Phenylketonuria Clinical Trial
Official title:
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
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.
Status | Recruiting |
Enrollment | 32 |
Est. completion date | July 31, 2027 |
Est. primary completion date | July 31, 2027 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 65 Years |
Eligibility | 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. |
Country | Name | City | State |
---|---|---|---|
Turkey | Investigational Site Number : 7920001 | Ankara | |
United States | Children's Hospital IMD Clinic Site Number : 8400015 | Aurora | Colorado |
United States | University of Florida-Genetics Site Number : 8400010 | Gainesville | Florida |
Lead Sponsor | Collaborator |
---|---|
Sanofi |
United States, Turkey,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Incidence of treatment-emergent adverse events (TEAEs) | From Baseline to Week 96 | ||
Secondary | 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 | ||
Secondary | 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 | ||
Secondary | 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 | ||
Secondary | 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 | ||
Secondary | 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 | ||
Secondary | 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 | ||
Secondary | Number of participants with abnormal laboratory chemistry values | From Baseline to Week 96 | ||
Secondary | 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 |
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