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)
Overview
- Phase
- Phase 1
- Intervention
- Not specified
- Conditions
- Mucopolysaccharidosis II
- Sponsor
- Homology Medicines, Inc
- Locations
- 6
- Primary Endpoint
- Evaluate the effect of HMI-203 single administration on urinary GAG levels within each dose cohort
- Status
- Withdrawn
- Last Updated
- 2 years ago
Overview
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.
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.
Investigators
Eligibility Criteria
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
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
Outcomes
Primary Outcomes
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
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
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)
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)
Secondary Outcomes
- Evaluate the long-term effect of HMI-203 single administration on plasma I2S activity and concentration within each dose cohort(week 52 to week 260)
- Determine immune response to the HMI-203 delivery capsid by evaluating the incidence of antibodies(Baseline; weeks 52 and 260)
- Changes from baseline in cardiac function(Baseline; weeks 52, 104, 156, 208, and 260)
- Changes from baseline in cardiac mass(Baseline; weeks 52, 104, 156, 208, and 260)
- Changes from baseline pulmonary function by evaluating spirometry with lung volumes for FEV1 (Forced Expired Volume).(Baseline; weeks 52, 104, 156, 208, and 260)
- Evaluate the long-term effect of HMI-203 single administration on urinary GAG levels within each dose cohort(week 52 to week 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)
- Evaluate the effect of HMI-203 on use of ERT(Baseline through week 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)
- Determine immune response to iduronate 2-sulfatase enzyme (I2S)(Baseline; weeks -1, 1, 4, 8, 12, 24, 52, 78, 104, and 260)
- Determine immune response via cytotoxic T-lymphocyte CD8+ (ELISpot)(Baseline; week 52)
- Changes from baseline in 6-minute Walk Test (6MWT) performance(Baseline to timepoints between Week 52 to Week 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)
- Change in CSF levels of heparan sulfate(Baseline; weeks 52, 260)
- Change in CSF levels of dermatan sulfate(Baseline; weeks 52, 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)
- Change in CSF levels I2S activity and concentration(Baseline; weeks 52, 260)