Safety and Efficacy of HMI-203 in ERT-Treated Adults With MPS II
Study Details
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 |
|---|---|---|
|
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 HMI 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 HMI independent DMC.
This entire study is comprised of 5 years, with the most frequent follow up visits occurring in the first year.
Study Design
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
- 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 [Baseline through 260 weeks]
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)
- Assess long-term safety of HMI-203 in single administration in adult participants with MPS II by monitoring changes in 12-lead electrocardiograms (ECGs) [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. [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. [Baseline through 260 weeks]
- Assess long-term safety of HMI-203 in single administration by monitoring pulse. [Baseline through 260 weeks]
- Assess long-term safety of HMI-203 in single administration by monitoring blood pressure. [Baseline through 260 weeks]
Three consecutive blood pressure readings will be taken and the average will be recorded.
- Assess change from baseline in urinary GAG levels by measuring total GAGs, Dermatan Sulfate GAGs, and Heparan Sulfate GAGs. [Baseline, weeks -6, -4, -2, weekly from week 1 through 12, every other week from week 14 through 24, every 4 weeks thereafter to week 52, quarterly up to week 247 and end of study week 260]
Single urine sample
- Evaluate the effect of HMI-203 single administration on plasma I2S activity [Baseline, weeks -6, -4, -2, weekly from week 1 through 12, every other week from week 14 through 24, every 4 weeks thereafter to week 52, quarterly up to week 247 and end of study week 260]
Measure trough I2S plasma levels
Secondary Outcome Measures
- Evaluate the effect of HMI-203 on use of ERT [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 [Baseline to timepoints between Week 52 to Week 260]
Change from baseline in mean 6-minute walk test (6MWT)
- Changes from baseline in spleen organ size. [Baseline; change at weeks 52, 104, 156, 208, and 260]
Spleen size will be evaluated by ultrasound.
- Changes from baseline in cardiac mass. [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. [Baseline; weeks 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). [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 the HMI-203 delivery capsid [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) [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 CD 8+ (ELISPOT) [Baseline; weeks 1, 2, 4, 8, 12, 24, 52]
Eligibility Criteria
Criteria
Key Inclusion Criteria:
-
Adult males 18-45 years of age at the time of informed consent
-
Has capacity, is able to understand the purpose and risks of the study, is willing and able to comply with all study procedures for a total of 5 years after gene therapy administration
-
Diagnosis of MPS II based on presence of IDS pathogenic variant
-
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
-
Able to complete the 6MWT
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-neutralizing antibodies
-
ALT and AST > ULN; Total and 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 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
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Utah Pediatric Genetic & Metabolism Clinic | Salt Lake City | Utah | United States | 84113 |
| 2 | Lysosomal and Rare Disorders Research and Treatment Center, Inc. | Fairfax | Virginia | United States | 22030 |
Sponsors and Collaborators
- Homology Medicines, Inc
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- HMI-203-101