A Gene Therapy Study for Homozygous Familial Hypercholesterolemia (HoFH)

Homozygous Familial Hypercholesterolemia (HoFH) is a rare genetic metabolic disorder
characterized by absent or severely reduced capacity to catabolize circulating LDL 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 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-humans 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.

Eligibility Criteria

Inclusion Criteria:

In order to be eligible to participate in this study, a subject must meet all of the
following 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 12 weeks after vector administration.
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

7. A baseline serum AAV8 NAb titer ≤ 1:10.

8. Subjects must be able to comprehend and be willing to provide a signed institutional
review board/ethics committee (IRB/EC) approved Informed Consent Form.

9. Subjects must be willing to comply with all study-related procedures and be available
for the duration of the study.

Exclusion Criteria

Subjects who meet any of the following exclusion criteria will not be eligible to
participate in the study:

1. Unwilling to wash out of the following lipid lowering therapies for the pre-specified
time period:

1. niacin > 250 mg/day: within 4 weeks of baseline

2. fibrates: within 4 weeks of baseline

3. Lomitapide: within 6 weeks of baseline

4. 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 surgery or 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. History of cirrhosis or chronic liver disease based on documented histological
evaluation or non-invasive imaging or testing.

6. Documented diagnosis of any of the following liver diseases:

1. Nonalcoholic steatohepatitis (biopsy-proven)

2. Alcoholic liver disease

3. Autoimmune hepatitis

4. Liver cancer

5. Primary biliary cirrhosis

6. Primary sclerosing cholangitis

7. Wilson's disease

8. Hemochromatosis

9. α1 anti-trypsin deficiency

7. Abnormal LFTs at screening (AST or ALT >2x upper limit of normal (ULN) and/or Total
Bilirubin of >1.5x ULN unless patient has unconjugated hyperbilirubinemia due to
Gilbert's syndrome).

8. Hepatitis B as defined by positive for HepB SAg, or Hep B Core Ab, and/or viral DNA

9. Chronic active Hepatitis C as defined by positive for HCV Ab and viral RNA.

10. History of alcohol abuse within 52 weeks.

11. Certain prohibited medications known to be potentially hepatotoxic, especially those
that can induce microvesicular or macrovesicular steatosis. These include but are not
limited to: acutane, amiodarone, HAART medications, heavy acetaminophen use (2g/day
more than 3 times a week), isoniazid, methotrexate, tetracyclines, tamoxifen,

12. Current use of systemic corticosteroids or active tuberculosis, systemic fungal
disease, or other chronic infection.

13. History of immunodeficiency diseases, including a positive HIV test result.

14. Chronic renal insufficiency defined as estimated GFR < 30 mL/min.

15. 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.

16. Previous organ transplantation.

17. 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 receiving

18. 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.

19. Serious or unstable medical or psychological conditions that, in the opinion of the
investigator, would compromise the subject's safety or successful participation in the

20. A baseline serum AAV8 NAb titer > 1:10.

21. Any other medical condition or finding that would make it not in the subject's best
interest to participate in the study

22. Study staff member or any direct family member.

Principal Investigator

Patrick Moriarty, MD

Study Contact

Julie-Ann Dutton, 913-588-4064, jdutton@kumc.edu

Estimated Completion Date

Tuesday, January 1, 2019

ClinicalTrials.gov #