Steep LDL Drop With Lomitapide in Homozygous FH: Phase 3 Trial Update

May 29, 2012

May 29, 2012 (Milan, Italy) — More details of the phase 3 study with a new drug for familial hypercholesterolemia (FH), lomitapide (Aegerion), showing large reductions in LDL, were presented at the European Atherosclerosis Society (EAS) 2012 Congress last weekend. Limited preliminary results of the study were released last year and reported then by heartwire .

Lomitapide is one of a cluster of new agents in development that offer the hope of achieving near-normal LDL levels in FH patients. Others include anti-proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) antibodies in development by Sanofi/Regneron and Amgen and the antisense agent mipomersen(Genzyme).

Presenting the latest data on lomitapide, Dr Marina Cuchel (University of Pennsylvania School of Medicine, Philadelphia) said: "These are results that a few years ago we could only dream about in homozygous FH patients."

EAS president Dr John Chapman (Hôpital de la Pitié-Salpêtrière, Paris, France) commented to heartwire : "These new drugs on the horizon for homozygous FH are not just promising: they are lifesaving. Homozygous FH is an incredibly severe disease. Life expectancy is very short. We need to the save the lives of these patients. These new drugs can help us achieve that goal."

Lomitapide is an oral inhibitor of the microsomal triglyceride transfer protein (MTP) enzyme that drives lipoprotein production and secretion. Phase 2 studies showed reduction in LDL of 50% to 60% in patients with homozygous FH, but the drug was also associated with a change in liver-fat content. Cuchel noted that this liver-fat effect appeared highly variable--some patients had no change in liver content, and others had a large increase. And there were other factors in some cases that could have influenced the effect, such as alcohol use, and in all cases liver-fat content returned to normal within a few months of drug discontinuation.

In the phase 3 study, lomitapide was titrated up to a maximum dose of 60 mg daily over 26 weeks, then patients were continued on the maximum tolerated dose for another 52 weeks. All patients were advised to eat a low-fat diet and had liver-function tests and liver-fat evaluation by MRI and spectroscopy.

Of 29 homozygous FH patients who started the trial, six discontinued--four because of adverse drug reactions, one withdrew consent, and one was noncompliant.

Average 40% Reduction in LDL

Results at 26 weeks showed an average 40% reduction in LDL with lomitapide. Those who completed the study had a mean reduction of LDL of 52%, with some patients who managed to take 40 to 60 mg achieving up to an 80% LDL reduction, Cuchel reported.

LDL fell from a baseline average of 330 mg/dL to 190 mg/dL at week 26. Eight patients reached levels below 100 mg/dL, and one patient even managed to get below 70 mg/dL.

Of 13 patients receiving LDL apheresis, three reduced the frequency of this intervention and three had stopped apheresis permanently by week 26. "This translates into a great increase in quality of life," Cuchel commented.

There were 23 patients who continued for the next 52-week drug-safety phase. During the whole 78-week treatment time they averaged a 32% LDL reduction. There was a small reduction in HDL, but this went back to baseline once the dose was stabilized, Cuchel noted.

Safety Results

Most patients experienced GI adverse events, but Cuchel said these were not serious. They were mainly mild to moderate diarrhea, nausea, or abdominal discomfort. The adverse events tended to be less during the later part of the trial, which Cuchel suggested meant that patients were adapting to the drug.

ADRs on Lomitapide

Reaction 0–26 weeks (n=29) 26–78 weeks (n=23)
Any 27 21
GI 27 17
Infections 15 10

Chapman said he did not believe the side effects would be a major issue. "Many of these patients are already being treated with LDL apheresis, where they have to be attached to a machine for three hours at a time, so a few stomachaches are not going to put them off too much."

Although liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were raised, "this did not occur on a substantial or sustained basis," Cuchel reported. Four patients experienced transient ALT levels greater than five times upper limit of normal, but this was reduced with dose interruption. Hepatic fat was raised but tended to stabilize between weeks 26 to 78.

Hepatic Fat Content in Patients on Lomitapide

Time (wk) Hepatic fat content (%)
Baseline 0.9
26 9
56 7.3
78 8.2

More Needs to Be Done to Identify FH Patients

Chapman called for more efforts to identify FH patients. "There are greater numbers of these patients than we realize. In many countries, the condition is not diagnosed. The incidence of homozygous FH is thought to be about one in a million, but in certain communities in Lebanon, South Africa, and Quebec it could be more like one in 100."

He added: "We have known that cholesterol is lethal in high concentration for 50 years. The problem is this message is not getting down to the primary-care physician. The diagnosis is often not made until the patient has had a cardiovascular event. That is far too late. Family physicians must seriously investigate the possibility that children of parents with premature cardiovascular disease may present with a severe form of FH. These patients at 20 have the arteries of an 80-year-old."

Chapman expects these new compounds to also be used for the treatment of heterozygous FH. This is estimated to affect about one in 500 individuals, but as it is so underdiagnosed it could actually be much more common, affecting as many as one in 200, thus being one of the most common human genetic diseases, he noted.

Asked whether lomitapide could also be used in non-FH patients who are finding it difficult to reach their LDL goals, Cuchel suggested this may be a possibility in the future. "There is a large unmet need for statin-intolerant patients. But right now the drug is being targeted initially for severe and uncontrolled FH patients," she said.


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