FDA advisory panel votes in favor of lomitapide

By a 13-2 vote, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee today recommended approval of lomitapide in combination with a low-fat diet and other lipid-lowering medications to reduce LDL in patients with homozygous familial hypercholesterolemia.

Despite the outcome of the vote, panel members raised extensive concern over the drug’s hepatic safety.

Researchers evaluated the safety and efficacy of lomitapide (Aegerion Pharmaceuticals), a small-molecule inhibitor of microsomal triglyceride transfer protein (MTP). This action of MTP inhibition is thought to prevent the synthesis of chylomicrons and VLDL, which are precursors to LDL.

“Despite the lack of a comparison group, I feel convinced of the effect [of lomitapide] on the LDL cholesterol. How this will translate to clinical benefit in long-term safety issues remains a huge question. However, for this extremely rare condition, it seems sufficient. It seems like we have sufficient information to approve given the magnitude of the LDL change,” committee member Erica Brittain, PhD, of the NIH, who voted in favor of the drug, said during the meeting.

The recommended starting dose is 5 mg daily, and after 2 weeks, the dose can be increased to 10 mg based on safety and tolerability. The dosage may be increased to 20 mg, 40 mg and 60 mg at 4-week intervals thereafter for the orphan disease that has a prevalence of one in 1 million in the United States.

Background data

Lomitapide’s development process began more than 16 years ago when initial clinical development by Bristol-Myers Squibb was abandoned due to concerns about drug’s gastrointestinal tolerability, hepatic steatosis and preclinical observations.

Since then, researchers have tested lomitapide in a single-arm trial involving 29 patients with homozygous familial hypercholesterolemia and an extension study. This was followed by a 16-week phase 2 study that included six patients at the University of Pennsylvania, in addition to the five phase 2 clinical trials over 4 to 12 weeks.

In the phase 3 database, the researchers reported that 29 patients were exposed to lomitapide. Of those patients, 23 were administered lomitapide for at least 1 year, 15 patients for at least 2 years, and five patients for at least 3 years.

By week 26, mean LDL was 190 mg/dL, compared with 336 mg/dL at baseline (–40.1% change; P<.0001). Further data presented during the advisory committee meeting showed that, of the 29 patients involved, 20 experienced a ≥15% reduction in LDL from baseline to week 26; 19 saw a ≥25% reduction; and 14 achieved a ≥50% reduction in LDL. The effects on HDL and apolipoprotein B were also found to be significant.

Safety and efficacy

Although committee members recommended approval for the lomitapide, nearly all harbored serious concerns about severe adverse events, including hepatic steatosis, and the use in lower-risk populations such as those with heterozygous familial hypercholesterolemia. Additionally, committee members questioned whether or not the drug would be suitable for the pediatric population, as the clinical trials did not include children.

“In a broad population, there’s not a doubt in my mind there will be severe liver toxicity occurring in a few patients,” committee member William R. Hiatt, MD, FACP, of the University of Colorado School of Medicine, who voted in favor of the drug application, said during the meeting.

In the phase 3 trial, 11 of 29 patients (38%) experienced ALT >3 times the upper limit of the normal range. Seven patients experienced a peak of more than 5 times the upper limit of the normal range.

The mean absolute change in hepatic fat from baseline to week 26 showed an increase of 8.1% and an increase of 7.4% at week 78.

Committee member Jeffrey B. Schwimmer, MD, of the University of California, San Diego, who voted against the proposed drug application, said risk–benefit ratio was not strong enough, calling it a “trade-off” for some patients.

“I think that it’s a trade-off and there are going to be people for whom that trade-off does favor a drug like this. If there were better measures to target a population and stronger measures in the [Risk Evaluation and Mitigation Strategy] than were proposed, I could see the type of package that would lead me to vote in favor of this,” Schwimmer said during the meeting.

The committee members said strong education about the liver issues for providers diagnosing patients with this disease is necessary. They also suggest follow-up with the patients on this agent to include full liver panel done at baseline and plus GGT.

Moving forward

With a favorable vote to move forward, the committee proposed a Risk Evaluation and Mitigation Strategy (REMS) that would restrict access to the drug to medically appropriate patients only, and provide education to prescribers on the uses of lomitapide and the risks associated with liver damage. This would also include monitoring patients and certifications for physicians and pharmacies.

For more information:

EMDAC Clinical Briefing Document. NDA 203858.