FDA Panel Recommends Approval of Lomitapide for Homozygous FH

October 18, 2012

BETHESDA, Massachusetts (Updated) — A US Food and Drug Administration (FDA) advisory panel voted 13 to 2 in favor of recommending approval of lomitapide (Aegerion Pharmaceuticals, Cambridge, MA) as an adjunct to a low-fat diet and other lipid-lowering drugs, with or without LDL apheresis, to reduce LDL-cholesterol levels in patients with homozygous familial hypercholesterolemia (FH).

The Endocrinologic and Metabolic Drugs Advisory Committee felt the drug was efficacious in reducing LDL cholesterol, and while panel members did have concerns about the potential for liver injury, including steatohepatitis in chronic long-term drug users, they felt that the benefits exceeded the risks, especially in a patient population with very limited treatment options.

Homozygous FH is an extremely rare genetic condition, affecting one in one million individuals in the US, or approximately 300 adults and children. During the meeting, committee members voiced concerns about how the drug would be used in the real world. For example, there were concerns about the use of lomitapide in children, but most important, there were concerns that patients with heterozygous FH or even statin-intolerant patients with elevated LDL-cholesterol levels would be treated with the drug.

Panel member Dr Edward Gregg (Centers for Disease Control and Prevention, Atlanta, GA) said that he was convinced of the drug's impressive efficacy, and while the liver risks of the drug are a concern, they were "trumped by the severity of the condition and the need for [treatment] options." He said, like all panel members, that postmarketing surveillance of the drug and the design of an outcome registry should be a critical component of approval.

Panel chair Dr Abraham Thomas (Henry Ford Hospital, Detroit, MI) also voted yes and noted that many physicians would be comfortable with future complications, such as a risk of liver disease, associated with increased longevity compared with the immediate or near risk of death associated the extreme LDL-cholesterol levels in patients with homozygous FH. "That being said, we definitively need to have adequate monitoring," commented Thomas.

Dr Jeffrey Schwimmer (University of California, San Diego), one of the two panel members who voted no, said he was concerned the drug would be used in children. As a pediatrician, he said he was not comfortable voting to approve a drug that had yet not been tested in young patients. Moreover, he is concerned about the potential for liver damage with lomitapide. Dr William Hiatt (University of Colorado School of Medicine, Aurora) was also concerned about liver toxicity with the drug.

"My level of concern is high, and in a broad population there is no doubt in mind that there will be severe liver toxicity occurring in a few patients," said Hiatt. For patients taking concomitant medications--and most homozygous FH patients will be taking other lipid-lowering drugs--it will be difficult to determine which drug is responsible for the adverse hepatic effects. "I would be prepared for a worst-case scenario here." On the whole, however, he said that "whatever is going in the liver" is not going to offset the cardiovascular benefits of lowering LDL-cholesterol levels.

Small Study to Base Approval

The recommendation for approval was based on a small phase 3 clinical study. In that trial, previously reported by heartwire , just 29 patients were exposed to lomitapide, with 23 patients exposed to the drug for one year, 15 patients exposed for two years, and five patients exposed for three years. At baseline, the mean LDL cholesterol in the homozygous FH patients was 336 mg/dL, and this was reduced 40.1% after 26 weeks of treatment, or down to 190 mg/dL.

Lomitapide is a first-in-class inhibitor of microsomal triglyceride transfer protein (MTP), an enzyme that is needed to assemble apolipoprotein B (apoB)-containing lipoproteins in enterocytes and hepatocytes. By inhibiting MTP, the drug prevents the synthesis of the precursors of the LDL particle.

The most common adverse events associated with lomitapide were gastrointestinal disorders, with 27 of the patients experiencing some form of diarrhea, nausea, vomiting, dyspepsia, or abdominal pain. In the extension study, three patients had one serious adverse event, with one patient having liver toxicity that led to drug . In total, 17% of patients had increased levels of alanine aminotransferase (ALT), 7% of patients had increased levels of aspartate aminotransferase (AST), and 7% of patients had increased transaminase levels.

The panel members were also in favor of the FDA's risk evaluation and mitigation strategy (REMS). With the REMS, access to lomitapide would be limited to patients with homozygous FH, and physicians would be educated on how to use the drug and how to monitor and prevent liver damage.