A Safety and Efficacy Study of AEGR-733 to Treat Homozygous Familial Hypercholesterolemia (FH)

Homozygous familial hypercholesterolemia (FH) is a serious life-threatening genetic disease. Total plasma cholesterol levels are generally over 500 mg/dl and markedly premature cardiovascular disease is the major consequence. Untreated, most patients develop atherosclerosis before age 20 and generally do not survive past age 30. The primary goal of therapy involves reducing cholesterol (specifically, LDL cholesterol) and preventing coronary artery disease. Unfortunately, patients with homozygous FH are minimally responsive or unresponsive to available drug therapy and thus there are limited treatment options. The current standard of care is LDL apheresis, a physical method of removing the plasma of LDL cholesterol which can transiently reduce cholesterol by more than 50%. However, there is rapid re-accumulation of LDL cholesterol in plasma, and therefore apheresis has to be repeated frequently (every 1-2 weeks) and requires 2 separate sites for IV access. Although anecdotally this procedure may delay the onset of atherosclerosis, it is laborious, expensive, and not readily available. Furthermore, although it is a procedure that is generally well tolerated, the fact that it needs frequent repetition and IV access can be challenging for many of these young patients. Therefore, there is a tremendous unmet medical need for new medical therapies for this orphan disease.

AEGR-733 is a novel oral therapeutic agent for hypercholesterolemia. Its mechanism involves inhibition of microsomal triglyceride transfer protein, resulting in a reduction of LDL cholesterol. Earlier studies in patients with homozygous FH reveal AEGR-733 is highly effective in lowering LDL cholesterol, yet long term safety and efficacy need to be established.

• AEGR-733 (Drug), also known as lomitapide, BMS-201038: 5-80 mg daily by mouth for 1.5 yrs

Primary outcomes

• Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) [Baseline and Week 26]: Percent change from Baseline in LDL-C

Secondary outcomes

• Percent Change From Baseline in Total Cholesterol (TC) [Baseline and Week 26]: Percent change from Baseline in TC
• Percent Change From Baseline for Apolipoprotein B (Apo B) [Baseline and Week 26]: Percent change from Baseline for Apo B
• Percent Change From Baseline in Triglycerides [Baseline and Week 26]: Percent change from Baseline in triglycerides
• Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) [Baseline and Week 26]: Percent change from Baseline in HDL-C
• Percent Change From Baseline in Non-HDL-C [Baseline and Week 26]: Percent change from Baseline in non-HDL-C
• Percent Change From Baseline in Apolipoprotein AI (Apo AI) [Baseline and Week 26]: Percent change from Baseline in Apo AI
• Absolute Change From Baseline in Hepatic Fat Percent [Baseline and Week 78]: Absolute change from Baseline in hepatic fat percent
• Absolute Change From Baseline in Alanine Aminotransferase (ALT) [Baseline and Week 78]: Absolute change from Baseline in ALT
• Absolute Change From Baseline in Aspartate Aminotransferase (AST) [Baseline and Week 78]: Absolute change from Baseline in AST
• Absolute Change From Baseline in Total Bilirubin [Baseline and Week 78]: Absolute change from Baseline in total bilirubin
• Absolute Change From Baseline in Weight [Baseline and Week 78]: Absolute change from Baseline in weight

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Males and females at least 18 years of age
2. Diagnosis of functional homozygous FH by at least one (a-c) of the following clinical criteria:

   * documented functional mutation(s) in both LDL receptor alleles or alleles known to affect LDL receptor functionality OR
   * skin fibroblast LDL receptor activity less than 20% normal OR
   * untreated TC greater than 500 mg/dL AND TG less then 300 mg/dL AND both parents have documented TC greater than 250 mg/dL
3. Concurrent lipid lowering medication/apheresis must be stable for at least 6 weeks before the baseline visit and must remain stable for the first 26 weeks.
4. Body weight at least 40 kg and less than 136 kg
5. Negative screening pregnancy test if female of child-bearing potential (females of child-bearing potential and all males must be following a medically accepted form of contraception)
6. Subjects must be willing to comply with all study-related procedures

Exclusion Criteria:

1. Uncontrolled hypertension
2. History of chronic renal insufficiency
3. History of biopsy proven cirrhosis or abnormal LFTs at screening (AST or ALT greater than 2 x upper limit of normal and/or Total Bilirubin greater than or equal to 1.5 mg/dl unless patient has unconjugated hyperbilirubinemia due to Gilbert's syndrome)
4. Chronic hepatitis B or chronic hepatitis C
5. Any major surgical procedure occurring less than 3 months prior to the screening visit
6. Cardiac insufficiency defined by the NYHA classification as functional Class III or Class IV
7. Previous organ transplantation
8. History of a non-skin malignancy within the previous 3 years
9. Male subjects reporting more than 2 drinks per day or females reporting more than 1 drink per day (1 drink= 12 oz beer, 1 oz hard liquor, 5 oz wine).
10. Participation in an investigational drug study within 6 weeks prior to the screening visit
11. Known significant gastrointestinal bowel disease or malabsorption such as inflammatory bowel disease or chronic pancreatitis requiring use of daily pancreatic enzymes.
12. 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.
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, amiodarone, heavy acetaminophen use (4g/day greater than 3 x q week), methotrexate, tetracyclines,and tamoxifen
14. Documented diagnosis of any of the following pulmonary conditions: Asthma, Chronic Obstructive Pulmonary Disease (COPD), Idiopathic pulmonary fibrosis
15. Documented diagnosis of any of the following liver diseases: Nonalcoholic Steatohepatitis, Alcoholic liver disease, Autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson's disease, hemochromatosis, alpha 1 anti-trypsin deficiency.
16. Current use of corticosteroids or betaine

