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

• ClinicalTrials.gov Identifier: NCT05238324
• Recruitment Status: Recruiting
• First Posted: February 14, 2022
• Last Update Posted: January 27, 2023
• Sponsor: Homology Medicines, Inc
• Information provided by (Responsible Party): Homology Medicines, Inc

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Mucopolysaccharidosis II	Biological: Genetic HMI-203	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 9 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Estimated Study Start Date: March 2023
• Estimated Primary Completion Date: October 2024
• Estimated Study Completion Date: January 2029

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: Baseline through 260 weeks ]

   The following events are defined as TEAEs;

   1. Elevation in serum transaminases (concentration that is > 1.5× ULN) and/or
   2. Elevation in serum direct bilirubin (concentration that is > 1.5× ULN)
2. 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 [ Time Frame: Baseline through 260 weeks ]

   The following events are defined as AESIs;

   1. Elevation in serum transaminases (concentration that is > 1.5× ULN) and/or
   2. Elevation in serum direct bilirubin (concentration that is > 1.5× ULN)
3. Evaluate the effect of HMI-203 single administration on urinary GAG levels within each dose cohort [ Time Frame: Baseline to week 52 ]
   Single urine sample GAG levels
4. Evaluate the effect of HMI-203 single administration on plasma I2S activity within each dose cohort [ Time Frame: Baseline to week 52 ]
   Measure trough I2S plasma activity

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Contacts

Contact: Tracy McGregor, M.D.; 781-819-0967; clinicaltrials@homologymedicines.com

Contact: Homology Medicines

Locations

United States, California

UCSF Benioff Children's Hospital Oakland; Recruiting

Oakland, California, United States, 94609

Contact: Jenna Fields 510-428-3885 ext 5156 jenna.fields@ucsf.edu

Principal Investigator: Paul Harmatz, MD

United States, Connecticut

Yale Center for Clinical Investigation; Recruiting

New Haven, Connecticut, United States, 06519

Contact: Michele Jasne 203-785-6351 michele.jasne@yale.edu

Principal Investigator: Yong-hui Jiang, MD, PhD

United States, New Jersey

Hackensack University Medical Center; Recruiting

Hackensack, New Jersey, United States, 07601

Contact: Susan B. Mathus, RN, BSN, CCRC 551-996-8178 susan.mathus@hmhn.org

Principal Investigator: Helio Pedro, MD

United States, Utah

University of Utah Pediatric Genetic & Metabolism Clinic; Not yet recruiting

Salt Lake City, Utah, United States, 84113

Contact: David H Viskochil, MD

United States, Virginia

Lysosomal and Rare Disorders Research and Treatment Center, Inc.; Recruiting

Fairfax, Virginia, United States, 22030

Contact: Ozlem Goker-Alpan, MD 703-261-6220

Contact: Lauren Noll 703-261-6220 ext 107 lnoll@ldrtc.org

Canada, Alberta

M.A.G.I.C. Clinic, Ltd.; Recruiting

Calgary, Alberta, Canada, T2E 7Z4

Contact: Pina Giuliano 587-885-3158 pina.giuliano@magiccalgary.ca

Principal Investigator: Aneal Khan, MD

Sponsors and Collaborators

Homology Medicines, Inc

More Information

• Responsible Party: Homology Medicines, Inc
• ClinicalTrials.gov Identifier: NCT05238324
• Other Study ID Numbers: HMI-203-101
• First Posted: February 14, 2022
• Last Update Posted: January 27, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by Homology Medicines, Inc:

MPS II; Hunter syndrome

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