AAV8-mediated Low Density Lipoprotein Receptor (LDLR) Gene Replacement in Subjects With Homozygous Familial Hypercholesterolemia (HoFH)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 9
- 试验地点
- 9
- 主要终点
- Number of Participants With IP (Investigational Product) Related Adverse Events
研究概览
简要总结
This first-in-human study is intended to evaluate the safety and preliminary effectiveness of AAV (Adeno-associated virus)-based liver-directed gene therapy in the treatment of adults with Homozygous Familial Hypercholesterolemia (HoFH).
详细描述
Homozygous Familial Hypercholesterolemia (HoFH) is a rare genetic metabolic disorder characterized by absent or severely reduced capacity to catabolize circulating LDL (Low density lipoprotein) particles by the hepatic LDL receptor. As a consequence, HoFH subjects present abnormal total plasma cholesterol (LDL-C) levels, resulting in severe atherosclerosis often leading to early onset of cardiovascular disease. Early initiation of aggressive treatment for these patients is therefore essential. Unfortunately, despite existing therapies, treated LDL-C (Low density lipoprotein cholesterol) levels could remain well above acceptable levels. Thus, the functional replacement of the defective LDLR via AAV-based liver-directed gene therapy may be a viable approach to treat this disease and improve response to current lipid-lowering treatments. This first-in-human study is intended to evaluate the safety of this gene therapy investigational product and assess preliminary evidence of efficacy using plasma LDL-C levels as a surrogate biomarker for human LDLR transgene expression.
Subjects may be asked to participate in an optional kinetics study to assess the metabolic mechanism by which LDL-C is reduced.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female ≥ 18 years of age.
- •Untreated and/or treated LDL-C levels and clinical presentation consistent with the diagnosis of homozygous FH (Familial hypercholesterolemia)
- •Molecularly defined LDLR mutations at both LDLR alleles.
- •A baseline serum AAV8 NAb (Neutralizing antibody) titer ≤ 1:10.
排除标准
- •Unwilling to wash out of the following lipid lowering therapies for the pre-specified time period:
- •niacin > 250 mg/day: within 6 weeks of baseline
- •fibrates: within 4 weeks of baseline
- •lomitapide: within 8 weeks of baseline
- •mipomersen: within 24 weeks of baseline
- •History of cirrhosis or chronic liver disease based on documented histological evaluation or non-invasive imaging or testing.
- •Abnormal liver function tests (LFTs) at screening (AST (Aspartate aminotransferase) or ALT (Alanine aminotransferase) > 2 × upper limit of normal (ULN) and/or Total Bilirubin of > 1.5 × ULN
研究组 & 干预措施
Cohort 1
2.5E12 (genome copies)/kg (kilogram) body weight (E means the exponential constant)
干预措施: AAV directed hLDLR gene therapy (Genetic)
Cohort 2
7.5E12 GC/kg body weight
干预措施: AAV directed hLDLR gene therapy (Genetic)
Cohort 2 Expansion
7.5E12 GC/kg body weight
DSMB (Data Safety Monitoring Board) approved expansion of Dose 2 cohort, 3 additional subjects enrolled and received prophylactic corticosteroids
干预措施: AAV directed hLDLR gene therapy (Genetic)
结局指标
主要结局
Number of Participants With IP (Investigational Product) Related Adverse Events
时间窗: Up to 24 weeks
Physical examinations; Clinical laboratory parameters; and adverse event reporting
次要结局
- Number of Participants With IP Related Adverse Events(up to 104 weeks)
- Amount of Vector Shedding, Plasma(up to 104 weeks)
- Percent Change in LDL-C(18 weeks, 12 weeks for cohort 1 only, compared to baseline)
- Percent Change in Lipid Parameters Compared to Baseline Values(18 weeks, 12 weeks for cohort 1 only, compared to baseline)
- Amount of Vector Shedding, Urine(up to 104 weeks)