Evaluation of Safety and Efficacy of JR-441 in Mucopolysaccharidosis Type IIIA via Weekly Intravenous Infusions

Trial ID: 2024-517045-14-00
Protocol: JR-441-101
Sponsor: Jcr Pharmaceuticals Co. Ltd.

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Diseases & Conditions

Mucopolysaccharidosis III

Objectives

The primary objective of this Phase I/II study is to evaluate the **safety** and explore the efficacy of JR-441 in patients with **mucopolysaccharidosis type IIIA (MPS IIIA)**. This is clinically relevant as MPS IIIA is a rare genetic disorder characterized by the accumulation of glycosaminoglycans, leading to progressive neurological decline. The study aims to assess the potential of JR-441, a lyophilized powder for injection, which contains **N-sulfoglucosamine sulfohydrolase fused to a humanised monoclonal antibody targeting human transferrin receptor**, to address the underlying enzyme deficiency in MPS IIIA. The secondary objectives are not specified in the provided data.

Participants

The clinical trial involves participants diagnosed with **Mucopolysaccharidosis type IIIA (MPS IIIA)**, a rare genetic disorder. The study population includes both male and female subjects, with an age range from 1 to 18 years. Participants are required to have a confirmed diagnosis of MPS IIIA, characterized by specific enzyme activity levels and genetic mutations. The trial does not involve a vulnerable population. Participants must be medically stable and able to comply with the study protocol, including travel requirements. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as the use of hearing aids for those with hearing impairments are encouraged to ensure accurate neurodevelopmental assessments. The selection process involves obtaining informed consent from participants or their legally acceptable representatives, with additional assent from the subjects when possible.

Plans and Procedures

The clinical trial is a **Phase I/II** study designed to evaluate the safety and explore the efficacy of JR-441 in patients diagnosed with **mucopolysaccharidosis type IIIA (MPS IIIA)**. The trial employs a **randomized, double-blind, controlled** design to ensure the reliability and validity of the results. The study is expected to span from September 28, 2023, to January 11, 2030, with a maximum treatment period of 260 weeks for each participant. Participants will receive weekly intravenous infusions of JR-441, a lyophilized powder for preparation for injection, which contains **N-sulfoglucosamine sulfohydrolase fused to a humanised monoclonal antibody targeting human transferrin receptor**.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as age, confirmed diagnosis of MPS IIIA, and medical stability. Following successful screening, participants will undergo baseline assessments before commencing treatment. Regular follow-up visits will be conducted to monitor safety and efficacy, including assessments of adverse events, laboratory tests, vital signs, and electrocardiograms. The primary endpoints focus on the occurrence of adverse events and changes in safety laboratory tests, while secondary endpoints include plasma drug concentration and changes in cognitive function and adaptive behavior.

The end-of-study visit will occur after the final infusion, where comprehensive evaluations will be conducted to assess the long-term effects of the treatment. Participant involvement is expected to last for the duration of the treatment period, with conditions for early termination including significant adverse events or withdrawal of consent. The study aims to provide valuable insights into the potential benefits and risks of JR-441 for patients with MPS IIIA, contributing to the development of effective treatments for this rare condition.

Treatment

The clinical trial involves the administration of the experimental medication **JR-441**, which is a **lyophilized powder for preparation for injection**. The active substance in JR-441 is **N-sulfoglucosamine sulfohydrolase fused to a humanised monoclonal antibody targeting the human transferrin receptor**. This formulation is intended for intravenous infusion. The dosing regimen consists of weekly infusions, with the treatment period extending up to 260 weeks. The dosage is measured in milligrams per kilogram (mg/kg), although specific maximum daily and total dose amounts are not defined in the trial data. The medication is not a paediatric formulation and has been designated as an orphan drug, indicating its use in treating a rare condition.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the safety and exploring the efficacy of JR-441 in patients diagnosed with **mucopolysaccharidosis type IIIA**. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol. The trial is conducted under the sponsorship of JCR Pharmaceuticals Co., Ltd, which is responsible for the development and provision of the investigational product.

Efficacy

The efficacy of JR-441 in the treatment of **mucopolysaccharidosis type IIIA** will be assessed through a series of secondary endpoints. These include the measurement of plasma drug concentration and plasma pharmacokinetic (PK) parameters. Additionally, changes from baseline in specific biomarkers and cognitive assessments will be evaluated at each designated time point. The biomarkers of interest include heparan sulfate (HS) concentration in cerebrospinal fluid (CSF) and serum, as well as HS concentration relative to creatinine concentration in urine. Cognitive function will be assessed using cognitive scales and/or the Nonverbal Index (NVI), alongside an evaluation of adaptive behavior.

