Aegerion's Drug Lomitapide Should Receive FDA Approval

On October 17, 2012, the FDA will hold an advisory committee meeting for Aegerion's (NASDAQ:AEGR) drug lomitapide. At this meeting, a panel of medical and scientific experts will consider the benefits of lomitapide together with associated safety concerns. We reviewed the relevant medical and scientific literature and believe lomitapide has an impressive efficacy-to-safety ratio and should receive a positive vote at its upcoming advisory committee meeting.


Lomitapide is a once-a-day oral treatment for elevated cholesterol. Its initial target population is patients with a rare disorder called homozygous familial hypercholesterolemia (HoFH). These patients are genetically predisposed to abnormally high levels of blood cholesterol and, consequently, often experience serious cardiovascular events at an early age. Current treatment for the condition includes statins and other standard cholesterol-reducing drugs. However, due to extremely high levels of cholesterol, these therapies are inadequate. For example, HoFH patients typically have low density lipoprotein cholesterol (LDL-C) between 400 and 1,000 mg/dL. Statins only reduce this LDL-C level by about 30%, leaving patients well above the National Cholesterol Education Program LDL-C target of 100 mg/dL for high-risk patients. Lomitapide lowers LDL-C levels by about 50% and does so on top of alternative therapies. That is, patients who receive both a statin and lomitapide may benefit from an overall 65% reduction in LDL-C.

Lomitapide and alternative cholesterol-lowering therapies have this multiplicative relationship because lomitapide targets a unique step in the pathway for cholesterol production. As discussed below, through this novel approach, lomitapide offers an acceptable efficacy-to-safety profile to reduce cholesterol in HoFH patients. Specifically, we highlight three reasons why lomitapide should be approved.

1. Lomitapide treats high-need patients

HoFH patients have disrupted copies of both genes encoding the LDL receptor, which is a cell-surface receptor that removes cholesterol from the blood. In the absence of fully functional LDL receptors, blood cholesterol levels remain high. Notably, existing cholesterol-lowering drugs, such as statins, work in part by increasing the activity of LDL receptors. HoFH patients can be especially difficult to treat because they are less likely to experience this beneficial effect, and are sometimes actually intolerant to existing cholesterol-lowering drugs. The standard of care for HoFH patients is apheresis, whereby blood is drawn and cholesterol is removed in a process analogous to kidney dialysis. This procedure is expensive (~ $150,000 per year), uncomfortable, and offered at only about 40 medical centers in the United States. Given that HoFH patients usually receive apheresis multiple times per month, HoFH can have a significant adverse impact on quality of life. Treatment with lomitapide would likely markedly, if not completely, reduce the need for apheresis. As a testament to lomitapide's potential to effectively treat HoFH patients, the FDA provided approximately $1 million in funding for lomitapide's phase III clinical trial.

2. Lomitapide's most worrisome safety concern may be unwarranted

Patients on lomitapide develop elevated levels of hepatic (i.e. liver) fat. Notably, the causal links between a fatty liver and disease are not well understood. Nevertheless, this observation may be worrisome because excess lipid accumulation (resulting in a fatty liver) sometimes progresses to serious outcomes, such as cirrhosis, liver failure, and hepatocellular cancer. It is well known that statins and other cholesterol-reducing drugs can stress the liver, and lomitapide actually targets a liver enzyme--microsomal triglyceride transfer protein (MTTP). Thus, it is not entirely surprising that patients receiving lomitapide have elevated aminotransferase activity (a sign of potential liver stress) and some hepatic fat accumulation. However, for reasons outlined below, this so-called adverse effect may not be worthy of strong concern.

A related disease, abetalipoproteinemia, results from genetically defective genes for MTTP, the very protein whose activity lomitapide disrupts. Like patients treated with lomitapide, abetalipoproteinemia patients have high hepatic fat content. Yet, for these patients, hepatic fat accumulation does not obviously result in long-term liver disease, or even the fibrosis that typically precedes liver disease. This is important because it allays worry that lomitapide overly stresses the liver. In Aegerion's phase III trial, patients receiving lomitapide for greater than a year did not have any discernible liver complications. Furthermore, after treatment discontinuation, hepatic fat content in these patients returned to pre-trial levels, providing additional evidence that the liver remains highly functional.

3. Lomitapide's mode of delivery offers an advantage over the other prospective treatment for HoFH

Lomitapide is not the sole potential new treatment for HoFH. The day after Aegerion's advisory committee meeting for lomitapide, Isis Pharmaceuticals and its partner Genzyme, a subsidiary of Sanofi (NYSE:SNY), will have an advisory committee meeting for its cholesterol-reducing drug mipomersen. Isis's drug is an antisense RNA delivered to patients subcutaneously, once per week. Mipomersen targets RNA transcripts encoding the ApoB protein, an integral structural component of LDL-C, to reduce LDL-C levels by 25%. This is approximately half the reduction seen for lomitapide. Notably, antisense RNA therapy is a highly promising, albeit relatively unsubstantiated technology. Medical professionals remain uncertain about whether antisense RNA drugs are sufficiently specific for their targets. Due to resulting safety concerns, the FDA has approved only one antisense RNA therapy (to treat an intraocular disorder). While mipomersen is an intriguing, effective drug and we feel it will ultimately receive FDA approval, lomitapide offers an advantage because of its oral mode of delivery. If an HoFH patient were to have an adverse reaction, lomitapide therapy can be discontinued quickly. This is not the case for mipomersen, which has a long half-life within the body (nearly 30 days, contrasted to a single day for lomitapide).


From a scientific and medical perspective, lomitapide soundly treats HoFH, and we anticipate a supportive vote during its upcoming advisory committee meeting. In contrast to Amarin (NASDAQ:AMRN) and Horizon Pharma (NASDAQ:HZNP), Aegerion may be underbought ahead of its FDA event and therefore presents a promising investment opportunity.

This article was written and contributed by James C. Charity on behalf of Beacon VP Investments.

Disclosure: I am long AEGR. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.