sub-investigator.\n- A patient who is judged by the principal investigator or sub- investigator to be ineligible to participate in the study due to a history of serious drug allergy or sensitivity including anesthesia or hypersensitivity to any component of JR-141 or idursulfase.\n- A patient who has a known or suspected local or general infection or is at risk of abnormal bleeding due to medical conditions* or therapies the investigator classifies as causing the patient to be ineligible to participate in the study. * Medical Conditions: 1. Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A [IgA] dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis) 2. Evidence or history of significant active bleeding or coagulation disorder or use of non-steroidal anti-inflammatory drugs or other drugs that affect coagulation or platelet function within 14 days prior to lumbar catheter insertion 3. Allergy to lidocaine (Xylocaine®) or its derivatives. These “Medical Conditions” are listed as major serious illnesses that can potentially affect evaluation of the test drug, but it rests with the investigator’s clinical judgement whether a candidate subject with these conditions, when in remittance or in good control under appropriate treatment, can be enrolled in the trial and undergo the defined procedures without concern.\n- A patient who has documented mutation of other genes, including loci adjacent to the IDS gene (e.g., fragile X mental retardation [FMR1] or AF4/FMR2 family member 2[i.e., AFF2 or FMR2]), that are known to be associated with developmental delay, seizures, or other significant CNS disorders.\n- A patient who has documented loss of activity of sulfatases other than IDS, indicating multiple sulfatase deficiency."}

Primary endpoints

• {"endpoint_text":"- Change in the raw scores from baseline to Week 105 measured by the BSID-III (cognitive domain) in Cohort A","definition_or_measurement_approach":"Change in raw scores from baseline to Week 105 measured using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), cognitive domain, in Cohort A."}
• {"endpoint_text":"- Change in levels of CSF HS from baseline to Week 53 in Cohort A","definition_or_measurement_approach":"Change in cerebrospinal fluid heparan sulfate (CSF HS) levels from baseline to Week 53 in Cohort A (biochemical measurement of HS concentration in CSF)."}

Secondary endpoints

• {"endpoint_text":"- Change in the age equivalent scores measured by the BSID-III (cognitive domain) or KABC-II (NVI) from baseline to Week 105 in Cohort A","definition_or_measurement_approach":"Change in age-equivalent scores measured by BSID-III (cognitive) or KABC-II Nonverbal Index from baseline to Week 105 in Cohort A."}
• {"endpoint_text":"- Change in the age equivalent scores of adaptive behavior measured by the VABS-II -from baseline to Week 105 in Cohort A","definition_or_measurement_approach":"Change in age-equivalent adaptive behavior scores measured by Vineland Adaptive Behavior Scales-II (VABS-II) from baseline to Week 105 in Cohort A."}
• {"endpoint_text":"- Relative change in liver volume relative to body weight from baseline to Week 53 in Cohort A and Cohort B","definition_or_measurement_approach":"Relative change in liver volume normalized to body weight from baseline to Week 53 in Cohorts A and B (imaging-based volumetric assessment)."}
• {"endpoint_text":"- Relative change in spleen volume relative to body weight from baseline to Week 53 in Cohort A and Cohort B","definition_or_measurement_approach":"Relative change in spleen volume normalized to body weight from baseline to Week 53 in Cohorts A and B (imaging-based volumetric assessment)."}
• {"endpoint_text":"- Relative change in distance walked using the 6-minute walk test from baseline to Week 53 in Cohort B","definition_or_measurement_approach":"Relative change in distance walked in the 6-minute walk test from baseline to Week 53 in Cohort B (functional capacity measure)."}
• {"endpoint_text":"- Gross and fine motor skills evaluated by age equivalent scores (VABS-II motor skills domain and BSID-III motor domain) from baseline to Week 26, Week 53, Week 78 and Week 105 for Cohort A.","definition_or_measurement_approach":"Assessment of gross and fine motor skills via age-equivalent scores on VABS-II motor domain and BSID-III motor domain at Weeks 26, 53, 78 and 105 versus baseline for Cohort A."}
• {"endpoint_text":"- Pulmonary assessment by absolute forced vital capacity (FVC) change from baseline to Week 26 and Week 53 in Cohort B.","definition_or_measurement_approach":"Absolute change in forced vital capacity (FVC) from baseline to Weeks 26 and 53 in Cohort B (pulmonary function testing)."}
• {"endpoint_text":"- Ongoing assessment of adverse events (AEs).","definition_or_measurement_approach":"Continuous monitoring and recording of adverse events (AEs) throughout the study period; frequency and severity tracked."}
• {"endpoint_text":"- Periodical assessment of laboratory tests (hematology, blood biochemistry, iron-related tests, and urinalysis); vital signs (pulse rate, body temperature, and blood pressure); 12-lead electrocardiogram (ECG); antibodies (anti-IDS antibodies and anti-JR 141 antibodies), and infusion-associated reactions (IARs)","definition_or_measurement_approach":"Periodic laboratory panels, vital signs, 12-lead ECGs, antibody testing (anti-IDS and anti-JR-141), and monitoring for infusion-associated reactions per protocol schedule."}
• {"endpoint_text":"- Plasma drug concentration (only in JR-141 groups): Week 1, Week 26, Week 53, and Week 104 for Cohort A and Week 1, Week 26, and Week 52 for Cohort B.","definition_or_measurement_approach":"Measurement of plasma concentrations of JR-141 at specified weeks for PK analysis in JR-141 groups."}
• {"endpoint_text":"- Plasma PK parameters (only in JR-141 groups): Week 1, Week 26, Week 53, and Week 104 for Cohort A and Week 1, Week 26, and Week 52 for Cohort B.","definition_or_measurement_approach":"Derivation of plasma pharmacokinetic parameters (e.g., AUC, Cmax) for JR-141 at specified timepoints in JR-141 groups."}
• {"endpoint_text":"- Drug concentration in CSF of 16 patients in the JR-141 group of Cohort A and Cohort B, at baseline and Week 26.","definition_or_measurement_approach":"Measurement of JR-141 concentration in cerebrospinal fluid for 16 patients in JR-141 groups at baseline and Week 26."}
• {"endpoint_text":"- Frequency of treatment-emergent adverse events (TEAEs) including infusion-associated reactions (IARs) over the period of the study.","definition_or_measurement_approach":"Tabulation and frequency analysis of TEAEs and IARs occurring during the study period."}
• {"endpoint_text":"- Incidence of clinically significant laboratory tests; vital signs; 12-lead electrocardiogram (ECG); antibodies (anti-IDS antibodies and anti-JR 141 antibodies) over the period of the study.","definition_or_measurement_approach":"Incidence rates of clinically significant abnormalities in labs, vital signs, ECGs, and antibody findings over study duration."}

