Gene Therapy Clinical Study in Adult PKU

Study Overview
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Brief Summary
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This is a Phase 1/2, open-label, randomized, concurrently-controlled, dose escalation study to evaluate the safety and efficacy of HMI-102 in adult PKU subjects with PAH deficiency. Participants will receive a single administration of HMI-102 and will be followed for safety and efficacy for 1 year.

Detailed Description
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Part 1 of this study will evaluate the safety and efficacy of HMI-102 gene therapy in adult subjects with PKU due to PAH deficiency. Subjects will receive a single dose of HMI-102 administered intravenously. Up to 3 dose levels of HMI-102 may be investigated in this study. At a given dose level, a minimum of 2 subjects will be enrolled and dosed. Dosing of the first two subjects will be staggered. Following evaluation of data from the first 2 subjects in a cohort, a decision can be made to either escalate to the next dose level or expand the cohort at the selected dose level. Additional doses may be added by HMI to investigate intermediate or higher doses. In Part 2 dose expansion, evaluation of up to 2 dose levels is planned. Subjects will be randomized to receive HMI-102 or a concurrent delayed treatment control arm. Subjects in the delayed treatment control will be eligible to receive HMI-102 after 28 weeks.

Official Title
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A Phase 1/2 Open-Label, Randomized, Concurrently-Controlled, Dose Escalation Study to Evaluate the Safety and Efficacy of HMI-102 in Adult PKU Subjects With PAH Deficiency

Conditions
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PAH Deficiency, Phenylketonurias

Intervention / Treatment
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* Genetic: HMI-102
* Genetic: HMI-102


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Adults 18-55 years of age at the time of informed consent Diagnosis of phenylketonuria (PKU) due to PAH deficiency Two plasma Phe values with a concentration of ≥ 600 μmol/L drawn at least 72 hours apart during the screening period and at least one historical value ≥ 600 μmol/L in the preceding 24 months. Subject has the ability and willingness to maintain their baseline diet, whether Phe-restricted or unrestricted for the duration of the trial, unless otherwise directed Key Exclusion Criteria: Subjects with PKU that is not due to PAH deficiency Presence of anti-AAVHSC15 neutralizing antibodies ALT > ULN and AST > ULN Alkaline phosphatase > ULN. Total bilirubin > ULN, direct bilirubin > ULN Serum creatinine >1.5x ULN International normalized ratio (INR) > 1.2 Hematology values outside of the normal range (hemoglobin <11.0 g/dL for males or <10.0 g/dL for females; white blood cells (WBC) <3,000/μL; absolute neutrophils <1500/μL; platelets <100,000/μL) Hemoglobin A1c >6.5% or fasting glucose >126 mg/dL Any clinically significant abnormal laboratory result at screening, in the opinion of the Investigator Contraindication to corticosteroid use or conditions that could worsen in the presence of corticosteroids, as assessed and determined by the investigator Previously received gene therapy for the treatment of any condition.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Dose Level 1 of HMI-102 delivered intravenously one time | Genetic: HMI-102<br>* HMI-102 is an AAVHSC15 vector containing a functional copy of the human PAH gene<br>|
| Experimental: Cohort 2<br>Dose Level 2 of HMI-102 delivered intravenously one time | Genetic: HMI-102<br>* HMI-102 is an AAVHSC15 vector containing a functional copy of the human PAH gene<br>|
| Experimental: Cohort 3<br>Dose Level 3 of HMI-102 delivered intravenously one time | Genetic: HMI-102<br>* HMI-102 is an AAVHSC15 vector containing a functional copy of the human PAH gene<br>|
| Experimental: Delayed Treatment Control<br>Delayed Treatment Control Arm | Genetic: HMI-102<br>* Control subjects will generally have the same assessments as treated subjects. Control subjects will undergo pre-baseline procedures to confirm that they are eligible to receive treatment with HMI-102. Once eligible control subjects are dosed with HMI-102, they will initiate the same post-dose procedures as subjects who received HMI-102.<br>|
| Experimental: Expansion Phase First Dose level<br>Expansion Phase First Dose Level of HMI-102 delivered intravenously one time | Genetic: HMI-102<br>* HMI-102 is an AAVHSC15 vector containing a functional copy of the human PAH gene<br>|
| Experimental: Expansion Phase Second Dose level<br>Expansion Phase Second Dose Level of HMI-102 delivered intravenously one time | Genetic: HMI-102<br>* HMI-102 is an AAVHSC15 vector containing a functional copy of the human PAH gene<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of treatment-emergent adverse events (TEAEs) (Dose Escalation Phase) | Subjects with at least one TEAE or serious TEAE | Baseline to Week 52 | 
| Change from baseline in clinical laboratory values (Dose Escalation Phase) | Change in serum chemistry values including liver function tests, hematology, and urinalysis | Baseline to Week 52 | 
| Change from baseline in 12-lead electrocardiograms (ECGs), vital signs, physical examinations (Dose Escalation Phase) | Subjects change from baseline in 12-lead electrocardiograms (ECGs), vital signs, physical examinations | Baseline to Week 52 | 
| Incidence of sustained plasma Phe concentration of ≤360 μmol/L at 28 weeks post dose (Dose Escalation Phase) | Subjects achieving a sustained plasma Phe concentration ≤360 μmol/L at 28 weeks post dose | Week 28 | 
| Change from baseline in Plasma Phe Concentration (Dose Escalation Phase) | Change from baseline in plasma Phe concentration during Weeks 24-28 | Weeks 24-28 | 
| Change from baseline in mean Plasma Phe Concentration (Dose Expansion Phase) | Change from baseline in mean plasma Phe concentration during Weeks 24-28 | Weeks 24-28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of plasma Phe concentration thresholds up to Week 28 post administration of HMI-102 (Dose Expansion Phase) | Subjects achieving plasma Phe concentration thresholds up to Week 28 post administration of HMI-102 | Baseline to Week 28 | 
| Incidence of plasma Phe concentration thresholds up to Week 52 post administration of HMI-102 (Dose Expansion Phase) | Subjects achieving plasma Phe concentration thresholds up to Week 52 post administration of HMI-102 | Baseline to Week 52 | 
| Change from baseline in total protein intake at Week 52 post-administration of HMI-102 (Dose Expansion Phase) | Subject Achieving a change from baseline in total protein intake at Week 52 post-administration of HMI-102 | Week 52 | 
| Incidence and severity of treatment-emergent adverse events (TEAEs) (Dose Expansion Phase) | Subjects with at least one TEAE or serious TEAE | Baseline to Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PKU, Phenylketonuria, PAH Deficiency, Hyperphenylalaninemia, Phenylalanine, Adeno Associated Virus, AAVHSC15