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

NCT ID: NCT00730236

Last Updated: 2018-03-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 29 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-12-31
• Study Completion Date: 2011-10-31

Brief Summary

The goal of this trial is to study the effects of AEGR-733 on LDL cholesterol, other lipids as well as measures of safety over the long-term.

Detailed Description

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.

Conditions

Homozygous Familial Hypercholesterolemia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

AEGR-733

Group Type: EXPERIMENTAL

AEGR-733

Intervention Type: DRUG

5-80 mg daily by mouth for 1.5 yrs

Interventions

AEGR-733

5-80 mg daily by mouth for 1.5 yrs

Intervention Type: DRUG

Other Intervention Names

lomitapide; BMS-201038

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

FDA Office of Orphan Products Development

FED

Sponsor Role: collaborator

Aegerion Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mark Sumeray, MD

Role: STUDY_DIRECTOR

Aegerion Pharmaceuticals, Inc.

Marina Cuchel, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Univerity of Pennsylvania

Locations

Cedars-Sinai Medical Center

Los Angeles, California, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Robarts Research Institute

London, Ontario, Canada

Lipid Clinic and University of Montreal Community Genomic Medicine Center

Chicoutimi, Quebec, Canada

Dipartimento di Medicina Clinica e Della Patalogie Emergenti

Palermo, Sicily, Italy

Medicina Interna Universitaria

Ferrara, , Italy

Centro Universitario Dislipidemie

Milan, , Italy

Dipartimento di Clinica e Terapia Medica

Roma, , Italy

Cardiology Research

Bloemfontein, , South Africa

University of Capetown

Cape Town, , South Africa

Countries

United States; Canada; Italy; South Africa

References

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.

Reference Type: BACKGROUND

PMID: 17215532 (View on PubMed)

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

Reference Type: RESULT

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.

Reference Type: DERIVED

PMID: 36520008 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26723464 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25897792 (View on PubMed)

Other Identifiers

AEGR-733-005 / UP1002

Identifier Type: -

Identifier Source: org_study_id

NCT00603161

Identifier Type: -

Identifier Source: nct_alias