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

• ClinicalTrials.gov Identifier: NCT05238324
• Recruitment Status: Withdrawn
• First Posted: February 14, 2022
• Last Update Posted: August 28, 2023
• Sponsor: Homology Medicines, Inc
• Information provided by (Responsible Party): Homology Medicines, Inc

Tracking Information

• First Submitted Date: December 7, 2021
• First Posted Date: February 14, 2022
• Last Update Posted Date: August 28, 2023
• Actual Study Start Date: September 8, 2022
• Estimated Primary Completion Date: October 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 13, 2023)

• 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)
• 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

Original Primary Outcome Measures (submitted: February 11, 2022)

• Evaluate the incidence and severity of adverse events of special interest (AESIs) and serious adverse events (SAEs) of 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)
• Assess long-term safety of HMI-203 in single administration in adult participants with MPS II by monitoring changes in 12-lead electrocardiograms (ECGs) [ Time Frame: Baseline through 260 weeks ]
  Twelve lead ECG measurements will be performed in triplicate, and will include QT, RR, PR, and QRS intervals
• Assess long-term safety of HMI-203 in single administration by monitoring body temperature. [ Time Frame: Baseline through 260 weeks ]
  Body temperature will be measured via orally, tympanic, or temporal artery.
• Assess long-term safety of HMI-203 in single administration by monitoring respiration rate. [ Time Frame: Baseline through 260 weeks ]
• Assess long-term safety of HMI-203 in single administration by monitoring pulse. [ Time Frame: Baseline through 260 weeks ]
• Assess long-term safety of HMI-203 in single administration by monitoring blood pressure. [ Time Frame: Baseline through 260 weeks ]
  Three consecutive blood pressure readings will be taken and the average will be recorded.
• Assess change from baseline in weekly urinary GAG levels by measuring total GAGs, Dermatan Sulfate GAGs, and Heparan Sulfate GAGs. [ Time Frame: Baseline through week 52 ]
  Weekly single urine sample
• Evaluate the effect of HMI-203 single administration on plasma I2S activity [ Time Frame: Baseline through week 52 ]
  Measure weekly trough I2S plasma levels

Current Secondary Outcome Measures (submitted: January 13, 2023)

• 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
• 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
• 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.
• 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)
• 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.
• 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.
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• Change in CSF levels of heparan sulfate [ Time Frame: Baseline; weeks 52, 260 ]
  Measure CSF heparan sulfate
• Change in CSF levels of dermatan sulfate [ Time Frame: Baseline; weeks 52, 260 ]
  Measure CSF dermatan sulfate
• Change in CSF levels I2S activity and concentration [ Time Frame: Baseline; weeks 52, 260 ]
  Measure CSF I2S activity and concentration
• 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)
• 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)
• Determine immune response via cytotoxic T-lymphocyte CD8+ (ELISpot) [ Time Frame: Baseline; week 52 ]

Original Secondary Outcome Measures (submitted: February 11, 2022)

• Evaluate the effect of HMI-203 on use of ERT [ Time Frame: Baseline through week 104 ]
  Incidence of ERT discontinuation by 52 weeks following HMI-203 administration and among participants who have discontinued ERT by 52 weeks an annualized frequency of ERT infusions at weeks 28-52, 37-52, and 53 to 104.
• 6-minute Walk Test (6MWT) performance [ Time Frame: Baseline through weeks 41-52, 53-104, and 92-104 ]
  Change from baseline in mean 6-minute walk test (6MWT)
• Changes from baseline in spleen organ size. [ Time Frame: Baseline; change at weeks 27, 52, 104, 156, 208, and 260 ]
  Spleen size will be evaluated by ultrasound.
• Changes from baseline in cardiac mass. [ Time Frame: Baseline; weeks 27, 52, 104, 156, 208, and 260 ]
  Cardiac mass will be evaluated by performing a transthoracic 2-dimensional echocardiogram.
• Changes from baseline in cardiac function. [ Time Frame: Baseline; weeks 27, 52, 104, 156, 208, and 260 ]
  Cardiac mass will be evaluated by performing a transthoracic 2-dimensional echocardiogram with doppler flow.
• Changes from baseline pulmonary function by evaluating spirometry with lung volumes for FEV1 (Forced Expired Volume). [ Time Frame: Baseline; weeks 27, 52, 104, 156, 208, and 260 ]
• Changes from baseline pulmonary function by evaluating spirometry with lung volumes for FVC (Forced Vital Capacity). [ Time Frame: Baseline; weeks 27, 52, 104, 156, 208, and 260 ]
• Changes from baseline pulmonary function by evaluating spirometry with lung volumes for TLC (Total Lung Capacity). [ Time Frame: Baseline; weeks 27, 52, 104, 156, 208, and 260 ]
• Changes from baseline pulmonary function by evaluating spirometry with lung volumes for RV (Residual Volume). [ Time Frame: Baseline; weeks 27, 52, 104, 156, 208, and 260 ]
• Changes from baseline pulmonary function by evaluating spirometry with lung volumes for TV (Tidal Volume all in L). [ Time Frame: Baseline; weeks 27, 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). [ Time Frame: Baseline; weeks 27, 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). [ Time Frame: Baseline; weeks 27, 52, 104, 156, 208, and 260 ]
• Determine immune response to the HMI-203 delivery capsid [ Time Frame: Baseline; weeks -1, 1, 11, 19, 27, 35, 43, 51, 78, 104, and 260 ]
  Measurement of anti-AAVHSC antibodies (total and neutralizing)
• Determine immune response to iduronate 2-sulfatase enzyme (I2S) [ Time Frame: Baseline; weeks -1, 1, 4, 8, 11, 27, 43, 78, 104, and 260 ]
  Measurement of anti-I2S antibodies (total and neutralizing)
• Determine immune response via cytotoxic T-lymphocyte CD 8+ (ELISPOT) [ Time Frame: Baseline; weeks 1, 4, 8, 11, 27, 43, and 260 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety and Efficacy of HMI-203 in ERT-Treated Adults With MPS II
• 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)
• 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.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Mucopolysaccharidosis II

Intervention

Biological: Genetic HMI-203

HMI-203 delivered intravenously

Study Arms

• Experimental: HMI-203 Low Dose Level Cohort 1
  Intervention: Biological: Genetic HMI-203
• Experimental: HMI-203 Intermediate Dose Level Cohort 2
  Intervention: Biological: Genetic HMI-203
• Experimental: HMI-203 High Dose Level Cohort 3
  Intervention: Biological: Genetic HMI-203

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Withdrawn
• Actual Enrollment (submitted: August 24, 2023): 0
• Original Estimated Enrollment (submitted: February 11, 2022): 9
• Estimated Study Completion Date: January 2029
• Estimated Primary Completion Date: October 2024 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years to 45 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT05238324
• Other Study ID Numbers: HMI-203-101
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Homology Medicines, Inc
• Original Responsible Party: Same as current
• Current Study Sponsor: Homology Medicines, Inc
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Homology Medicines, Inc
• Verification Date: August 2023