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

• Sponsor: Aegerion Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00730236
• Collaborator: FDA Office of Orphan Products Development (U.S. Fed)
• Enrollment: 29
• Locations: 10
• Arm: 1
• Duration (Months): 46
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Homozygous Familial Hypercholesterolemia	Drug: AEGR-733	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Study of Microsomal Triglyceride Transfer Protein (MTP) Inhibitor AEGR-733 in Patients With Homozygous Familial Hypercholesterolemia on Current Lipid-lowering Therapy
• Study Start Date: Dec 1, 2007
• Actual Primary Completion Date: Sep 1, 2010
• Actual Study Completion Date: Oct 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AEGR-733	Drug: AEGR-733; 5-80 mg daily by mouth for 1.5 yrs; Other Names: lomitapide BMS-201038

Outcome Measures

Primary Outcome Measures

1. Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) [Baseline and Week 26]

   Percent change from Baseline in LDL-C

Secondary Outcome Measures

1. Percent Change From Baseline in Total Cholesterol (TC) [Baseline and Week 26]

   Percent change from Baseline in TC

2. Percent Change From Baseline for Apolipoprotein B (Apo B) [Baseline and Week 26]

   Percent change from Baseline for Apo B

3. Percent Change From Baseline in Triglycerides [Baseline and Week 26]

   Percent change from Baseline in triglycerides

4. Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) [Baseline and Week 26]

   Percent change from Baseline in HDL-C

5. Percent Change From Baseline in Non-HDL-C [Baseline and Week 26]

   Percent change from Baseline in non-HDL-C

6. Percent Change From Baseline in Apolipoprotein AI (Apo AI) [Baseline and Week 26]

   Percent change from Baseline in Apo AI

7. Absolute Change From Baseline in Hepatic Fat Percent [Baseline and Week 78]

   Absolute change from Baseline in hepatic fat percent

8. Absolute Change From Baseline in Alanine Aminotransferase (ALT) [Baseline and Week 78]

   Absolute change from Baseline in ALT

9. Absolute Change From Baseline in Aspartate Aminotransferase (AST) [Baseline and Week 78]

   Absolute change from Baseline in AST

10. Absolute Change From Baseline in Total Bilirubin [Baseline and Week 78]

    Absolute change from Baseline in total bilirubin

11. Absolute Change From Baseline in Weight [Baseline and Week 78]

    Absolute change from Baseline in weight

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

1. 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.

2. Body weight at least 40 kg and less than 136 kg

3. 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)

4. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
2	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
3	Robarts Research Institute	London	Ontario	Canada	N6A 5K8
4	Lipid Clinic and University of Montreal Community Genomic Medicine Center	Chicoutimi	Quebec	Canada	G7H 5H6
5	Dipartimento di Medicina Clinica e Della Patalogie Emergenti	Palermo	Sicily	Italy
6	Medicina Interna Universitaria	Ferrara		Italy
7	Centro Universitario Dislipidemie	Milano		Italy
8	Dipartimento di Clinica e Terapia Medica	Roma		Italy
9	Cardiology Research	Bloemfontein		South Africa	9300
10	University of Capetown	Cape town		South Africa	7925

Sponsors and Collaborators

• Aegerion Pharmaceuticals, Inc.
• FDA Office of Orphan Products Development

Investigators

• Study Director: Mark Sumeray, MD, Aegerion Pharmaceuticals, Inc.
• Principal Investigator: Marina Cuchel, MD, PhD, Univerity of Pennsylvania

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.

• Responsible Party: Aegerion Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT00730236
• Other Study ID Numbers: AEGR-733-005 / UP1002; NCT00603161
• First Posted: Aug 8, 2008
• Last Update Posted: Mar 20, 2018
• Last Verified: Jan 1, 2013

• Additional relevant MeSH terms: Hyperlipoproteinemia Type II; Hypercholesterolemia

Study Results

Participant Flow

Recruitment Details	The study was performed from 18 Dec 2007 to 13 Oct 2011. A total of 11 medical clinics participated in the study.
Pre-assignment Detail	6-week Run-in Phase. Following screening, patients entered a 6-week Run-in Phase to stabilize their regimen of current lipid-lowering therapy(ies) and to be placed on a low-fat diet containing <20% energy from fat.

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	Lomitapide escalated with an initial oral dose of 5 mg/day for 2 weeks and then escalated at 4 week intervals to 60 mg/day. In rare situations (1 patient)who met strict safety and efficacy criteria could have their dose escalated to 80 mg/day.
Period Title: Overall Study
STARTED	29
COMPLETED	23
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	Lomitapide escalated with an initial oral dose of 5 mg/day for 2 weeks and then escalated at 4 week intervals to 60 mg/day. In rare situations (1 patient)who met strict safety and efficacy criteria could have their dose escalated to 80 mg/day.
Overall Participants	29
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	30.7 (10.64)
Sex: Female, Male (Count of Participants)
Female	13 44.8%
Male	16 55.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 6.9%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 3.4%
White	25 86.2%
More than one race	0 0%
Unknown or Not Reported	1 3.4%
Region of Enrollment (participants) [Number]
United States	7 24.1%
Canada	5 17.2%
South Africa	11 37.9%
Italy	6 20.7%

