Safety and Efficacy of HMI-103 in Participants With Classical PKU Due to PAH Deficiency

A Phase 1, Open-Label, Dose-Escalation Study to Evaluate the Safety and Efficacy of HMI-103 Administered Intravenously in Adult Participants With Classical PKU Due to PAH Deficiency

This is an open-label, sequential ascending dose-escalation, Phase 1 study to evaluate the safety and efficacy of a single intravenous (I.V.) administration of HMI-103, a gene editing development candidate, in adult participants aged 18 to 55 years, inclusive, with classical PKU due to PAH deficiency who have uncontrolled disease despite Phe restricted dietary management.

Study Overview

• Status: Terminated
• Conditions: Phenylketonuria; Phenylketonurias; PAH Deficiency
• Intervention / Treatment: Drug: HMI-103

Detailed Description

This is an open-label, sequential ascending dose-escalation, Phase 1 study to evaluate the safety and efficacy of a single intravenous administration of HMI-103, a gene editing development candidate, in adult participants aged 18 to 55 years, inclusive, with classical PKU due to PAH deficiency who have uncontrolled disease despite Phe-restricted dietary management. Up to 3 dose levels of HMI-103 may be investigated. At a given dose level, 3 participants are planned to be enrolled and dosed. Participant dosing will be staggered.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Julie Jordan, M.D.; Phone Number: 781-819-0967; Email: clinicaltrials@homologymedicines.com

Study Locations

• United States
  • Indiana
    • Topeka, Indiana, United States, 46571
      • The Community Health Clinic
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17579
      • Clinic for Special Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adults 18-55 years of age at the time of informed consent
• Diagnosis of classical phenylketonuria (PKU) due to PAH deficiency
• Four baseline plasma Phe values with a concentration of ≥ 600 μmol/L and at least one historical value ≥ 600 μmol/L in the preceding 24 months.
• Participants must have uncontrolled classical PKU disease (despite Phe-restricted dietary management) in the judgment of the investigator and confirmed by the independent DMC at the end of the Screening period.
• Participant has the ability and willingness to maintain their baseline diet, for the duration of the trial, unless otherwise directed

Exclusion Criteria:

• Subjects with PKU that is not due to PAH deficiency
• Presence of anti-AAVHSC15 neutralizing antibodies
• Participants who are well controlled on a Phe-restricted diet.
• Hemoglobin A1c >6.5% or fasting glucose >126 mg/dL
• Liver function tests > ULN
• International normalized ratio (INR) > 1.2
• Hematology values outside of the normal range
• Previously received gene therapy for the treatment of any condition.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low Dose Cohort; HMI-103 delivered IV one time	Drug: HMI-103; HMI-103 is an AAVHSC15 capsid containing a functional copy of the human PAH gene
Experimental: Intermediate Dose Cohort; HMI-103 delivered IV one time	Drug: HMI-103; HMI-103 is an AAVHSC15 capsid containing a functional copy of the human PAH gene
Experimental: High Dose Cohort; HMI-103 delivered IV one time	Drug: HMI-103; HMI-103 is an AAVHSC15 capsid containing a functional copy of the human PAH gene

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the efficacy of HMI-103 on reduction of plasma Phe concentration at each dose level	Mean percent change from baseline at Weeks 24-32 in plasma Phe concentration within each dose cohort post-administration of HMI-103	Baseline to Weeks 24-32
To measure incidence and severity of Treatment Emergent Adverse Events (TEAEs) and adverse events of special interest (AESIs) of a single administration of HMI-103		Baseline to Week 104

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the effect of HMI-103 on plasma Phe concentration relative to treatment guidelines for PKU	Incidence of plasma Phe of ≤ 360 μmol/L within each dose cohort at each timepoint post-administration of HMI-103	Baseline to Week 104
To assess durability of response	Incidence of plasma Phe ≤ 360 μmol/L during Weeks 48-52 post-administration of HMI-103	Weeks 48-52
To assess the changes in dietary protein intake	Change from baseline in natural and total protein intake (g/day) at each timepoint post-administration of HMI-103	Baseline to Week 104

Collaborators and Investigators

• Sponsor: Homology Medicines, Inc

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2022
• Primary Completion (Actual): September 14, 2023
• Study Completion (Actual): September 14, 2023

Study Registration Dates

• First Submitted: December 21, 2021
• First Submitted That Met QC Criteria: February 1, 2022
• First Posted (Actual): February 3, 2022

Study Record Updates

• Last Update Posted (Estimated): October 9, 2023
• Last Update Submitted That Met QC Criteria: October 5, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: PKU; Gene editing; AAVHSC
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Phenylketonurias
• Other Study ID Numbers: HMI-103-101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No