Safety and Efficacy of HMI-203 in ERT-Treated Adults With MPS II

A Phase 1 Open-Label Dose Escalation Study to Evaluate the Safety and Efficacy of HMI-203 in ERT-Treated Adults With Mucopolysaccharidosis Type II (MPS II) (juMPStart Trial)

Phase 1, open-label, sequential ascending dose-escalation study. Designed to evaluate the safety and efficacy of a single IV infusion of investigational gene therapy HMI-203. Males, ages 18 to 45 years inclusive, with MPS II (Hunter syndrome) currently receiving idursulfase ERT (or the equivalent) are eligible to participate. Participants will be followed for safety and efficacy for 5 years.

Study Overview

• Status: Withdrawn
• Conditions: Mucopolysaccharidosis II
• Intervention / Treatment: Biological: Genetic HMI-203

Detailed Description

This Phase 1 study will evaluate the safety and efficacy of HMI-203 gene therapy in adult male participants with MPS II currently being treated with standard-of-care idursulfase ERT or equivalent. Participants will receive a single dose of HMI-203 administered intravenously. There are 3 planned dose cohorts which will consist of 3 participants each.

Entry into the first dose cohort will be separated by a 60-day dosing interval between each participant to allow the Homology Medicines medical monitor to review safety and efficacy data prior to the second and third participants being enrolled. Enrollment of subsequent participants, in cohorts 2 and 3, will be separated by a 21-day dosing interval between each participant for review of safety and efficacy data.

Escalation to the next dose cohort will occur after 21 days of safety, efficacy, and biomarker data have been reviewed by the Homology Medicines independent DMC.

This entire study is comprised of 5 years, with the most frequent follow up visits occurring in the first year.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Homology Medicines
• Study Contact Backup: Name: Tracy McGregor, M.D.; Phone Number: 781-819-0967; Email: clinicaltrials@homologymedicines.com

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2E 7Z4
      • M.A.G.I.C. Clinic, Ltd.
• United States
  • California
    • Oakland, California, United States, 94609
      • UCSF Benioff Children's Hospital Oakland
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Yale Center for Clinical Investigation
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • University of Utah Pediatric Genetic & Metabolism Clinic
  • Virginia
    • Fairfax, Virginia, United States, 22030
      • Lysosomal and Rare Disorders Research and Treatment Center, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Adult males 18-45 years of age at the time of informed consent
• Has capacity and is able to understand the purpose and risks of the study and is willing, able and committed to comply with all study procedures for the duration of the trial (a total of 5 years after gene therapy administration)
• Diagnosis of MPS II based on historically decreased I2S enzyme activity and elevated urine GAGs and/or presence of hemizygous IDS pathogenic variant
• Kaufman Brief Intelligence Test-Second Edition (KBIT2) score ≥ 80
• Compliance with regular treatments of ERT for MPS II for at least 12 months prior to enrollment
• Clinically stable relative to urinary GAG levels, ambulation, and cardiopulmonary status for 12 months preceding enrollment

Key Exclusion Criteria:

• Multiple sulfatase disorder as determined by abnormal activity of another lysosomal sulfatase
• Unresponsive and/or intolerant to idursulfase treatment
• History of BMT, stem cell transplant, or gene therapy
• Presence of anti-capsid neutralizing antibodies
• ALT or AST > ULN; Total or Direct bilirubin > ULN
• International normalized ratio (INR) >1.2 ULN
• Hematology values below the normal range
• Hemoglobin A1c ≥ 6.5% or fasting glucose ≥126 mg/dL
• Contraindication to corticosteroid or tacrolimus use
• Any condition that would not allow the potential participant to complete follow-up examinations during the course of the study or, in the opinion of the investigator, makes the potential participant unsuitable for the study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HMI-203 Low Dose Level Cohort 1	Biological: Genetic HMI-203; HMI-203 delivered intravenously
Experimental: HMI-203 Intermediate Dose Level Cohort 2	Biological: Genetic HMI-203; HMI-203 delivered intravenously
Experimental: HMI-203 High Dose Level Cohort 3	Biological: Genetic HMI-203; HMI-203 delivered intravenously