Participant flow

Outcome results

• Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) (Primary), Mean, Percent Change: Lomitapide Escalated -40.1 +/- 31.25
• Percent Change From Baseline in Total Cholesterol (TC) (Secondary), Mean, Percent Change: Lomitapide Escalated -36.4 +/- 28.2
• Percent Change From Baseline for Apolipoprotein B (Apo B) (Secondary), Mean, Percent Change: Lomitapide Escalated -39.4 +/- 30.01
• Percent Change From Baseline in Triglycerides (Secondary), Mean, Percent Change: Lomitapide Escalated -29.0 +/- 55.72
• Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) (Secondary), Median, Percent Change: Lomitapide Escalated -6.9 +/- 19.76
• Percent Change From Baseline in Non-HDL-C (Secondary), Mean, Percent Change: Lomitapide Escalated -40.0 +/- 29.66
• Percent Change From Baseline in Apolipoprotein AI (Apo AI) (Secondary), Mean, Percent Change: Lomitapide Escalated -6.5 +/- 16.12
• Absolute Change From Baseline in Hepatic Fat Percent (Secondary), Mean, Percent Hepatic Fat: Lomitapide Escalated 6.9 +/- 5.03
• Absolute Change From Baseline in Alanine Aminotransferase (ALT) (Secondary), Mean, U/L: Lomitapide Escalated 15.0 +/- 29.05
• Absolute Change From Baseline in Aspartate Aminotransferase (AST) (Secondary), Mean, U/L: Lomitapide Escalated 8.9 +/- 20.22
• Absolute Change From Baseline in Total Bilirubin (Secondary), Mean, mg/dL: Lomitapide Escalated 0.1 +/- 0.30
• Absolute Change From Baseline in Weight (Secondary), Mean, kg: Lomitapide Escalated -2.3 +/- 3.46

Adverse events

Time frame: First dose to 28 days post treatment

Serious adverse events by term

Other adverse events by term

• Cuchel M, Bloedon LT, Szapary PO, Kolansky DM, Wolfe ML, Sarkis A, Millar JS, Ikewaki K, Siegelman ES, Gregg RE, Rader DJ. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med. 2007 Jan 11;356(2):148-56. doi: 10.1056/NEJMoa061189. PMID 17215532
• Results publication: Cuchel M, Meagher E, Marais AD, et.al. Abstract 1077: A phase III study of microsomal triglyceride transfer protein inhibitor lomitapide (AEGR-733) in patients with homozygous familial hypercholesterolemia: interim results at 6 months. Circulation, Nov 2009; 120: S441
• Results publication: Larrey D, D'Erasmo L, O'Brien S, Arca M; Italian Working Group on Lomitapide. Long-term hepatic safety of lomitapide in homozygous familial hypercholesterolaemia. Liver Int. 2023 Feb;43(2):413-423. doi: 10.1111/liv.15497. Epub 2022 Dec 30. PMID 36520008
• Results publication: Averna M, Cefalu AB, Stefanutti C, Di Giacomo S, Sirtori CR, Vigna G. Individual analysis of patients with HoFH participating in a phase 3 trial with lomitapide: The Italian cohort. Nutr Metab Cardiovasc Dis. 2016 Jan;26(1):36-44. doi: 10.1016/j.numecd.2015.11.001. Epub 2015 Nov 11. PMID 26723464
• Results publication: Stefanutti C, Blom DJ, Averna MR, Meagher EA, Theron Hd, Marais AD, Hegele RA, Sirtori CR, Shah PK, Gaudet D, Vigna GB, Sachais BS, Di Giacomo S, du Plessis AM, Bloedon LT, Balser J, Rader DJ, Cuchel M; Phase 3 HoFH Lomitapide Study Investigators. The lipid-lowering effects of lomitapide are unaffected by adjunctive apheresis in patients with homozygous familial hypercholesterolaemia - a post-hoc analysis of a Phase 3, single-arm, open-label trial. Atherosclerosis. 2015 Jun;240(2):408-14. doi: 10.1016/j.atherosclerosis.2015.03.014. Epub 2015 Mar 14. PMID 25897792

• Mark Sumeray, MD, Study director, Aegerion Pharmaceuticals, Inc.
• Marina Cuchel, MD, PhD, Principal investigator, Univerity of Pennsylvania