A Gene Therapy Study for Homozygous Familial Hypercholesterolemia (HoFH)

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

TERMINATED

Clinical Phase

PHASE1/PHASE2

Total Enrollment

9 participants

Study Classification

INTERVENTIONAL

Study Start Date

2016-03-31

Study Completion Date

2020-11-27

Brief Summary

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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).

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Detailed Description

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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.

Conditions

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Homozygous Familial Hypercholesterolemia (HoFH)

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

SEQUENTIAL

dose escalation

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Cohort 1

2.5E12 (genome copies)/kg (kilogram) body weight (E means the exponential constant)

Group Type EXPERIMENTAL

AAV directed hLDLR gene therapy

Intervention Type GENETIC

AAV directed hLDLR gene therapy is a novel adeno-associated viral (AAV8) vector with human low-density lipoprotein receptor (hLDLR) gene

Cohort 2

7.5E12 GC/kg body weight

Group Type EXPERIMENTAL

AAV directed hLDLR gene therapy

Intervention Type GENETIC

AAV directed hLDLR gene therapy is a novel adeno-associated viral (AAV8) vector with human low-density lipoprotein receptor (hLDLR) gene

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

Group Type EXPERIMENTAL

AAV directed hLDLR gene therapy

Intervention Type GENETIC

AAV directed hLDLR gene therapy is a novel adeno-associated viral (AAV8) vector with human low-density lipoprotein receptor (hLDLR) gene

Interventions

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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

Intervention Type GENETIC

Eligibility Criteria

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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

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No