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

Study Overview
=================
Brief Summary
-----------------
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.

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.

Official Title
-----------------
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

Conditions
-----------------
Phenylketonurias, PAH Deficiency, Phenylketonuria

Intervention / Treatment
-----------------
* Drug: HMI-103


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose Escalation
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PKU, Gene editing, AAVHSC