PAH Deficiency, Phenylketonurias
Conditions
Keywords
PKU, Phenylketonuria, PAH Deficiency, Hyperphenylalaninemia, Phenylalanine, Adeno Associated Virus, AAVHSC15
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.
Interventions
GENETICHMI-102
HMI-102 is an AAVHSC15 vector containing a functional copy of the human PAH gene
Sponsors
Homology Medicines, Inc
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 clinical laboratory values (Dose Escalation Phase) | Baseline to Week 52 | Change in serum chemistry values including liver function tests, hematology, and urinalysis |
| 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 |
| 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 |
| Change from baseline in Plasma Phe Concentration (Dose Escalation Phase) | Weeks 24-28 | Change from baseline in plasma Phe concentration during Weeks 24-28 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 and severity of treatment-emergent adverse events (TEAEs) (Dose Expansion Phase) | Baseline to Week 52 | Subjects with at least one TEAE or serious TEAE |
Other
| Measure | Time frame | Description |
|---|---|---|
| Phenylketonuria Quality of Life Questionnaire (PKU-QOL) | Baseline to Week 52 | Change in PKU-QOL |
Countries
United States
Outcome results
None listed