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)
Description	Percent change from Baseline in LDL-C
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

Intention To Treat (ITT) Population

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	Lomitapide escalated with an initial oral dose of 5 mg/day for 2 weeks and then escalated at 4 week intervals to 60 mg/day. In rare situations (1 patient)who met strict safety and efficacy criteria could have their dose escalated to 80 mg/day.
Measure Participants	29
Mean (Standard Deviation) [Percent Change]	-40.1 (31.25)

2. Secondary Outcome

Title	Percent Change From Baseline in Total Cholesterol (TC)
Description	Percent change from Baseline in TC
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	Lomitapide escalated with an initial oral dose of 5 mg/day for 2 weeks and then escalated at 4 week intervals to 60 mg/day. In rare situations (1 patient)who met strict safety and efficacy criteria could have their dose escalated to 80 mg/day.
Measure Participants	29
Mean (Standard Deviation) [Percent Change]	-36.4 (28.2)

3. Secondary Outcome

Title	Percent Change From Baseline for Apolipoprotein B (Apo B)
Description	Percent change from Baseline for Apo B
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	Lomitapide escalated with an initial oral dose of 5 mg/day for 2 weeks and then escalated at 4 week intervals to 60 mg/day. In rare situations (1 patient)who met strict safety and efficacy criteria could have their dose escalated to 80 mg/day.
Measure Participants	29
Mean (Standard Deviation) [Percent Change]	-39.4 (30.01)

4. Secondary Outcome

Title	Percent Change From Baseline in Triglycerides
Description	Percent change from Baseline in triglycerides
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	Lomitapide escalated with an initial oral dose of 5 mg/day for 2 weeks and then escalated at 4 week intervals to 60 mg/day. In rare situations (1 patient)who met strict safety and efficacy criteria could have their dose escalated to 80 mg/day.
Measure Participants	29
Mean (Standard Deviation) [Percent Change]	-29.0 (55.72)

5. Secondary Outcome

Title	Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C)
Description	Percent change from Baseline in HDL-C
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	Lomitapide escalated with an initial oral dose of 5 mg/day for 2 weeks and then escalated at 4 week intervals to 60 mg/day. In rare situations (1 patient)who met strict safety and efficacy criteria could have their dose escalated to 80 mg/day.
Measure Participants	29
Median (Standard Deviation) [Percent Change]	-6.9 (19.76)

6. Secondary Outcome

Title	Percent Change From Baseline in Non-HDL-C
Description	Percent change from Baseline in non-HDL-C
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	Lomitapide escalated with an initial oral dose of 5 mg/day for 2 weeks and then escalated at 4 week intervals to 60 mg/day. In rare situations (1 patient)who met strict safety and efficacy criteria could have their dose escalated to 80 mg/day.
Measure Participants	29
Mean (Standard Deviation) [Percent Change]	-40.0 (29.66)

7. Secondary Outcome

Title	Percent Change From Baseline in Apolipoprotein AI (Apo AI)
Description	Percent change from Baseline in Apo AI
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	Lomitapide escalated with an initial oral dose of 5 mg/day for 2 weeks and then escalated at 4 week intervals to 60 mg/day. In rare situations (1 patient)who met strict safety and efficacy criteria could have their dose escalated to 80 mg/day.
Measure Participants	29
Mean (Standard Deviation) [Percent Change]	-6.5 (16.12)

8. Secondary Outcome

Title	Absolute Change From Baseline in Hepatic Fat Percent
Description	Absolute change from Baseline in hepatic fat percent
Time Frame	Baseline and Week 78

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	Lomitapide escalated with an initial oral dose of 5 mg/day for 2 weeks and then escalated at 4 week intervals to 60 mg/day. In rare situations (1 patient)who met strict safety and efficacy criteria could have their dose escalated to 80 mg/day.
Measure Participants	29
Mean (Standard Deviation) [Percent Hepatic Fat]	6.9 (5.03)

9. Secondary Outcome

Title	Absolute Change From Baseline in Alanine Aminotransferase (ALT)
Description	Absolute change from Baseline in ALT
Time Frame	Baseline and Week 78

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	Lomitapide escalated with an initial oral dose of 5 mg/day for 2 weeks and then escalated at 4 week intervals to 60 mg/day. In rare situations (1 patient)who met strict safety and efficacy criteria could have their dose escalated to 80 mg/day.
Measure Participants	29
Mean (Standard Deviation) [U/L]	15.0 (29.05)

10. Secondary Outcome

Title	Absolute Change From Baseline in Aspartate Aminotransferase (AST)
Description	Absolute change from Baseline in AST
Time Frame	Baseline and Week 78

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	Lomitapide escalated with an initial oral dose of 5 mg/day for 2 weeks and then escalated at 4 week intervals to 60 mg/day. In rare situations (1 patient)who met strict safety and efficacy criteria could have their dose escalated to 80 mg/day.
Measure Participants	29
Mean (Standard Deviation) [U/L]	8.9 (20.22)

11. Secondary Outcome

Title	Absolute Change From Baseline in Total Bilirubin
Description	Absolute change from Baseline in total bilirubin
Time Frame	Baseline and Week 78

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	Lomitapide escalated with an initial oral dose of 5 mg/day for 2 weeks and then escalated at 4 week intervals to 60 mg/day. In rare situations (1 patient)who met strict safety and efficacy criteria could have their dose escalated to 80 mg/day.
Measure Participants	29
Mean (Standard Deviation) [mg/dL]	0.1 (0.30)

12. Secondary Outcome

Title	Absolute Change From Baseline in Weight
Description	Absolute change from Baseline in weight
Time Frame	Baseline and Week 78

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Lomitapide Escalated
Arm/Group Description	Lomitapide escalated with an initial oral dose of 5 mg/day for 2 weeks and then escalated at 4 week intervals to 60 mg/day. In rare situations (1 patient)who met strict safety and efficacy criteria could have their dose escalated to 80 mg/day.
Measure Participants	29
Mean (Standard Deviation) [kg]	-2.3 (3.46)

Adverse Events

Time Frame	First dose to 28 days post treatment
Arm/Group Title	Lomitapide Escalated
Arm/Group Description	Lomitapide escalated with an initial oral dose of 5 mg/day for 2 weeks and then escalated at 4 week intervals to 60 mg/day. In rare situations (1 patient)who met strict safety and efficacy criteria could have their dose escalated to 80 mg/day.
All Cause Mortality
	Lomitapide Escalated
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Lomitapide Escalated
	Affected / at Risk (%)	# Events
Total	3/29 (10.3%)
Cardiac disorders
Angina pectoris	1/29 (3.4%)
Coronary artery arteriosclerosis	1/29 (3.4%)
Acute coronary syndrome	1/29 (3.4%)
Infections and infestations
Lower respiratory tract infection	1/29 (3.4%)
Reproductive system and breast disorders
Menorrhagia	1/29 (3.4%)
Other (Not Including Serious) Adverse Events
	Lomitapide Escalated
	Affected / at Risk (%)	# Events
Total	23/29 (79.3%)
Blood and lymphatic system disorders
Anaemia	2/29 (6.9%)
Lymphadenopathy	2/29 (6.9%)
Cardiac disorders
Palpitations	3/29 (10.3%)
Angina pectoris	2/29 (6.9%)
Eye disorders
Conjunctivitis	2/29 (6.9%)
Gastrointestinal disorders
Diarrhoea	23/29 (79.3%)
Nausea	19/29 (65.5%)
Vomiting	10/29 (34.5%)
Dyspepsia	10/29 (34.5%)
Abdominal discomfort	9/29 (31%)
Abdominal pain	8/29 (27.6%)
Abdominal pain upper	5/29 (17.2%)
Constipation	6/29 (20.7%)
Flatulence	6/29 (20.7%)
Abdominal distension	5/29 (17.2%)
Rectal tenesmus	3/29 (10.3%)
Defaecation urgency	2/29 (6.9%)
Eructation	2/29 (6.9%)
Gastritis	2/29 (6.9%)
Gastrooesophageal reflux disease	2/29 (6.9%)
Gingivitis	2/29 (6.9%)
General disorders
Chest pain	7/29 (24.1%)
Fatigue	5/29 (17.2%)
Pyrexia	3/29 (10.3%)
Hepatobiliary disorders
Hepatic steatosis	2/29 (6.9%)
Infections and infestations
Influenza	6/29 (20.7%)
Nasopharyngitis	5/29 (17.2%)
Gastroenteritis	4/29 (13.8%)
Bronchitis	2/29 (6.9%)
Upper respiratory tract infection	2/29 (6.9%)
Injury, poisoning and procedural complications
Laceration	2/29 (6.9%)
Limb injury	2/29 (6.9%)
Thermal burn	2/29 (6.9%)
Investigations
Alanine aminotransferase increased	5/29 (17.2%)
Weight decreased	7/29 (24.1%)
Aspartate aminotransferase increased	2/29 (6.9%)
Transaminases increased	2/29 (6.9%)
Metabolism and nutrition disorders
Decreased appetite	2/29 (6.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/29 (6.9%)
Back pain	4/29 (13.8%)
Myalgia	2/29 (6.9%)
Pain in extremity	2/29 (6.9%)
Musculoskeletal pain	2/29 (6.9%)
Nervous system disorders
Headache	3/29 (10.3%)
Dizziness	3/29 (10.3%)
Paraesthesia	2/29 (6.9%)
Psychiatric disorders
Anxiety	2/29 (6.9%)
Depression	2/29 (6.9%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	4/29 (13.8%)
Nasal congestion	3/29 (10.3%)
Cough	2/29 (6.9%)
Epistaxis	2/29 (6.9%)
Vascular disorders
Hot flush	2/29 (6.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The CTAs generally envision a multisite publication, with the PI's right to publish individually if the pooled publication does not occur within 12 months of study completion. Sponsor has a 45 to 60 day review/approval period to request deletion of confidential information or to request limited deferral to protect its proprietary technology. In one case, the publication provision is more general, specifying that the Sponsor and clinical site will agree on the manner/terms of publication.