A Gene Therapy Study for Homozygous Familial Hypercholesterolemia (HoFH)

R

Regenxbio

Status and phase

Terminated
Phase 2
Phase 1

Conditions

Homozygous Familial Hypercholesterolemia (HoFH)

Treatments

Genetic: AAV directed hLDLR gene therapy

Study type

Interventional

Funder types

Industry
NIH

Identifiers

NCT02651675
P01HL059407 (U.S. NIH Grant/Contract)
FHGT002

Details and patient eligibility

About

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).

Full 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.

Enrollment

9 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose

Treatment

Allocation

Non-Randomized

Interventional model

Sequential Assignment

Masking

None (Open label)

9 participants in 3 patient groups

Cohort 1
Experimental group
Description:
2.5E12 (genome copies)/kg (kilogram) body weight (E means the exponential constant)
Treatment:
Genetic: AAV directed hLDLR gene therapy
Cohort 2
Experimental group
Description:
7.5E12 GC/kg body weight
Treatment:
Genetic: AAV directed hLDLR gene therapy
Cohort 2 Expansion
Experimental group
Description:
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
Treatment:
Genetic: AAV directed hLDLR gene therapy

Trial documents
2

Trial contacts and locations

9

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Data sourced from clinicaltrials.gov

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