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
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- Sanofi
- 入组人数
- 32
- 试验地点
- 11
- 主要终点
- Incidence of treatment-emergent adverse events (TEAEs)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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:
- •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.
研究组 & 干预措施
SAR444836
Participants will receive a single dose of SAR444836 on Day 1
干预措施: SAR444836 (Drug)
结局指标
主要结局
Incidence of treatment-emergent adverse events (TEAEs)
时间窗: From Baseline to Week 260
次要结局
- Change from baseline in plasma level of Phe at Week 24, 48, and Week 96 or Early Termination Visit following SAR444836 administration(From Baseline to Week 96)
- Change from baseline in dietary protein intake at Week 24, 48, and Week 96 or Early Termination Visit following SAR444836 administration(From Baseline to Week 96)
- Proportion of participants with sustained plasma level of Phe<360 μmol/L for ≥4 weeks without dietary Phe restriction at Week 24, 48, and Week 96 or Early Termination Visit 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, 48, and Week 96 or Early Termination Visit 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, 48, and Week 96 or Early Termination Visit following SAR444836 administration(From Baseline to Week 96)
- Change from baseline in plasma Phe: Tyr ratio at Week 24, 48, and Week 96 or Early Termination Visit 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)