Methods

• Country-specific recruitment emails to patients and doctors (documents: Recruitment E-Mail Doctor to Patient, Doctor to Patient Email) – languages include Italian, Spanish, German.
• Recruitment brochures, flyers and posters (country-specific) – used to inform and recruit potential participants in Italy, Spain, Poland, France, Germany.
• Website copy (country-specific) to advertise the trial and provide information (documents list includes Website Copy in multiple languages).
• Advocacy/advocacy-letter outreach (Advocacy Email/Advocacy Messages) to patient groups and advocacy contacts (country-specific messages referenced).
• Doctor-to-patient letters and direct outreach materials (Dear Patient Letter) provided in local languages to clinicians to facilitate referral.

Italy

Earliest CTIS Part Ii Submission Date

01-08-2024

Latest Decision Or Authorization Date

14-10-2025

Processing Time Days

439

Number Of Sites

2

Number Of Participants

2

Spain

Earliest CTIS Part Ii Submission Date

01-08-2024

Latest Decision Or Authorization Date

15-10-2025

Processing Time Days

440

Number Of Sites

2

Number Of Participants

10

Germany

Earliest CTIS Part Ii Submission Date

01-08-2024

Latest Decision Or Authorization Date

11-03-2026

Processing Time Days

587

Number Of Sites

5

Number Of Participants

10

Poland

Earliest CTIS Part Ii Submission Date

01-08-2024

Latest Decision Or Authorization Date

11-03-2026

Processing Time Days

587

Number Of Sites

1

Number Of Participants

3

France

Earliest CTIS Part Ii Submission Date

01-08-2024

Latest Decision Or Authorization Date

11-03-2026

Processing Time Days

587

Number Of Sites

3

Number Of Participants

10

Primary sponsor

Full Name

Jcr Pharmaceuticals Co. Ltd.

Organisation Type

Pharmaceutical company

Country Of Registered Address

Japan

Contract research organisations

Name

Parexel International (IRL) Limited

Responsibilities

Clinical operations and multiple delegated sponsor duties (codes listed: 1,12,15 with 'SUSAR reporting' specified, 2,5,8).

Name

WCG Clinical Inc.

Responsibilities

Review of neurocognitive assessments.

Third parties

• {"country":"United States","full_name":"Scout Clinical","duties_or_roles":"Subject and caregiver travel bookings and reimbursements","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"Frontage Laboratories Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Japan","full_name":"Shin Nippon Biomedical Laboratories Ltd.","duties_or_roles":"HS DS measurement and JR-141 level; Antibody testing (two entries for SNBL with different addresses)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Duke University Health System (DUHS) Clinical Laboratories","duties_or_roles":"CRIM status","organisation_type":"Industry"}
• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"Multiple sponsor duties including codes [1,12,15 (SUSAR reporting),2,5,8]","organisation_type":"Pharmaceutical company"}
• {"country":"Japan","full_name":"Advanced Medical Laboratory of National Center for Child Health and Development","duties_or_roles":"Gene testing","organisation_type":"Industry"}
• {"country":"United States","full_name":"WCG Clinical Inc.","duties_or_roles":"Review of neurocognitive assessments","organisation_type":"Pharmaceutical company"}
• {"country":"Japan","full_name":"Micron, Inc.","duties_or_roles":"Medical image analysis/review - X-ray, MRI, ultrasound, etc.","organisation_type":"Industry"}