A Gene Therapy Study for Homozygous Familial Hypercholesterolemia (HoFH)

Phase 1

Terminated

• Conditions: Homozygous Familial Hypercholesterolemia (HoFH)
• Interventions: Genetic: AAV directed hLDLR gene therapy

• Registration Number: NCT02651675
• Lead Sponsor: REGENXBIO Inc.

Brief Summary

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).

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 Timeline

• Study First Submitted: 2016-01-04
• Study First Submitted QC: 2016-01-07
• Study First Posted: 2016-01-11
• Study Start: 2016-03
• Primary Completion: 2020-11-27
• Study Completion: 2020-11-27
• Results First Submitted: 2023-03-28
• Status Verified: 2023-06
• Results First Submitted QC: 2023-06-21
• Last Update Submitted: 2023-06-21
• Results First Posted: 2023-07-13
• Last Update Posted: 2023-07-13

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 9

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

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

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

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (9)

Kansas City Location; 🇺🇸 Kansas City, Kansas, United States

Palermo location; 🇮🇹 Palermo, PA, Italy

Portland location; 🇺🇸 Portland, Oregon, United States

Boca Raton location; 🇺🇸 Boca Raton, Florida, United States

Nashville location; 🇺🇸 Nashville, Tennessee, United States

Rome location; 🇮🇹 Roma, RM, Italy

Rotterdam location; 🇳🇱 Rotterdam, Netherlands

Montreal location; 🇨🇦 Montreal, Quebec, Canada

Philadelphia Location; 🇺🇸 Philadelphia, Pennsylvania, United States