A Gene Therapy Study for Homozygous Familial Hypercholesterolemia (HoFH)

AAV8-mediated Low Density Lipoprotein Receptor (LDLR) Gene Replacement in Subjects With Homozygous Familial Hypercholesterolemia (HoFH)

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).

Study Overview

• Status: Terminated
• Conditions: Homozygous Familial Hypercholesterolemia (HoFH)
• Intervention / Treatment: Genetic: AAV directed hLDLR gene therapy

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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H1T1C8
      • Montreal location
• Italy
  • PA
    • Palermo, PA, Italy, 90127
      • Palermo location
  • RM
    • Roma, RM, Italy, 00161
      • Rome location
• Netherlands
  • Rotterdam, Netherlands, 3015 CE
    • Rotterdam location
• United States
  • Florida
    • Boca Raton, Florida, United States, 33434
      • Boca Raton location
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Kansas City Location
  • Oregon
    • Portland, Oregon, United States, 97239
      • Portland location
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Philadelphia Location
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Nashville location

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With IP (Investigational Product) Related Adverse Events	Physical examinations; Clinical laboratory parameters; and adverse event reporting	Up to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in LDL-C	Percent change in LDL-C compared to baseline	18 weeks, 12 weeks for cohort 1 only, compared to baseline
Percent Change in Lipid Parameters Compared to Baseline Values	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)	18 weeks, 12 weeks for cohort 1 only, compared to baseline
Number of Participants With IP Related Adverse Events	Physical examinations; Clinical laboratory parameters; and adverse event reporting	up to 104 weeks
Amount of Vector Shedding, Urine	Amount of virus secreted in urine	up to 104 weeks
Amount of Vector Shedding, Plasma	Amount of virus secreted in plasma	up to 104 weeks

Collaborators and Investigators

• Sponsor: REGENXBIO Inc.
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2016
• Primary Completion (Actual): November 27, 2020
• Study Completion (Actual): November 27, 2020

Study Registration Dates

• First Submitted: January 4, 2016
• First Submitted That Met QC Criteria: January 7, 2016
• First Posted (Estimated): January 11, 2016

Study Record Updates

• Last Update Posted (Actual): July 13, 2023
• Last Update Submitted That Met QC Criteria: June 21, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Atherosclerosis; cardiovascular disease; Gene therapy; Genetic Diseases; Metabolic Diseases; LDL Receptors; Rare diseases
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Hypercholesterolemia; Hyperlipoproteinemia Type II; Homozygous Familial Hypercholesterolemia
• Other Study ID Numbers: FHGT002; P01HL059407 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No