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A Gene Therapy Study for Homozygous Familial Hypercholesterolemia (HoFH)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02651675
Recruitment Status : Completed
First Posted : January 11, 2016
Last Update Posted : February 1, 2021
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
REGENXBIO Inc.

Study Description
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Brief Summary:
This first-in-human study is intended to evaluate the safety and preliminary effectiveness of AAV-based liver-directed gene therapy in the treatment of adults with Homozygous Familial Hypercholesterolemia (HoFH).

Condition or disease Intervention/treatment Phase
Homozygous Familial Hypercholesterolemia (HoFH) Biological: AAV directed hLDLR gene therapy Phase 1 Phase 2

Detailed Description:
Homozygous Familial Hypercholesterolemia (HoFH) is a rare genetic metabolic disorder characterized by absent or severely reduced capacity to catabolize circulating LDL 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 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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: AAV8-mediated Low Density Lipoprotein Receptor (LDLR) Gene Replacement in Subjects With Homozygous Familial Hypercholesterolemia (HoFH)
Actual Study Start Date : March 2016
Actual Primary Completion Date : November 27, 2020
Actual Study Completion Date : November 27, 2020

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: AAV directed hLDLR gene therapy
Single intravenous (IV) dose of human Low Density Lipoprotein Receptor (LDLR) Gene Therapy
 Biological: AAV directed hLDLR gene therapy
A novel adeno-associated viral (AAV) vector with human low-density lipoprotein receptor (hLDLR) gene


Outcome Measures
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Primary Outcome Measures :
  1. Number of participants experiencing investigational product-related adverse events [ Time Frame: Up to 24 weeks ]
    Physical examinations; Clinical laboratory parameters; and adverse event reporting


Secondary Outcome Measures :
  1. Percent change in in LDL-C [ Time Frame: 18 weeks, 12 weeks for cohort 1 only, compared to baseline. ]
    Percent change in LDL-C compared to baseline

  2. Percent change in lipid parameters compared to baseline values [ Time Frame: 18 weeks, 12 weeks for cohort 1 only, compared to baseline. ]
    total cholesterol (TC); non-high density lipoprotein cholesterol (non-HDL-C); HDL-C; fasting triglycerides (TG); overflow density lipoprotein cholesterol (VLDL-C); lipoprotein(a) (Lp(a)); apolipoprotein B (apoB) and apolipoprotein A-I (apo A-I)

  3. Number of participants experiencing investigational product-related adverse events [ Time Frame: up to 104 weeks ]
    Physical examinations; Clinical laboratory parameters; and adverse event reporting

  4. Amount of vector shedding [ Time Frame: up to 104 weeks ]
    Amount of virus secreted in urine and plasma


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • Molecularly defined LDLR mutations at both LDLR alleles.
  • A baseline serum AAV8 NAb 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 or ALT > 2 × upper limit of normal (ULN) and/or Total Bilirubin of > 1.5 × ULN
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02651675


Locations
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United States, Florida
Boca Raton location
Boca Raton, Florida, United States, 33434
United States, Kansas
Kansas City Location
Kansas City, Kansas, United States, 66160
United States, Oregon
Portland location
Portland, Oregon, United States, 97239
United States, Pennsylvania
Philadelphia Location
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
Nashville location
Nashville, Tennessee, United States, 37232
Canada, Quebec
Montreal location
Montreal, Quebec, Canada, H1T1C8
Italy
Palermo location
Palermo, PA, Italy, 90127
Rome location
Roma, RM, Italy, 00161
Netherlands
Rotterdam location
Rotterdam, Netherlands, 3015 CE
Sponsors and Collaborators
REGENXBIO Inc.
National Heart, Lung, and Blood Institute (NHLBI)
More Information
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Responsible Party: REGENXBIO Inc.
ClinicalTrials.gov Identifier: NCT02651675    
Other Study ID Numbers: FHGT002
P01HL059407 ( U.S. NIH Grant/Contract )
First Posted: January 11, 2016    Key Record Dates
Last Update Posted: February 1, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by REGENXBIO Inc.:
LDL Receptors
Gene therapy
Metabolic Diseases
Rare diseases
 Genetic Diseases
Atherosclerosis
cardiovascular disease
Additional relevant MeSH terms:
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Hyperlipoproteinemia Type II
Homozygous Familial Hypercholesterolemia
Hypercholesterolemia
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
 Metabolic Diseases
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Hyperlipoproteinemias