A Phase 1/Phase 2 Open-label Study to Evaluate the Safety, Tolerability, and Efficacy of a Single Intravenous Administration of SAR444836 in Adult Participants With Phenylketonuria

Study Overview
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Brief Summary
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This is a single group Phase 1/Phase 2, 1-arm, open-label study with SAR444836, an adeno-associated virus (AAV) vector-mediated gene transfer of human phenylalanine hydroxylase (PAH), for the treatment of adult participants with phenylketonuria (PKU) on a chronic, stable diet. The purpose of the study is to evaluate the safety and efficacy of SAR444836 in reducing phenylalanine (Phe) levels and in the elimination of a Phe restricted diet. Participants will receive a one-time intravenous (IV) administration of SAR444836. The study is constituted of 2 separate parts: a dose escalation part, and a dose expansion part where subsequent participants will be administered a safe and effective dose level identified during the dose escalation part. In both study parts, clinical and laboratory assessments will be collected to: a) assess the incidence of adverse events, and b) evaluate the effect of SAR444836 on reductions in blood Phe levels and maintenance of these Phe levels after elimination of a Phe restricted diet. The study duration will be approximately 102 weeks (approximately 2 years) for each participant and includes a 6-week screening phase and 96-week follow-up period after SAR444836 administration. There will be a total of 41 study visits. Many study visits may occur as remote visits and be performed by a qualified in-home service provider. Actual study duration for an individual participant may be longer than 102 weeks due to the administration of SAR444836 to participants in Stage 1A in a serial fashion, or other factors such as delays in scheduling study visits.

Official Title
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A Phase 1/Phase 2, Open-label, Dose-escalation, and Dose Expansion Study to Evaluate the Safety, Tolerability, and Efficacy of SAR444836, an Adeno-associated Viral Vector-mediated Gene Transfer of Human Phenylalanine Hydroxylase, in Adult Participants With Phenylketonuria

Conditions
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Phenylketonuria

Intervention / Treatment
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* Drug: SAR444836


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult males, and females of non-child bearing potential, 18-65 years of age at the time of informed consent. Participants who have the diagnosis of PKU due to PAH deficiency One historical plasma Phe value ≥ 600 μmol/L in the preceding 24 months while on Phe restricted diet therapy. Two plasma Phe values ≥ 600 μmol/L drawn at least 72 hours apart during the screening period while on Phe restricted diet therapy in the absence of an acute illness. Participant has the ability and willingness to maintain their present diet for the duration of the trial, unless otherwise directed as per protocol Body mass index (BMI) ≤ 35 kg/m2 Willingness to use effective methods of contraception. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Exclusion Criteria: Presence of neutralizing antibodies against the AAV SNY001 capsid Abnormal liver function laboratory testing evidenced by alanine aminotransferase (ALT)>1.5X upper limit normal (ULN), aspartate transaminase (AST)>1.5X ULN, alkaline phosphatase >1.5X ULN, Total and direct bilirubin >1.5X ULN (bilirubin levels above the laboratory's normal range are acceptable in individuals with a documented history or laboratory evidence of Gilbert's Disease) Any significant underlying liver disease or any of the following documented diagnoses, indicative of significant underlying liver disease: Portal hypertension; or Splenomegaly; or Hepatic encephalopathy Serum albumin measurement below the lower limit of normal of the laboratory OR AST-to-Platelet Ratio Index > 1.0 Serum creatinine >1.5X ULN Hemoglobin A1c >6.5% or fasting glucose >126 mg/dL Screening laboratory testing demonstrating any of the following: HIV; or active or prior hepatitis B virus (HBV) infection defined as positive test for hepatitis B surface antigen (HBsAg) or positive test for hepatitis B core antibody (total HBcAb) or detectable HBV DNA; or active hepatitis C virus (HCV) infection defined as positive test for hepatitis C antibody followed by detectable HCV RNA or if a participant is presently receiving (or has received within 6 months prior to screening) anti-viral therapy for hepatitis C Clinically significant, active bacterial, viral, fungal, or parasitic infection (based on Investigator's judgement) The above information is not intended to contain all considerations relevant to a potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAR444836<br>Participants will receive a single dose of SAR444836 on Day 1 | Drug: SAR444836<br>* Infusion pump, intravenous infusion (IV)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (TEAEs) |  | From Baseline to Week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with sustained plasma level of Phe<360 μmol/L for ≥4 weeks without dietary Phe restriction at Week 24 and Week 96 or End of Study following SAR444836 administration |  | From Baseline to Week 96 | 
| Change from baseline in plasma level of Phe at Week 24 and Week 96 or End of Study following SAR444836 administration |  | From Baseline to Week 96 | 
| Change from baseline in dietary protein intake at Week 24 and Week 96 or End of Study following SAR444836 administration |  | From Baseline to Week 96 | 
| Proportion of participants with sustained plasma level of Phe <600 μmol/L for ≥ 4 weeks without dietary Phe restriction at Week 24 and Week 96 or End of Study following SAR444836 administration |  | From Baseline to Week 96 | 
| Proportion of participants with sustained plasma level of Phe <120 μmol/L for ≥ 4 weeks without dietary Phe restriction at Week 24 and Week 96 or End of Study following SAR444836 administration |  | From Baseline to Week 96 | 
| Change from baseline in plasma Phe: Tyr ratio at Week 24 and Week 96 or End of Study following SAR444836 administration |  | From Baseline to Week 96 | 
| Number of participants with abnormal laboratory chemistry values |  | From Baseline to Week 96 | 
| Assessment of the duration of viral vector shedding of SAR444836 in sampling of urine, saliva, and semen at 4-week intervals following SAR444836 administration |  | From Baseline to Week 96 |