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
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 for a minimum duration of 5 years following SAR444836 administration, for each participant and includes a 6-week screening phase, a 96-week treatment follow-up period after SAR444836 administration, followed by an additional 3 years of long-term safety (and efficacy) monitoring.
There will be a total of 47 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 5 years due to the administration of SAR444836 to participants in Stage 1A in a serial fashion, the duration of the screening period, and/or other factors such as delays in scheduling study visits.
Eligibility
Sex
ALL
Min age
18 Years
Max age
65 Years
Healthy volunteers
No
Inclusion Criteria:
* Adult males, and females of non-childbearing 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 Post-treatment Follow-up Phase (through Week 96), 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.
Primary outcome measure(s)
Incidence of treatment-emergent adverse events (TEAEs) — From Baseline to Week 260
Trial sites (11)
Facility
City
Region
Status
University of California San Francisco- Site Number : 8400007
San Francisco
California
Children's Hospital IMD Clinic- Site Number : 8400015
Aurora
Colorado
University of Florida-Genetics- Site Number : 8400010
Gainesville
Florida
UHCMC- Site Number : 8400014
Cleveland
Ohio
UPMC Children's Hospital of Pittsburgh-4401 Penn Ave- Site Number : 8400018
Pittsburgh
Pennsylvania
Medical University of SC- Site Number : 8400004
Charleston
South Carolina
University of Texas- Site Number : 8400002
Houston
Texas
Investigational Site Number : 0320002
Ciudad Autonoma Buenos Aires
Buenos Aires
Hospital de Clinicas de Porto Alegre - HCPA- Site Number : 0760001
This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.
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