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

Completed

• Conditions: familial hypercholesterolaemia; 10021605

• Registration Number: NL-OMON47467
• Lead Sponsor: REGENXBIO Inc

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Last Update Posted: 23 April 2024

Recruitment & Eligibility

• Status: Completed
• Sex: Not specified
• Target Recruitment: 2

Inclusion Criteria

1. Male or female * 18 years of age.
2. Untreated and/or treated LDL-C levels and clinical presentation consistent with the
diagnosis of homozygous FH
3. Molecularly defined LDLR mutations at both LDLR alleles.
4. Concurrent allowed lipid lowering medication must be stable for * 4 weeks before the
baseline visit and must remain stable until 18 weeks after vector administration (or 4 weeks
post steroid termination). These include but are not limited to: statins, ezetimibe, bile acid
sequestrants, PCSK9 inhibitors, and LDL and/or plasma apheresis. Subjects on other
lipid-lowering medications are eligible for the study but must wash out of these medications
for the pre-specified time period.
5. Females of childbearing potential must have a negative pregnancy test at screening and
baseline visits and be willing to have additional pregnancy tests during the study.
6. Sexually active subjects (both female and male) must be willing to use a medically accepted
method of contraception from screening visit until 6 months after vector administration
7. A baseline serum AAV8 NAb titer * 1:10.

Exclusion Criteria

1. Unwilling to wash out of the following lipid lowering therapies for the pre-specified time
period:
a. niacin > 250 mg/day: within 6 weeks of baseline
b. fibrates: within 4 weeks of baseline
c. lomitapide: within 8 weeks of baseline
d. mipomersen: within 24 weeks of baseline
2. Heart failure defined by the NYHA classification as functional Class III with history of
hospitalization(s) within 12 weeks of the baseline visit or functional Class IV.
3. History within 12 weeks of the baseline visit of a myocardial infarction (MI), unstable
angina leading to hospitalization, coronary artery bypass graft surgery (CABG),
percutaneous coronary intervention (PCI), uncontrolled cardiac arrhythmia, carotid surgeryor stenting, stroke, transient ischemic attack, carotid revascularization, endovascular
procedure or surgical intervention.
4. Uncontrolled hypertension defined as: systolic blood pressure > 180 mmHg, diastolic blood
pressure > 95 mmHg.
5. Uncontrolled diabetes defined as HbA1c > 8.5% or an average fasting glucose * 160 mg/dl.
6. Known hypersensitivity to prednisone
7. History of cirrhosis or chronic liver disease based on documented histological evaluation
or non-invasive imaging or testing.
8. Documented diagnosis of any of the following liver diseases:
a. Nonalcoholic steatohepatitis (biopsy-proven)
b. Alcoholic liver disease
c. Autoimmune hepatitis
d. Liver cancer
e. Primary biliary cirrhosis
f. Primary sclerosing cholangitis
g. Wilson*s disease
h. Hemochromatosis
i. *1 anti-trypsin deficiency
9. Abnormal liver function tests (LFTs) at screening (AST or ALT > 2 × upper limit of normal
(ULN) and/or Total Bilirubin of * 1.5 × ULN unless patient has unconjugated
hyperbilirubinemia due to Gilbert*s syndrome).
10. Hepatitis B as defined by positive for HepB SAg, or Hep B Core Ab, and/or viral DNA
11. Chronic active Hepatitis C as defined by positive for HCV Ab and viral RNA.
12. History of chronic alcohol abuse within 52 weeks of the screening visit.
13. Certain prohibited medications known to be potentially hepatotoxic, especially those that
can induce microvesicular or macrovesicular steatosis. These include but are not limited to:
Accutane (isotretinoin), amiodarone, HAART medications, heavy acetaminophen use
(2 g/day more than 3 times a week), isoniazid, methotrexate, tetracyclines, tamoxifen, or
valproate.
14. Active tuberculosis, systemic fungal disease, or other chronic infection.
15. History of immunodeficiency diseases, including a positive HIV test result.
16. Chronic renal insufficiency defined as estimated GFR < 30 mL/min/1.73m2.
17. History of cancer within the past 5 years, except for adequately treated basal cell skin
cancer, squamous cell skin cancer, or in situ cervical cancer.
18. Previous organ transplantation.
19. Administration of an investigational drug within 12 weeks or 5 half-lives of the drug
(whichever is longer) prior to the screening visit and until 52 weeks after receivingAAV8.TBG.hLDLR. Subjects are not prohibited from receiving investigational drugs after
52 weeks.
20. Any major surgical procedure occurring less than 3 months prior to the screening visit, or
any planned future surgical procedure within 3 months of baseline.
21. Serious or unstable medical or psychological conditions that, in the opinion of th

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Primary Objectives<br /><br>To determine the safety of AAV8.TBG.hLDLR administration in patients with<br /><br>homozygous familial hypercholesterolemia (HoFH) as assessed by the number of<br /><br>reported adverse events, changes noted on physical examinations, and clinical<br /><br>laboratory parameters assessed up to 24 weeks post vector administration.</p><br>