Aegerion’s Lomitapide Gets Standard Review For Rare Genetic Cholesterol Disease

Aegerion is preparing for an advisory committee meeting after submitting its LDL-C lowering oral drug lomitapide to FDA for patients with homozygous familial hypercholesterolemia. The NDA was submitted ahead of that for Isis/Genzyme’s injectable competitor, mipomersen.

Aegerion Pharmaceuticals Inc. is receiving a standard 10-month FDA review for its just-submitted oral drug lomitapide – somewhat of a surprise given that the application is for the orphan indication of homozygous familial hypercholesterolemia, a rare genetic form of very high cholesterol with poor treatment options, execs explained during a March 6 earnings call.

Lomitapide is a microsomal triglyceride transfer protein inhibitor (MTP-I) that has been shown to significantly lower LDL-cholesterol in clinical studies as an add-on therapy, albeit at the cost of elevated liver enzymes and liver fat . The drug originally was developed by Bristol-Myers Squibb Co., which donated the candidate to University of Pennsylvania lipidologist Daniel Rader; it was ultimately licensed to Aegerion.

Applications were submitted to FDA and the European Medicines Agency for use of the small molecule as an add-on to diet and other lipid-lowering therapies in homozygous familial hypercholesterolemia (HoFH), the company announced March 5.

Patients with HoFH have LDL-C levels three to six times higher than normal and are at much higher risk of having a cardiovascular event and dying. Approximately 3,000 people have the condition in the U.S., with about the same number in Europe. Treatment options for HoFH are limited, consisting of statins – which are not effective enough for reaching LDL targets because the baseline is so high – and removal of cholesterol from the blood by mechanical filtration, or apheresis.

The company had expected and requested priority review from FDA, given the lack of effective treatments for the disease, but during the earnings call Aegerion explained that late on March 5 it received a form letter from FDA indicating a standard review.

Execs said that they have no clarity at this time regarding the reasons for denial of the faster review clock. Having just received the letter “literally yesterday,” the company has not had the opportunity to get an explanation, Martha Carter, Aegerion regulatory officer, said during the call.

Writing in a March 6 note, Jefferies analyst Eun Yang observed: “Much earlier-than-expected FDA designation of review timeline upon the receipt of the NDA (vs. normally upon acceptance of NDA) is surprising. Thus it appears to us that the [standard] review for lomitapide has been predetermined by the FDA prior to filing.”

Analysts questioned whether submission of a Risk Evaluation and Mitigation Strategy impacted the review designation, but Carter said the company does not believe it has held up the process. Aegerion submitted a complete REMS plan but has not made the details public.

Aegerion expects an advisory committee review will be held late in the third quarter. The company’s regulatory team will “now focus its efforts on preparing for an advisory committee meeting in the U.S. and responding to questions from the FDA and EU regulator as they conclude their reviews of our applications,” Carter said.

Pushing The Efficacy Bar

In the U.S., the timing of the lomitapide submission puts Aegerion ahead of Isis Pharmaceuticals Inc./Genzyme Corp.’s injectable Kynamro (mipomersen), which is also slated for a first quarter NDA submission for the same disease. Kynamro was submitted in Europe in July 2011.

Lomitapide and mipomersen represent a new wave of anti-cholesterol drugs making their way to market following Pfizer Inc.’s loss of exclusivity on its blockbuster statin Lipitor (atorvastatin). In an era in which cheap generics will be widely available and effective for most patients, drug developers are looking at the peripheries, focusing on developing treatments for patients who are genetically predisposed to having extremely high cholesterol and/or who can’t reach LDL-C targets with statins and other lipid-lowering therapies.

While the HoFH patient population is small, severe cholesterol disease is viewed by some sponsors as a gateway to treating larger patient populations. It may be possible to start with approval in a small population for whom the risk is very high without the need for an outcomes study, expanding later to broader groups.

Lomitapide inhibits transfer of triglycerides to apolipoprotein B, the main protein component of VLDL-C and LDL-C. This prevents the liver and intestines from producing and secreting lipoproteins and reduces circulating levels of LDL-C.

Isis/Genzyme’s competing once-weekly injectable antisense oligonucleotide mipomersen reduces production and secretion of lipoproteins from the liver by inhibiting synthesis of apo B. Per FDA’s request, the company is running a 12-month safety study to support approval in a larger population of patients with severe heterozygous FH, meaning the disease is inherited from one parent instead of both (Also see "Genzyme/Isis On Track To Submit Cholesterol Drug Mipomersen In 1H 2011" - Pink Sheet, 1 Sep, 2010.). Mipomersen has also been associated with elevated liver enzymes and liver fat.

The lomitapide application is supported by one pivotal, single-arm, open-label, dose-escalating Phase III study in 29 patients who had a mean LDL-C of 337 mg/dL (353 mg/dL for completers) and who were taking a variety of lipid-lowering therapies, including statins and apheresis in most cases. Patients were given up to 60 mg/day of lomitapide in addition to their other lipid-lowering treatment. According to final results reported in January, LDL-C was reduced 40.1% at week 26; 44% at week 56; and 38.4% at week 78 – all significant findings. The 56-week data from the Phase III trial were submitted to FDA, along with other data from preclinical and earlier stage clinical studies.

By comparison, in a placebo-controlled HoFH study of 51 patients, Isis’ mipomersen as an add-on to standard treatments cut LDL by 25% after 26 weeks of treatment, compared to 3% for placebo (Also see "Mipomersen Brings Better-Than-Expected Phase III Results, But Some Questions Linger" - Pink Sheet, 22 May, 2009.).

Aegerion CEO Marc Beer said during the call that in pre-NDA meetings with FDA, the company received reassurances that its “atypical” trial was adequate for approval. FDA also indicated that with exposure to 1,000 patients (from Phase I and II trials), the safety database supporting lomitapide was sufficient, Beer said.

In the lomitapide trial, mild-to-moderate gastrointestinal adverse events were the most commonly reported side effects. Three patients discontinued the study due to gastrointestinal adverse events and three withdrew consent.

Investigators reported that four patients had consecutive aminotransferase (ALT or AST) elevations of between five times to 11 times the upper limit of normal, but none dropped out due to liver function test results. At the 56-week mark, patients’ mean hepatic fat was 7.3% compared to 1.2% at baseline, rising to 8.2% at 78 weeks.

Expansion Plans In Sight

In addition to preparing for an advisory committee, Aegerion is “turning its attention to working with the HoFH community to identify patients, educate on the disease and increase awareness,” Leerink Swann analyst Joseph Schwartz said in a March 6 note.

The firm is also gearing up to expand lomitapide in additional patient populations, such as familial chylomicronemia, a disease associated with extremely high triglyceride levels.

“In 2012, we plan to focus our efforts and trials to expand indications and broaden patient populations. The clinical protocol for familial chylomicronemia, or FC, has been developed internally and we plan to seek FDA and EMA feedback prior to initiation of this trial later this year,” Beer said.

In a Jan. 9 note, Leerink’s Schwartz noted that “robust triglyceride lowering of 45% observed in HoFH opens up the possibility for AEGR to pursue familial chylomicronemia as a follow-on indication beyond HoFH.”

The company is also interested in getting a pediatric indication for the drug and is at work on a “sprinkle” formulation intended to ease pediatric use.