Patient case: 24-year-old female with familial hypercholesterolemia; genetic feature: PCSK9

Clinical trial: A Gene Therapy Study for Homozygous Familial Hypercholesterolemia (HoFH)

Summary: 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.

Detailed description: Subjects will be asked to participate in an optional kinetics study. Subjects who agree will be admitted to the research inpatient unit at University of Pennsylvania or selected sites for the LDL kinetics study prior to vector administration.
  The LDL kinetic assessment will be performed using a primed constant infusion of deuterated leucine for 12 hours with repeated blood draws up to 48 hours. 2- 14 days following the start of the leucine infusion, subjects will be admitted to the research inpatient unit at University of Pennsylvania where the AAV8.TBG.hLDLR gene therapy vector will be administered. Vital signs will be monitored frequently for 24 hours. Blood will be drawn for safety testing daily for 3 days up to 72 hours and then weekly up to 12 weeks. More comprehensive assessment of safety parameters will occur every 4 weeks up to 12 weeks. Twelve weeks after vector administration, subjects that participated in the first optional kinetics study will be re-admitted to the inpatient unit at University of Pennsylvania or selected sites for a repeat LDL kinetics study. After this visit subjects will be permitted to resume LDL apheresis and/or plasma exchange, and other lipid lowering treatments at the discretion of their caring physician. Subjects will have a safety visit with blood draw every 12 weeks up to 52 weeks, and will be followed with bi-annual telephone calls and annual lipid tests thereafter up to 260 weeks.

Eligibility: 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 administration
  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, valproate.
  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 AAV8.TBG.hLDLR.
  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 study.
  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.

Relevance to patient case: not relevant