When the Food and Drug Administration’s Endocrinologic and Metabolic Drugs Advisory Committee takes up the homozygous familial hypercholesterolemia therapy lomitapide on Oct. 17, the big question will be whether the company has enough data to convince regulators of the drug’s efficacy and safety, particularly in light of a liver toxicity signal that appears manageable but likely to set off warnings.
The lomitapide application, by Aegerion Pharmaceuticals, was supported by one single-arm, open-label, dose-escalating, phase III trial in 29 patients averaging 31 years of age with a mean LDL cholesterol of 337 mg/dL (353 mg/dL for the 23 completers), who already were on a variety of lipid-lowering therapies, including low-fat diet, statins, and removal of cholesterol from the blood via apheresis. In addition to the phase III data, Aegerion submitted a 1,000-patient safety database documenting patient exposure during phase I and phase II trials.
The company is asking to use the drug, which is administered orally in capsule form, as an add-on to diet and other lipid-lowering therapies in HoFH patients.
In the pivotal trial, patients were given up to 60 mg/day of lomitapide in addition to their other lipid-lowering treatment. In January, Aegerion reported 78-week data "consistent with earlier results," showing that baseline LDL cholesterol was reduced 40% on average at week 26, 44% at week 56, and 38% at week 75, all significant findings.
MTP-Is Block Lipoprotein Production
Homozygous familial hypercholesterolemia is a rare and challenging genetic disorder that affects an estimated 20,000 people in the United States and Europe. Patients inherit a mutation from both parents that triggers overproduction of atherogenic lipoproteins, which transport cholesterol through the bloodstream.
Lomitapide is the first of a new class of investigational lipid-lowering drugs known as microsomal triglyceride transfer protein inhibitors (MTP-Is). By blocking transfer of triglycerides to apolipoprotein B (the main protein component of LDL cholesterol), MTP-Is prevent the liver and intestines from producing and secreting lipoproteins, thus reducing circulating LDL levels.
Because of the unmet need, Aegerion, based in Cambridge, Mass., had asked for and anticipated 6-month priority review, but the FDA denied the request and defaulted to the regular 10 month user fee clock.
Potential Liver Tox May Have Raised a Flag
Mild to moderate gastrointestinal adverse events were the most commonly reported side effects in the lomitapide trial. Three patients discontinued the study because of GI events and three withdrew consent, all before week 26.
Perhaps of more concern to reviewers are reports that four of the remaining patients had consecutive aminotransferase elevations of 5-11 times the upper limit of normal during the first 56 weeks of the trial; during the final phase, no patients had consecutive elevations greater than 5 times ULN. Patients responded to temporary reductions in lomitapide dosing, and no one discontinued treatment because of liver function test elevations.
Potentially, the most problematic adverse effect associated with lomitapide is accumulation of liver fat. Hepatic fat content climbed from a mean baseline of 1.3% to 7.9% after 26 weeks of treatment, investigators reported at the American Heart Association meeting in 2009. In January, Aegerion reported that the 26-week average gain from a baseline of 1% was 9%, with 7.3% and 8.2% increases, respectively, at 56 and 78 weeks from a baseline of 1.2%.
Mipomersen
Also a first-in-class drug, mipomersen (Kynamro), an injectable anti-HoFH molecule from Isis Pharmaceuticals Inc. and partner Sanofi, works by preventing the formation of lipoproteins. The mipomersen New Drug Application was submitted March 29, a month after the lomitapide application was filed, but with the results of a 2-year, ongoing, open-extension study that followed patients from the phase III program.
Although elevated liver enzymes and dropout rates were problematic throughout mipomersen’s development, liver function apparently was not found to be a problem either in the phase III program (which tested the drug in different high-risk patient groups) or in the extension study (which followed 141 patients). Median liver-fat levels rose incrementally for the first year, but they plateaued and then fell to baseline as the liver adapted to the changes wrought by the medication, Genzyme said.
Although the FDA cannot compare lomitapide to another pending application, the experts on the advisory panel will almost certainly be familiar with the mipomersen profile.
Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.