As Isis and Genzyme announced better-than-expected top-line results for their cholesterol-lowering mipomersen in homozygous familial hypercholesterolemia, some questions remain regarding the compound - a higher-than-usual dropout rate and the antisense drug candidate's effect on the liver.

Still, the drug candidate, which commanded a premium price from Genzyme in a well attended 2008 licensing auction, exhibits superior efficacy in a patient group with particularly high unmet need. It is expected to clear federal hurdles to launch in 2011, at the very least for the ultra-orphan indication of homozygous FH, which affects about 600 individuals in the U.S. and EU.

Depending on the results of ongoing Phase III studies, the firms also may file simultaneously for approval for severe hypercholesterolemia, a much-larger market of roughly 25,000 patients in the U.S. and EU (¹ Also see "Genzyme/Isis Expand Clinical Trial Program For Mipomersen" - Pink Sheet, 12 January, 2009.).

The homozygous FH patients in the current Phase III study, whose results were released May 20, were on the maximum tolerated dose of statins and other lipid-lowering therapies and had average baseline LDL-cholesterol readings greater than 400 mg/dL. Previous studies in small populations showed a significant reduction in LDL in patients already on cholesterol-lowering therapies versus placebo (² Also see "Isis VP-Corporate Development Kate Winkler Corcoran: An Interview With “The Pink Sheet” DAILY (Part 1 of 2)" - Pink Sheet, 18 July, 2007.).

Considering how the compound fared in earlier trials, it's no surprise that mipomersen turned in such outstanding results, meeting the primary endpoint with a 25 percent reduction in LDL cholesterol after 26 weeks of treatment versus 3 percent for patients on placebo (<0.001). the="" study="" was="" powered="" for="" a="" 20="" percent="" improvement="" over="" placebo,="" so="" company="" officials="" and="" investors="" were="" pleased="" with="" the="" results.="" it="" also="" met="" all="" secondary="" endpoints:="" reduction="" in="" apolipoprotein="" b,="" total="" cholesterol="" and="" non-hdl="" cholesterol,="" with="" all="" p-values="" less="" than="">

However, some concerns linger over the compound, especially the risk of liver damage. Elevated liver function tests were noted in Phase II, with the trend continuing in the current trial. While no patients met Hy's Law, one patient was dropped from the trial due to elevated liver transaminases.

Of 34 patients enrolled, 28 remained through the trial's end, for a 17.6 percent dropout rate. Other adverse events were consistent with earlier studies: injection site reactions and flu-like symptoms.

To further elucidate the LFT concern, Isis is conducting a randomized, placebo-controlled study of the effect of mipomersen on liver triglycerides in about 70 patients with high cholesterol levels. Those results are expected in mid-2010.

Genzyme paid $325 million upfront in January 2008 for exclusive rights to commercialize mipomersen worldwide. The drug candidate meets Genzyme's product profile of drugs for conditions with high unmet need that can thus command a high price in the market space (³ Also see "Genzyme, Isis Partner On Lipid Lowering Treatment Based On Antisense Technology" - Pink Sheet, 7 January, 2008.).

With the deal, Genzyme purchased five million shares of Isis common stock at $30 per share and paid a $175 million upfront licensing fee. Isis is paying $125 million in initial development costs. After that, Genzyme and Isis split the costs.

Isis is due to receive $50 million for approval of the compound in homozygous FH and $150 million for approval in heterozygous FH ($75 million each in the U.S. and Europe). Isis could see up to $375 million in milestone payments for approval in a non-FH indication and $250 million for a follow-on product. Genzyme and Isis plan to split profits on the drug.

Isis discovered the drug, an injectable small molecule that targets apolipoprotein B-100, through its second-generation antisense research. It is exploring methods to make the compound orally available.

During a recent R&D day, Genzyme said discussions with FDA have led it to believe that it can file an NDA in the second half of 2010 for both homozygous FH and severe hypercholesterolemia. The high unmet need in those spaces will allow the firm to charge a "significant premium in price," said John P. Butler, senior VP for Genzyme's cardiometabolic and renal businesses ( ⁴ Also see "Genzyme Plays Up Emerging Blood Cancer Business In R&D Review" - Pink Sheet, 1 May, 2009. , p. 8).

But getting a regulatory green light for the much larger commercial indications will require outcomes studies. In 2008, the firms changed their projected filing time for the broader indication of reduction of cholesterol in patients with hypercholesterolemia at high risk of cardiovascular events. They now plan to file for the high-risk indication in 2012, after results of outcomes studies are in hand.

- Pamela Taulbee (p.taulbee@elsevier.com)

Mipomersen Brings Better-Than-Expected Phase III Results, But Some Questions Linger

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