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

Conditions: Phenylketonuria

Summary: 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 criteria:
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.