Inclusion and Exclusion Criteria

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Inclusion Criteria

(1) Chronological age of ≥1 year and ≤18 years at the time of signing ICF.
(2) A participant who voluntarily signs an IRB or IEC-approved written ICF. If the participant is aged 1year to <18 years at the time of informed consent, or willingness to participate in the study cannot be confirmed due to MPS IIIA-related intellectual disability, the participant’s legally acceptable representative (e.g., his/her parents or guardians) may sign the ICF on behalf of the participant. Written informed assent must be obtained from the participant, wherever possible..
(3) A participant with a confirmed diagnosis of MPS IIIA, based on all the following criteria: ○ Activity of the N-sulphoglucosamine sulphohydrolase (SGSH) enzyme below 10% of the lower reference level in white blood cells or cultured skin fibroblasts. ○ A normal enzyme activity level of at least one other sulfatase (to rule out multiple sulfatase deficiency) as measured in leukocytes. ○ Presence of a pathological mutation in each of the individual alleles of the SGSH gene. Note: if SGSH enzyme activity results are abnormal (i.e., below the normal range of the assay) but still above the threshold of 10% of the lower reference level, MPS IIIA diagnosis may be confirmed based on family history and genotype following discussion and approval from the sponsor’s Medical Monitor.
(4) Study participants should have a minimal body weight of 10 kg.
(5) Female participants of childbearing potential or participants whose female partner is of child-bearing potential agree to use a medically accepted, highly effective method of contraception as described in Section 10.5, from the time of signing the ICF. The method of contraception must be used during the study until 90 days for male participants, and 30 days for female participants after the final study drug administration or vasectomy at least 13 weeks prior to signing ICF..
(6) For participants 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 neurodevelopmental assessments, and parent/legally acceptable representative or participant agrees to encourage wearing them during the study and on neurodevelopmental function test days.
(7) Medically stable and able to accommodate the protocol requirements, including travel without placing an undue burden on the participant/participant’s family, as determined by the principal investigator.

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Exclusion Criteria

(1) A participant who has received gene therapy treatment or hematopoietic stem cell transplantation (HSCT) with successful engraftment.
(2) A participant who is pregnant or breast feeding.
(3) A participant who has received another investigational drug or product within 4 months or 5 half-lives (whichever is longer) before the time of providing informed consent.
(4) A participant who is participating concurrently or who has participated prior (within 30 days of enrolment into this study) in a study involving invasive procedures.
(5) A participant who has received Genistein within 4 months before the time of providing informed consent.
(6) A participant who has received KINERET® (anakinra) within 4 months before the time of providing informed consent.
(7) A participant who has developed serious drug allergy or hypersensitivity to any components of JR-441 or medications likely prescribed during the study, which, in the opinion of the principal investigator or sub-investigator, would be an impediment towards completion of the study.
(8) A participant unable to undergo lumbar puncture.
(9) A participant unable to undergo MRI.
(10) A participant who has had a ventriculoperitoneal (VP) shunt placed or any other brain surgery
(11) A participant has a history of bleeding disorder or current use of medications that, in the opinion of the investigator, place them at risk of bleeding following lumbar puncture.
(12) A participant who has a history of poorly controlled seizures.
(13) Serology consistent with human immunodeficiency virus (HIV) exposure or consistent with active hepatitis B (HepB) or C (HepC) infection.
(14) A participant who has lab abnormalities with CTCAE grade ≥ II for liver function test, bilirubin, creatinine, hemoglobin, white blood cell count, platelet count, prothrombin time, and activated partial thromboplastin time (aPTT), except subject whose bilirubin elevated due to Gilbert’s Syndrome.
(15) A participant with known iron-metabolism disorder.
(16) A participant with visual or hearing impairment sufficient, in the clinical judgment of the principal investigator or sub-investigator, to preclude cooperation with neurodevelopmental testing.
(17) A participant currently receiving psychotropic or other medications which in the principal investigator’s or sub-investigator’s opinion, would be likely to substantially confound test results.
(18) A participant who has a medical condition or extenuating circumstance that, in the opinion of the principal investigator or sub-investigator, might compromise the participant’s ability to comply with protocol requirements, the participant’s well-being or safety, or the interpretability of the participant’s clinical data.
(19) A participant who is ineligible to participate in the study in the opinion of the principal investigator or sub-investigator.