Gene Therapy Clinical Study in Adult PKU (pheNIX)

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

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.

Study Overview

• Status: Terminated
• Conditions: Phenylketonurias; PAH Deficiency
• Intervention / Treatment: Genetic: HMI-102; Genetic: HMI-102

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2; 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
  • California
    • Los Angeles, California, United States, 90027
      • Kaiser Permanente Los Angeles Medical Center
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
  • Florida
    • Tampa, Florida, United States, 33606
      • University of South Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Lurie Children's Hospital of Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • The University of North Carolina at Chapel Hill
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • UPMC Children's Hospital of Pittsburgh
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; Dose Level 1 of HMI-102 delivered intravenously one time	Genetic: HMI-102; HMI-102 is an AAVHSC15 vector containing a functional copy of the human PAH gene; Genetic: HMI-102; 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.
Experimental: Cohort 2; Dose Level 2 of HMI-102 delivered intravenously one time	Genetic: HMI-102; HMI-102 is an AAVHSC15 vector containing a functional copy of the human PAH gene; Genetic: HMI-102; 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.
Experimental: Cohort 3; Dose Level 3 of HMI-102 delivered intravenously one time	Genetic: HMI-102; HMI-102 is an AAVHSC15 vector containing a functional copy of the human PAH gene; Genetic: HMI-102; 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.
Experimental: Delayed Treatment Control; Delayed Treatment Control Arm	Genetic: HMI-102; HMI-102 is an AAVHSC15 vector containing a functional copy of the human PAH gene; Genetic: HMI-102; 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.
Experimental: Expansion Phase First Dose level; Expansion Phase First Dose Level of HMI-102 delivered intravenously one time	Genetic: HMI-102; HMI-102 is an AAVHSC15 vector containing a functional copy of the human PAH gene; Genetic: HMI-102; 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.
Experimental: Expansion Phase Second Dose level; Expansion Phase Second Dose Level of HMI-102 delivered intravenously one time	Genetic: HMI-102; HMI-102 is an AAVHSC15 vector containing a functional copy of the human PAH gene; Genetic: HMI-102; 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.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phenylketonuria Quality of Life Questionnaire (PKU-QOL)	Change in PKU-QOL	Baseline to Week 52

Collaborators and Investigators

• Sponsor: Homology Medicines, Inc
• Investigators: Principal Investigator: Olaf A Bodamer, M.D., Boston Children's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2019
• Primary Completion (Actual): January 10, 2023
• Study Completion (Actual): August 1, 2023

Study Registration Dates

• First Submitted: May 9, 2019
• First Submitted That Met QC Criteria: May 14, 2019
• First Posted (Actual): May 16, 2019

Study Record Updates

• Last Update Posted (Actual): August 29, 2023
• Last Update Submitted That Met QC Criteria: August 24, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Phenylketonuria; PKU; PAH Deficiency; Phenylalanine; Adeno Associated Virus; AAVHSC15; Hyperphenylalaninemia
• 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-102-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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