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 on Gene Therapy for Phenylketonuria (PKU)
Study Overview
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.
Eligibility Criteria
You may be eligible for this study if you meet the following criteria:
- Conditions: Phenylketonuria
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Age: Between 18 Years - 65 Years
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Gender: All
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.
This study investigates the use of an investigational medication delivered through a virus vector to treat adults with phenylketonuria (PKU). PKU is a genetic disorder where the body cannot break down an amino acid called phenylalanine, leading to its buildup in the body. The purpose of this study is to see if the investigational medication can safely lower phenylalanine levels and allow participants to stop following a strict diet that limits phenylalanine.
Participants will receive a one-time dose of the investigational medication through an IV. The study has two parts: first, the dose escalation part to find a safe dose, and then the dose expansion part where more participants receive the identified dose. Throughout the study, participants will have clinical and lab tests to check for side effects and to see how well the medication works in lowering phenylalanine levels.
- Who can participate
- Adults aged 18-65 years with uncontrolled classical PKU.
- Must have a body mass index (BMI) of 35 kg/m2 or less and be willing to maintain their current diet.
- Females must be of non-child bearing potential.
- Participants must have specific Phe levels as per study requirements - Study Details
- Participants will receive a one-time IV administration of the investigational medication.
- The study includes clinical and laboratory assessments to monitor safety and effectiveness. A placebo, which is an inactive substance, is not used in this study - Study Timelines and Visits: The study will last approximately 102 weeks.The study requires 41 visits
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