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 Details
Study Description
Brief 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 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: SAR444836 Participants will receive a single dose of SAR444836 on Day 1 |
Drug: SAR444836
Infusion pump, intravenous infusion (IV)
|
Outcome Measures
Primary Outcome Measures
- Incidence of treatment-emergent adverse events (TEAEs) [From Baseline to Week 96]
Secondary Outcome Measures
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- Number of participants with abnormal laboratory chemistry values [From Baseline to Week 96]
- 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]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Adult males, and females of non-child bearing potential, 18-65 years of age at the time of informed consent.
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Participants who have the diagnosis of PKU due to PAH deficiency
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One historical plasma Phe value ≥ 600 μmol/L in the preceding 24 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.
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Participant has the ability and willingness to maintain their present diet for the duration of the trial, unless otherwise directed as per protocol
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Body mass index (BMI) ≤ 35 kg/m2
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Willingness to use effective methods of contraception.
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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:
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Presence of neutralizing antibodies against the AAV SNY001 capsid
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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)
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Any significant underlying liver disease or any of the following documented diagnoses, indicative of significant underlying liver disease:
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Portal hypertension; or
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Splenomegaly; or
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Hepatic encephalopathy
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Serum albumin measurement below the lower limit of normal of the laboratory OR AST-to-Platelet Ratio Index > 1.0
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Serum creatinine >1.5X ULN
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Hemoglobin A1c >6.5% or fasting glucose >126 mg/dL
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Screening laboratory testing demonstrating any of the following:
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HIV; or
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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
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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
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Investigational Site Number: 7920001 | Ankara | Turkey | 06351 |
Sponsors and Collaborators
- Sanofi
Investigators
- Study Director: Clinical Sciences & Operations, Sanofi
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- DFI17545
- U1111-1271-1293
- 2022-501200-98