Isis Pharmaceuticals, Inc. (ISIS) and Genzyme Corp. (GENZ) recently announced the publication of phase III data on mipomersen in The Lancet. The data was published from a study that was conducted in patients with homozygous familial hypercholesterolemia (hoFH). 

Results, which were presented at the annual American Heart Association meeting in November 2009, showed that mipomersen met its primary endpoint. The candidate achieved a 25% reduction in low-density lipoprotein – cholesterol (LDL-C) in an intent-to-treat analysis. 

Besides meeting the primary endpoint, the study also met each of its secondary and tertiary endpoints, which included statistically significant reductions in apolipoprotein-B, total cholesterol, non- high-density lipoprotein (HDL) cholesterol, lipoprotein (a) [Lp(a)], very low density lipoprotein-cholesterol (VLDL-C) and triglycerides. 

Mipomersen is Isis’ lead pipeline candidate. It is an antisense drug that targets apolipoprotein B (apoB) -100, which is critical to the synthesis and transport of low density lipoprotein (LDL) or bad cholesterol. By potentially knocking out the apoB-100 protein via antisense technology, Isis scientists believe they can effectively lower the cholesterol of patients and reduce the risk of serious cardiovascular disease. 

Genzyme intends to file for approval in the U.S. and EU in the first half of 2011 for the treatment of patients with homozygous FH (hoFH), which represents a much smaller patient population. hoFH is a very rare condition that is estimated to affect about 1 in a million people. 

Given the novel mechanism and narrow initial market focus of homozygous (Ho) FH, the US Food and Drug Administration (FDA) granted mipomersen orphan drug status. 

Isis and Genzyme stated that the regulatory filing could also include patients with severe hypercholesterolemia. Results from an ongoing phase III study in patients with severe hypercholesterolemia are expected in mid-2010. 

Meanwhile, data from another phase III study involving hypercholesterolemic patients at high risk for coronary heart disease are expected in the same time-frame. 

We currently have a Neutral recommendation on Isis. While we remain positive on the company’s antisense technology, we are concerned about Isis’ dependence on mipomersen for future growth. A delay in the development and commercialization of the candidate would be a major setback for the company.

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