A Gene Therapy Study for Homozygous Familial Hypercholesterolemia (HoFH)
Purpose
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).
Condition
- Homozygous Familial Hypercholesterolemia (HoFH)
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- 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.
Exclusion Criteria
- Unwilling to wash out of the following lipid lowering therapies for the pre-specified time period: 1. niacin > 250 mg/day: within 6 weeks of baseline 2. fibrates: within 4 weeks of baseline 3. lomitapide: within 8 weeks of baseline 4. 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
Study Design
- Phase
- Phase 1/Phase 2
- Study Type
- Interventional
- Allocation
- Non-Randomized
- Intervention Model
- Sequential Assignment
- Intervention Model Description
- dose escalation
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental Cohort 1 |
2.5E12 (genome copies)/kg (kilogram) body weight (E means the exponential constant) |
|
|
Experimental Cohort 2 |
7.5E12 GC/kg body weight |
|
|
Experimental 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 |
|
More Details
- Status
- Terminated
- Sponsor
- REGENXBIO Inc.
Study Contact
Detailed Description
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.