DFI17545

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.

Inclusion Criteria:

• Adult males, and females of non-child bearing potential, 18-65 years of age at the time of informed consent.

• Participants must have uncontrolled classical PKU due to PAH deficiency (despite Phe-restricted dietary management or Palynziq) in the judgement of the Investigator.

• Two historical plasma Phe values ≥ 600 μmol/L in the preceding 12 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.