Phase III Evaluation of Pabinafusp Alfa and Idursulfase in Patients with Mucopolysaccharidosis Type II (Hunter Syndrome)
- Trial ID
- 2024-512289-33-00
- Protocol
- JR-141-GS31
- Sponsor
- Jcr Pharmaceuticals Co. Ltd.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase III study is to evaluate the **efficacy** of JR-141 on central nervous system (CNS) and somatic symptoms in patients with **Mucopolysaccharidosis type II** (Hunter Syndrome). This is clinically relevant as it aims to address both neurological and physical manifestations of the disease, potentially improving patient outcomes. Additionally, the study seeks to assess the **safety** of JR-141 in this patient population, ensuring that the treatment does not pose undue risks. Another key aspect of the primary objective is to evaluate the **pharmacokinetics** (PKs) of JR-141, which is crucial for understanding the drug's absorption, distribution, metabolism, and excretion in the body.
Participants
The clinical trial involves a total of **45 participants** diagnosed with **Hunter Syndrome**, also known as **Mucopolysaccharidosis type II**. The study population includes both male and female subjects, with an age range primarily focusing on children and young adults. Participants are categorized into two cohorts: Cohort A includes patients aged 30 to 71 months, while Cohort B consists of individuals aged 6 years and older. The trial population was selected based on specific diagnostic criteria, including deficient activity of iduronate-2-sulfatase (IDS) and documented mutations in the IDS gene. Participants may be either naïve to treatment or have been receiving stable enzyme replacement therapy. Lifestyle considerations such as the use of hearing aids are encouraged for those with hearing impairments. The study includes a vulnerable population, as it involves children and individuals with intellectual disabilities. Key inclusion criteria require participants to have a confirmed diagnosis of MPS II, with specific cognitive assessments conducted to determine eligibility for each cohort.
Plans and Procedures
The clinical trial is designed to evaluate the **efficacy** and safety of JR-141 in patients with **Mucopolysaccharidosis type II** (Hunter Syndrome). This is a Phase III, randomized, double-blind, controlled study. The trial will involve two cohorts: Cohort A, consisting of younger patients, and Cohort B, consisting of older patients. The study will span approximately 104 weeks, with the estimated end date set for December 31, 2026. Participants will be randomly assigned to receive either JR-141 or a comparator, Elaprase, both administered via intravenous infusion or injection.
The sequence of study visits includes an initial screening visit to confirm eligibility based on specific inclusion criteria, such as a confirmed diagnosis of Mucopolysaccharidosis type II and specific cognitive assessments. Following the screening, participants will undergo baseline assessments before the commencement of the treatment phase. Regular follow-up visits will be scheduled to monitor the primary and secondary endpoints, including changes in cognitive scores, levels of CSF HS, liver and spleen volume, and motor skills. These visits will also include safety assessments, such as monitoring for adverse events, laboratory tests, and vital signs.
The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted to evaluate the long-term effects of the treatment. The expected length of participant involvement is approximately two years, with conditions for early termination including significant adverse events or withdrawal of consent. Participants or their legal representatives must provide informed consent, and adherence to the study protocol is required throughout the trial duration.
Treatment
The clinical trial involves the administration of two experimental medications for the treatment of **Mucopolysaccharidosis Type II** (Hunter Syndrome). The first medication, **Elaprase**, is a 2 mg/ml concentrate for solution for infusion. The active substance in Elaprase is **idursulfase**, a protein-based therapeutic agent. This medication is administered via **intravenous use**. The dosage is set at a maximum of 0.5 mg/kg per day, with a total treatment period not exceeding 104 weeks. Elaprase is provided by Takeda Pharmaceuticals International AG Ireland Branch and is classified as an orphan drug, indicating its use for a rare condition.
The second experimental medication is **JR-141**, which is a lyophilized powder for preparation for injection. The active substance in JR-141 is **pabinafusp alfa**, also a protein-based therapeutic agent. This medication is administered as a solution for injection. The dosage for JR-141 is set at a maximum of 2.0 mg/kg per day, with a total treatment period also not exceeding 104 weeks. JR-141 is provided by JCR Pharmaceuticals Co., Ltd and is similarly classified as an orphan drug. The trial aims to evaluate the efficacy of JR-141 on central nervous system and somatic symptoms in patients with Mucopolysaccharidosis Type II, as well as to assess its safety and pharmacokinetics.
Both medications are used in the context of a Phase III clinical trial, with Elaprase serving as the comparator and JR-141 as the test product. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol. No non-experimental treatments, such as standard-of-care therapy or placebo, are mentioned in the trial documentation.
Efficacy
The efficacy of JR-141 in the treatment of **Mucopolysaccharidosis Type II (Hunter Syndrome)** will be assessed through a series of primary and secondary endpoints. The primary endpoints include the change in raw scores from baseline to Week 105 measured by the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) cognitive domain in Cohort A, and the change in levels of cerebrospinal fluid heparan sulfate (CSF HS) from baseline to Week 53 in Cohort A. Secondary endpoints encompass a variety of measures, such as changes in age-equivalent scores of the cognitive domain measured by the BSID-III from baseline to Week 105 in Cohort A, and changes in age-equivalent scores of adaptive behavior measured by the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) from baseline to Week 105 in Cohort A.
Additional secondary endpoints include relative changes in liver and spleen volume relative to body weight from baseline to Week 53 in both Cohort A and Cohort B, and relative changes in distance walked using the 6-minute walk test from baseline to Week 53 in Cohort B. Motor skills will be evaluated by age-equivalent scores in the VABS-II motor skill domain and BSID-III motor domain at multiple timepoints, including Week 26, Week 53, Week 78, and Week 105 for Cohort A. Pulmonary function will be assessed by changes in absolute forced vital capacity (FVC) from baseline to Week 26 and Week 53 in Cohort B. Ongoing assessments will include adverse events, laboratory tests, vital signs, electrocardiograms, antibodies, and infusion-associated reactions. Plasma drug concentration and pharmacokinetic parameters will be measured at specified intervals, and drug concentration in CSF will be evaluated in a subset of patients.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- 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)
- 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.
- 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.
- 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
- 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.
- 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
- A patient with a history of engrafted hematopoietic stem cell transplantation (HSCT), with successful engraftment.
- 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).
- 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.
- A patient who otherwise is judged by the principal investigator or sub-investigator to be ineligible to participate in the study.
- The subject has a positive pregnancy test or is breastfeeding at screening or randomization.
- A patient who has received gene therapy treatment at any point.
- 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.
- 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
- 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.
- 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.
- 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.
- 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.
- A patient who has documented loss of activity of sulfatases other than IDS, indicating multiple sulfatase deficiency.
- [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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 15 Nov 2021 | 10 |
 Germany | Not Recruiting | 15 Nov 2021 | 10 |
 Italy | Not Recruiting | 15 Nov 2021 | 2 |
 Poland | Not Recruiting | 15 Nov 2021 | 3 |
 Spain | Not Recruiting | 15 Nov 2021 | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
JR-141 | Test | LYOPHILIZED POWDER FOR PREPARATION FOR INJECTION (8) | SOLUTION FOR INJECTION | 2.0 | 104 | PRD9373650 |
Elaprase 2 mg/ml concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 0.5 | 104 | PRD359108 |