Clinical trial NCT02651675: A Gene Therapy Study for Homozygous Familial Hypercholesterolemia (HoFH)
Official title: AAV8-mediated Low Density Lipoprotein Receptor (LDLR) Gene Replacement in Subjects With Homozygous Familial Hypercholesterolemia (HoFH)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Homozygous Familial Hypercholesterolemia (HoFH)
Keywords: LDL Receptors
Gene therapy
Metabolic Diseases
Rare diseases
Genetic Diseases
Atherosclerosis
cardiovascular disease
Lead sponsor: REGENXBIO Inc.
Sponsor class: INDUSTRY
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2016-01-11
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: dose escalation
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Number of Participants With IP (Investigational Product) Related Adverse Events
timeFrame: Up to 24 weeks
Secondary outcomes:
measure: Percent Change in LDL-C
timeFrame: 18 weeks, 12 weeks for cohort 1 only, compared to baseline
measure: Percent Change in Lipid Parameters Compared to Baseline Values
timeFrame: 18 weeks, 12 weeks for cohort 1 only, compared to baseline
measure: Number of Participants With IP Related Adverse Events
timeFrame: up to 104 weeks
measure: Amount of Vector Shedding, Urine
timeFrame: up to 104 weeks
measure: Amount of Vector Shedding, Plasma
timeFrame: up to 104 weeks
Other outcomes:
Locations:
city: Boca Raton
country: United States
facility: Boca Raton location
state: Florida
city: Kansas City
country: United States
facility: Kansas City Location
state: Kansas
city: Portland
country: United States
facility: Portland location
state: Oregon
city: Philadelphia
country: United States
facility: Philadelphia Location
state: Pennsylvania
city: Nashville
country: United States
facility: Nashville location
state: Tennessee
city: Montreal
country: Canada
facility: Montreal location
state: Quebec
city: Palermo
country: Italy
facility: Palermo location
state: PA
city: Roma
country: Italy
facility: Rome location
state: RM
city: Rotterdam
country: Netherlands
facility: Rotterdam location
Study officials:
References: