Aegerion Pharmaceuticals Presents Data From Phase 3 Extension Study of JUXTAPID(TM) (lomitapide) Capsules in Homozygous Familial Hypercholesterolemia (HoFH) at AHA Scientific Sessions
- Category: Small Molecules
- Published on Tuesday, 19 November 2013 09:38
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CAMBRIDGE, MA, USA I November 18, 2013 I Aegerion Pharmaceuticals, Inc. (AEGR), a biopharmaceutical company dedicated to the development and commercialization of novel, life-altering therapies for patients with debilitating, often fatal, rare diseases, today presented data from its open-label Phase 3 extension study of JUXTAPID(TM) (lomitapide) capsules in patients with homozygous familial hypercholesterolemia (HoFH). The data were presented in a poster at the American Heart Association's Scientific Sessions taking place in Dallas.
Nineteen of 23 patients who completed the 78 week pivotal study entered the extension study and continued lomitapide at their individualized maintenance dose, with 17 (89%) completing 126 weeks of treatment. The primary efficacy endpoint of the extension study was mean percent change in low-density lipoprotein cholesterol (LDL-C) from baseline to Week 126. Baseline was determined at the beginning of the pivotal study (Week 0) after a six week run-in period during which patients were stabilized on their other lipid-lowering therapies. Patients remained on a stable regimen of lipid-lowering therapies during the 26-week efficacy phase of the pivotal study. Adjustments to concomitant lipid-lowering treatments were allowed after 26 weeks during the safety phase of the pivotal study and in the extension study. Mean LDL-C levels were reduced by 45.5% from baseline at week 126 (356 +/- 127 mg/dL vs. 189 +/- 120 mg/dL; P <0.001). Similar mean % reductions were observed for Apo B, non-HDL-C, and total cholesterol. On at least one time point during the study, an LDL-C of <=100 or <=70 mg/dL was achieved by 13 (68%) and nine (47%) patients, respectively.
|Mean percent change in lipid parameters at pivotal endpoint* (ITT Analysis)||Mean percent change in lipid parameters versus baseline in the pivotal phase 3 and long-term extension studies (Completer Analysis)|
|Mean change at Week 26, % (SD)||Mean change at Week 26, % (SD)||Mean change at Week 78, % (SD)||Mean change at Week 126, % (SD)|
|LDL-C||-40.1 (31.25)||-55.7 (21.3)||-50.8 (19.8)||-45.5 (31.4)|
|TC||-36.4 (28.2)||-49.8 (19.9)||-46.2 (18.8)||-43.2 (25.4)|
|Non-HDL-C||-40.0 (29.66)||-54.7 (20.3)||-51.0 (19.3)||-47.1 (27.8)|
|ApoB||-39.4 (30.01)||-54.1 (21.5)||-54.9 (17.0)||-53.6 (23.7)|
|* The primary endpoint of the pivotal study was mean % reduction in LDL-C at week 26 in the intention-to-treat (ITT) population (n=29) with last observation carried forward for the patients who discontinued prematurely. LDL-C values in the ITT population were 336 +/- 117 mg/dL at baseline and 190 +/- 104 mg/dL at week 26.|
The adverse event (AE) profile observed in the extension study was consistent with that observed during the pivotal trial. Gastrointestinal symptoms were the most common AE, reported in 63% (12/19) of patients in the extension study. Transient aminotransferase elevations (ALT or AST) >=3x the upper limit of normal (ULN) occurred in nine of the patients who completed Week 126 of the extension study either in the pivotal phase or the extension phase or both, including five patients who had elevations >=5x ULN. Of these patients, one patient had an ALT elevation of 24x ULN that was reversible with temporary suspension of lomitapide, and a second patient had a reversible ALT elevation of >=10--20x ULN following co-administration of other drugs that may precipitate liver injury or interact with lomitapide. One patient who used excessive alcohol was withdrawn due to persistent ALT elevations >=5x ULN. No Hy's law cases were reported. One sudden cardiac death occurred in a 58 year old patient with known coronary artery disease. Median hepatic fat levels (measured by nuclear magnetic resonance spectroscopy) were 6.5% at entry into the extension phase and remained stable over the additional two year period (median 7.7% (range 0.6, 35.2)).
Results presented were through a data cut-off of December 31, 2012. The study is currently ongoing with a mean duration of treatment of 3.3 years and maximum duration of treatment of 4.5 years.
"We are encouraged by the data which show evidence of sustained efficacy and a similar safety profile to that observed up to 78 weeks of treatment with lomitapide in adult HoFH patients," said Mark Sumeray, MD, MS, FRCS, Chief Medical Officer of Aegerion.
Poster 16516 titled, "Sustained LDL-C Lowering and Stable Hepatic Fat Levels in Patients with Homozygous Familial Hypercholesterolemia Treated with the Microsomal Triglyceride Transfer Protein Inhibitor, Lomitapide: Results of an Ongoing Long-Term Extension Study" can be viewed during the poster session on Monday, November 18, 2013 from 3:00pm to 4:30pm CST.
HoFH is a serious, rare genetic disease that impairs the function of the receptor responsible for removing low-density lipoprotein cholesterol (LDL-C or "bad" cholesterol) from the body. A loss of LDL receptor function results in extreme elevation of blood cholesterol levels. HoFH patients often develop premature and progressive atherosclerosis, a narrowing or blocking of the arteries.
Lomitapide, marketed as JUXTAPID(TM) in the U.S. and LOJUXTA(R) in the EU, is a microsomal triglyceride transfer protein (MTP) inhibitor and works independently of the LDL receptor functionality. JUXTAPID is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B) and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH). The safety and effectiveness of lomitapide have not been established in patients with hypercholesterolemia who do not have HoFH. The effect of lomitapide on cardiovascular morbidity and mortality has not been determined.
Important Safety Information, including BOXED WARNING which states:
WARNING: RISK OF HEPATOTOXICITY
JUXTAPID can cause elevations in transaminases. In the JUXTAPID clinical trial, 10 (34%) of the 29 patients treated with JUXTAPID had at least one elevation in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >=3x upper limit of normal (ULN). There were no concomitant clinically meaningful elevations of total bilirubin, international normalized ratio (INR), or alkaline phosphatase.
JUXTAPID also increases hepatic fat, with or without concomitant increases in transaminases. The median absolute increase in hepatic fat was 6% after both 26 and 78 weeks of treatment, from 1% at baseline, measured by magnetic resonance spectroscopy. Hepatic steatosis associated with JUXTAPID treatment may be a risk factor for progressive liver disease, including steatohepatitis and cirrhosis.
Measure ALT, AST, alkaline phosphatase, and total bilirubin before initiating treatment and then ALT and AST regularly as recommended. During treatment, adjust the dose of JUXTAPID if the ALT or AST are >=3x ULN. Discontinue JUXTAPID for clinically significant liver toxicity.
Because of the risk of hepatotoxicity, JUXTAPID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the JUXTAPID REMS PROGRAM.
- Concomitant administration of moderate or strong CYP3A4 inhibitors
- Moderate or severe hepatic impairment or active liver disease including unexplained persistent elevations of serum transaminases
WARNINGS AND PRECAUTIONS
JUXTAPID can cause elevations in transaminases and hepatic steatosis. Although cases of hepatic failure have not been reported, there is concern that JUXTAPID could induce steatohepatitis, which can progress to cirrhosis over several years. Modify the dose of JUXTAPID if elevations of transaminases are observed and discontinue JUXTAPID for persistent or clinically significant elevations. If transaminase elevations are accompanied by clinical symptoms of liver injury, such as nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like-symptoms, increases in bilirubin >=2x ULN, or active liver disease, discontinue treatment with JUXTAPID and identify the probable cause. Use JUXTAPID with caution when co-administered with agents known to be hepatotoxic. Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury.
Measure ALT, AST, alkaline phosphatase, and total bilirubin before initiating treatment. During the first year, measure liver-related tests (ALT and AST, at a minimum) prior to each increase in dose or monthly, whichever occurs first. After the first year, do these tests at least every 3 months and before any increase in dose.
Females of reproductive potential should have a negative pregnancy test before starting JUXTAPID and should use effective contraception during therapy with JUXTAPID.
Given its mechanism of action in the small intestine, JUXTAPID may reduce the absorption of fat-soluble nutrients. Patients treated with JUXTAPID should take daily supplements that contain 400 international units vitamin E and at least 200 mg linoleic acid, 210 mg alpha-linolenic acid (ALA), 110 mg eicosapentaenoic acid (EPA), and 80 mg docosahexaenoic acid (DHA).
Gastrointestinal adverse reactions are common and may lead to treatment discontinuation. To reduce the risk of gastrointestinal adverse reactions, patients should adhere to a low-fat diet supplying less than 20% of energy from fat and the dosage of JUXTAPID should be increased gradually.
Combination with CYP3A4 inhibitors increases exposure to lomitapide. Strong and moderate CYP3A4 inhibitors should not be used with JUXTAPID. JUXTAPID dosage should not exceed 30 mg daily when used concomitantly with weak CYP3A4 inhibitors.
Due to risk of myopathy associated with simvastatin or lovastatin, doses of these agents should be limited when co-administered with JUXTAPID.
JUXTAPID increases the plasma concentrations of warfarin. Increases or decreases in the dose of JUXTAPID may lead to supra- or subtherapeutic anticoagulation, respectively. Patients taking warfarin should undergo regular monitoring of the INR, especially after any changes in JUXTAPID dosage.
Avoid use of JUXTAPID in patients with rare hereditary disorders of galactose intolerance.
The most common adverse reactions were gastrointestinal, reported by 27 (93%) of 29 patients. Adverse reactions reported by >=8 (28%) or more patients in the HoFH clinical trial included diarrhea, nausea, vomiting, dyspepsia and abdominal pain. Other common adverse reactions, reported by 5 to 7 (17-24%) patients, included weight loss, abdominal discomfort, abdominal distension, constipation, flatulence, increased ALT, chest pain, influenza, nasopharyngitis, and fatigue.
About Aegerion Pharmaceuticals
Aegerion Pharmaceuticals is a biopharmaceutical company dedicated to the development and commercialization of innovative, life-altering therapies for patients with debilitating, often fatal, rare diseases. For more information about the company, please visit www.aegerion.com.
SOURCE: Aegerion Pharmaceuticals