Vanderbilt Clinical Trials

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)	Genetic: AAV directed hLDLR gene therapy AAV directed hLDLR gene therapy is a novel adeno-associated viral (AAV8) vector with human low-density lipoprotein receptor (hLDLR) gene
Experimental Cohort 2	7.5E12 GC/kg body weight	Genetic: AAV directed hLDLR gene therapy AAV directed hLDLR gene therapy is a novel adeno-associated viral (AAV8) vector with human low-density lipoprotein receptor (hLDLR) gene
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	Genetic: AAV directed hLDLR gene therapy AAV directed hLDLR gene therapy is a novel adeno-associated viral (AAV8) vector with human low-density lipoprotein receptor (hLDLR) gene

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.