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate the incidence and severity of treatment emergent adverse events (TEAEs) after a single dose administration of HMI-203 (at each dose level) in adult participants with MPS II	The following events are defined as TEAEs; Elevation in serum transaminases (concentration that is > 1.5× ULN) and/or; Elevation in serum direct bilirubin (concentration that is > 1.5× ULN)	Baseline through 260 weeks
Evaluate the incidence and severity of adverse events of special interest (AESIs) after a single dose administration of HMI-203 (at each dose level) in adult participants with MPS II	The following events are defined as AESIs; Elevation in serum transaminases (concentration that is > 1.5× ULN) and/or; Elevation in serum direct bilirubin (concentration that is > 1.5× ULN)	Baseline through 260 weeks
Evaluate the effect of HMI-203 single administration on urinary GAG levels within each dose cohort	Single urine sample GAG levels	Baseline to week 52
Evaluate the effect of HMI-203 single administration on plasma I2S activity within each dose cohort	Measure trough I2S plasma activity	Baseline to week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes from baseline pulmonary function by evaluating spirometry with lung volumes for FEV1 (Forced Expired Volume).		Baseline; weeks 52, 104, 156, 208, and 260
Changes from baseline pulmonary function by evaluating spirometry with lung volumes for FVC (Forced Vital Capacity).		Baseline; weeks 52, 104, 156, 208, and 260
Changes from baseline pulmonary function by evaluating spirometry with lung volumes for TLC (Total Lung Capacity).		Baseline; weeks 52, 104, 156, 208, and 260
Changes from baseline pulmonary function by evaluating spirometry with lung volumes for RV (Residual Volume).		Baseline; weeks 52, 104, 156, 208, and 260
Changes from baseline pulmonary function by evaluating spirometry with lung volumes for TV (Tidal Volume all in L).		Baseline; weeks 52, 104, 156, 208, and 260
Changes from baseline pulmonary function by evaluating spirometry with lung volumes for FEV1/FVC ratio (Forced Expiry Volume in 1 second/Forced Vital Capacity).		Baseline; weeks 52, 104, 156, 208, and 260
Changes from baseline pulmonary function by evaluating spirometry by DLCO (Diffusing Capacity of the Lungs for Carbon Monoxide mL/min/mmHg).		Baseline; weeks 52, 104, 156, 208, and 260
Determine immune response to iduronate 2-sulfatase enzyme (I2S)	Measurement of anti-I2S antibodies (total and neutralizing)	Baseline; weeks -1, 1, 4, 8, 12, 24, 52, 78, 104, and 260
Evaluate the long-term effect of HMI-203 single administration on plasma I2S activity and concentration within each dose cohort	Measure trough I2S plasma activity and measure trough I2S plasma concentration	week 52 to week 260
Evaluate the long-term effect of HMI-203 single administration on urinary GAG levels within each dose cohort	Single urine sample GAG levels	week 52 to week 260
Evaluate the effect of HMI-203 on use of ERT	Incidence of ERT discontinuation by 52 weeks following HMI-203 administration and among participants who have discontinued ERT by 52 weeks. Annualized frequency of ERT infusions at weeks 24, 52, 76, 104, 156, 208 and 260.	Baseline through week 260
Changes from baseline in 6-minute Walk Test (6MWT) performance	Change from baseline in mean 6-minute walk test (6MWT)	Baseline to timepoints between Week 52 to Week 260
Changes from baseline in cardiac mass	Cardiac mass will be evaluated by performing a transthoracic 2-dimensional echocardiogram.	Baseline; weeks 52, 104, 156, 208, and 260
Changes from baseline in cardiac function	Cardiac function will be evaluated by performing a transthoracic 2-dimensional echocardiogram with doppler flow.	Baseline; weeks 52, 104, 156, 208, and 260
Change in CSF levels of heparan sulfate	Measure CSF heparan sulfate	Baseline; weeks 52, 260
Change in CSF levels of dermatan sulfate	Measure CSF dermatan sulfate	Baseline; weeks 52, 260
Change in CSF levels I2S activity and concentration	Measure CSF I2S activity and concentration	Baseline; weeks 52, 260
Determine immune response to the HMI-203 delivery capsid by evaluating the incidence of antibodies	Measurement of anti-AAVHSC antibodies (total and neutralizing)	Baseline; weeks 52 and 260
Determine immune response via cytotoxic T-lymphocyte CD8+ (ELISpot)		Baseline; week 52

Collaborators and Investigators

• Sponsor: Homology Medicines, Inc

Study record dates

Study Major Dates

• Study Start (Actual): September 8, 2022
• Primary Completion (Estimated): October 1, 2024
• Study Completion (Estimated): January 1, 2029

Study Registration Dates

• First Submitted: December 7, 2021
• First Submitted That Met QC Criteria: February 11, 2022
• First Posted (Actual): February 14, 2022

Study Record Updates

• Last Update Posted (Actual): August 28, 2023
• Last Update Submitted That Met QC Criteria: August 24, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: MPS II; Hunter syndrome
• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Connective Tissue Diseases; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Mucopolysaccharidosis II; Mucopolysaccharidoses
• Other Study ID Numbers: HMI-203-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No