A Gene Therapy Study for Homozygous Familial Hypercholesterolemia (HoFH)

Homozygous Familial Hypercholesterolemia (HoFH) Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02651675
• Other study ID #: FHGT002
• Secondary ID: P01HL059407
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: March 2016
• Est. completion date: November 27, 2020

Study information

• Verified date: June 2023
• Source: REGENXBIO Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 9
• Est. completion date: November 27, 2020
• Est. primary completion date: November 27, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Homozygous Familial Hypercholesterolemia
• Homozygous Familial Hypercholesterolemia (HoFH)
• Hypercholesterolemia
• Hyperlipoproteinemia Type II

Intervention

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

Locations

Country	Name	City	State
Canada	Montreal location	Montreal	Quebec
Italy	Palermo location	Palermo	PA
Italy	Rome location	Roma	RM
Netherlands	Rotterdam location	Rotterdam
United States	Boca Raton location	Boca Raton	Florida
United States	Kansas City Location	Kansas City	Kansas
United States	Nashville location	Nashville	Tennessee
United States	Philadelphia Location	Philadelphia	Pennsylvania
United States	Portland location	Portland	Oregon

Sponsors (2)

Lead Sponsor	Collaborator
REGENXBIO Inc.	National Heart, Lung, and Blood Institute (NHLBI)

Countries where clinical trial is conducted

United States,  Canada,  Italy,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With IP (Investigational Product) Related Adverse Events	Physical examinations; Clinical laboratory parameters; and adverse event reporting	Up to 24 weeks
Secondary	Percent Change in LDL-C	Percent change in LDL-C compared to baseline	18 weeks, 12 weeks for cohort 1 only, compared to baseline
Secondary	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
Secondary	Number of Participants With IP Related Adverse Events	Physical examinations; Clinical laboratory parameters; and adverse event reporting	up to 104 weeks
Secondary	Amount of Vector Shedding, Urine	Amount of virus secreted in urine	up to 104 weeks
Secondary	Amount of Vector Shedding, Plasma	Amount of virus secreted in plasma	up to 104 weeks