Gene Therapy Clinical Study in Adult PKU

Phase 1

Terminated

Brief Summary: 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: 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.

Recruitment & Eligibility

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.

Arm && Interventions

Group	Intervention	Description
Cohort 2	HMI-102	Dose Level 2 of HMI-102 delivered intravenously one time
Expansion Phase First Dose level	HMI-102	Expansion Phase First Dose Level of HMI-102 delivered intravenously one time
Cohort 3	HMI-102	Dose Level 3 of HMI-102 delivered intravenously one time
Cohort 1	HMI-102	Dose Level 1 of HMI-102 delivered intravenously one time
Delayed Treatment Control	HMI-102	Delayed Treatment Control Arm
Expansion Phase Second Dose level	HMI-102	Expansion Phase Second Dose Level of HMI-102 delivered intravenously one time

Primary Outcome Measures

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

Secondary Outcome Measures

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

Locations (13): Icahn School of Medicine at Mount Sinai
🇺🇸
New York, New York, United States
Children's Hospital of Orange County
🇺🇸
Orange, California, United States
The University of North Carolina At Chapel Hill
🇺🇸
Chapel Hill, North Carolina, United States
Emory University Hospital
🇺🇸
Atlanta, Georgia, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Lurie Children's Hospital of Chicago
🇺🇸
Chicago, Illinois, United States
Boston Children's Hospital
🇺🇸
Boston, Massachusetts, United States
UPMC Children's Hospital of Pittsburgh
🇺🇸
Pittsburgh, Pennsylvania, United States
University of Texas Southwestern Medical Center
🇺🇸
Dallas, Texas, United States
Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
University of Utah
🇺🇸
Salt Lake City, Utah, United States
Kaiser Permanente Los Angeles Medical Center
🇺🇸
Los Angeles, California, United States
University of South Florida
🇺🇸
Tampa, Florida, United States