Clinical trial NCT03952156: Gene Therapy Clinical Study in Adult PKU
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Phenylketonurias
PAH Deficiency
Keywords: PKU
Phenylketonuria
PAH Deficiency
Hyperphenylalaninemia
Phenylalanine
Adeno Associated Virus
AAVHSC15
Lead sponsor: Homology Medicines, Inc
Sponsor class: INDUSTRY
First posted: 2019-05-16
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence and severity of treatment-emergent adverse events (TEAEs) (Dose Escalation Phase)
timeFrame: Baseline to Week 52
measure: Change from baseline in clinical laboratory values (Dose Escalation Phase)
timeFrame: Baseline to Week 52
measure: Change from baseline in 12-lead electrocardiograms (ECGs), vital signs, physical examinations (Dose Escalation Phase)
timeFrame: Baseline to Week 52
measure: Incidence of sustained plasma Phe concentration of ≤360 μmol/L at 28 weeks post dose (Dose Escalation Phase)
timeFrame: Week 28
measure: Change from baseline in Plasma Phe Concentration (Dose Escalation Phase)
timeFrame: Weeks 24-28
measure: Change from baseline in mean Plasma Phe Concentration (Dose Expansion Phase)
timeFrame: Weeks 24-28
Secondary outcomes:
measure: Incidence of plasma Phe concentration thresholds up to Week 28 post administration of HMI-102 (Dose Expansion Phase)
timeFrame: Baseline to Week 28
measure: Incidence of plasma Phe concentration thresholds up to Week 52 post administration of HMI-102 (Dose Expansion Phase)
timeFrame: Baseline to Week 52
measure: Change from baseline in total protein intake at Week 52 post-administration of HMI-102 (Dose Expansion Phase)
timeFrame: Week 52
measure: Incidence and severity of treatment-emergent adverse events (TEAEs) (Dose Expansion Phase)
timeFrame: Baseline to Week 52
Other outcomes:
measure: Phenylketonuria Quality of Life Questionnaire (PKU-QOL)
timeFrame: Baseline to Week 52
Locations:
city: Los Angeles
country: United States
facility: Kaiser Permanente Los Angeles Medical Center
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Chicago
country: United States
facility: Lurie Children's Hospital of Chicago
state: Illinois
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Chapel Hill
country: United States
facility: The University of North Carolina At Chapel Hill
state: North Carolina
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Children's Hospital of Pittsburgh
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: Boston Children's Hospital
name: Olaf A Bodamer, M.D.
role: PRINCIPAL_INVESTIGATOR
References: