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.

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.

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)

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)

Evaluate the long-term effect of HMI-203 single administration on plasma I2S activity and concentration within each dose cohort

Evaluate the long-term effect of HMI-203 single administration on urinary GAG levels within each dose cohort

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.

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).

Changes from baseline pulmonary function by evaluating spirometry with lung volumes for FVC (Forced Vital Capacity).

Changes from baseline pulmonary function by evaluating spirometry with lung volumes for TLC (Total Lung Capacity).

Changes from baseline pulmonary function by evaluating spirometry with lung volumes for RV (Residual Volume).

Changes from baseline pulmonary function by evaluating spirometry with lung volumes for TV (Tidal Volume all in L).

Changes from baseline pulmonary function by evaluating spirometry with lung volumes for FEV1/FVC ratio (Forced Expiry Volume in 1 second/Forced Vital Capacity).

Changes from baseline pulmonary function by evaluating spirometry by DLCO (Diffusing Capacity of the Lungs for Carbon Monoxide mL/min/mmHg).

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