Staff Writer

Aegerion Pharmaceuticals Inc. said preliminary data from an ongoing Phase III trial and top-line results of three Phase II trials all indicated that AEGR-733 lowers levels of low-density lipoprotein (LDL) cholesterol.

The ongoing Phase III trial is an open-label study of 25 patients with homozygous familial hypercholesterolemia, a rare genetic disorder involving extremely high cholesterol levels. In the study, patients are receiving escalating doses of AEGR-733 on top of their existing treatments, which often include high-dose statins and physical cleansing of LDL from the blood via apheresis.

Full results are expected in 2010, but initial data showed LDL reductions of more than 50 percent on top of the effects of the background treatments in most patients that had reached the maximum AEGR-733 dose of 60 mg per day. Aegerion's chief medical officer William Sasiela said that given the orphan indication, successful completion of the single open-label trial would be sufficient to support filing a new drug application.

After pursuing approval for AEGR-733 in familial hypercholesterolemia, Aegerion plans to advance the drug for dyslipidemia.

On Thursday, the Bridgewater, N.J.-based company also revealed top-line data from three Phase II dyslipidemia trials. The first study compared 5-mg and 10-mg doses of AEGR-733 as a monotherapy and combined with Lipitor (atorvastatin, Pfizer Inc.) to Lipitor alone and to placebo in 157 patients.

The second trial compared escalating doses of AEGR-733 plus Lipitor to Lipitor alone in 44 patients. The third study, in 260 patients, used magnetic resonance spectroscopy to evaluate hepatic fat levels during treatment with placebo, various doses of AEGR-733 as a monotherapy and combination dosing with Lipitor, Zetia (ezetimibe, Schering Plough Corp.) or fenofibrate.

Sasiela declined to provide specific data because Aegerion plans to publish or present its findings in the future. But he said the first two trials met their endpoints in terms of reducing LDL, while the third trial, which was designed to explore the effects of AEGR-733 on hepatic fat, also exceeded expectations.

At the high end of the doses in the trials, AEGR-733 reduced LDL by up to 35 percent when used as a monotherapy and by up to 66 percent when the drug was combined with Lipitor. The drug also induced reductions of up to 50 percent in triglycerides and up to 3 percent in weight.

Hepatic fat levels, which Sasiela said had been a concern at much higher doses in previous studies, were about 7 percent in the study - much lower than the 30 percent he cited as clinically significant.

Aegerion also is "in the process of addressing" FDA concerns about pulmonary phospholipidosis. AEGR-733 is a microsomal triglyceride transfer protein (MTP) inhibitor, and the agency last year instituted a partial clinical hold on all MTP inhibitor trials longer than six months and asked sponsors for preclinical studies.

The ongoing Phase III trial of AEGR-733 was exempted from the hold, and Sasiela noted that Aegerion has not seen "any signs of pulmonary issues" in clinical trials of its drug. He added that results in rats - the most sensitive species for pulmonary tests - were "mild to moderate."

Aegerion plans to start Phase III trials in dyslipidemia in the second half of next year. Yet the company has no plans to compete with statins, which Sasiela said "are and will be the foundation for lipid-lowering treatment."

Instead, the company plans to target the estimated 80 percent of high cardiovascular risk patients who fail to meet their target cholesterol levels using statins, including those who can't tolerate statins.

Another drug on a similar course is Isis Pharmaceuticals Inc.'s mipomersen, an antisense compound targeting apolipoprotein B-100. The drug is in two Phase III trials for homozygous and heterozygous familial hypercholesterolemia, and Isis plans to file for approval in 2010 and then expand into the broader high-risk dyslipidemia market.

Earlier this year, Isis signed a $1.9 billion deal for mipomersen with Genzyme Corp. (See BioWorld Today, Jan. 9, 2008.)

Aegerion, on the other hand, still holds the rights to AEGR-733, which it licensed from Bristol-Myers Squibb Co. through the University of Pennsylvania.

Senior Vice President and Chief Financial Officer William Lewis said the company has been "in dialogue on and off" with potential partners and he fully expects those discussions to accelerate in the wake of the Phase II and preliminary Phase III data.

Behind AEGR-733, Aegerion is in Phase II with hyperlipidemia drug AEGR-427, which was licensed from Bayer AG. Sasiela said the company is working on enhancing manufacturing consistency for the drug and plans to kick off more Phase II trials next year.