Mipomersen (ISIS-301012) is a 20-mer antisense chimeric phosphorothiate oligonucleotide that selectively targets apolipoprotein B (apoB), a protein critical to the synthesis and transport of LDL and VLDL cholesterol, both involved in the development of heart disease. It is in phase III clinical trials at Isis Pharmaceuticals for the subcutaneous treatment of familial hypercholesterolemia. The compound is also in phase II clinical development for the treatment of hypercholesterolemia, and in phase II in combination with simvastatin for the treatment of atherosclerosis in patients with high cholesterol. In June 2006, mipomersen received orphan drug status from the FDA for the treatment of homozygous familial hypercholesterolemia. In 2008, the compound was licensed by Isis to Genzyme for worldwide development and commercialization as a lipid-lowering treatment for high-risk cardiovascular patients.

Results reported late last year from a phase II clinical trial of mipomersen administered at 200 mg/week for 3 months in patients with routine high cholesterol on stable doses of statins showed that mipomersen treatment resulted in a 42% reduction in apoB and a 48% reduction in LDL-cholesterol, beyond reductions achieved with statin therapy alone. Furthermore, results of an integrated safety analysis including data from more than 250 subjects treated with mipomersen in phase I and phase II studies demonstrated that mipomersen was well tolerated, with no evidence of liver toxicity. The most common adverse event to date has been mild to moderate injection-site reactions.

In August 2008, Genzyme and Isis initiated a phase III study (NCT00706849) of mipomersen in patients with heterozygous familial hypercholesterolemia (heFH). This was the first of four new trials the companies plan to initiate by the end of this year. The trial will evaluate the safety and efficacy of mipomersen in patients who have heFH and coronary artery disease. The randomized, double-blind, placebo-controlled study will enroll around 100 patients at some 30 sites in the U.S. and Canada. Patients on a stable dose of other lipid-lowering agents are being randomized 2:1 to receive a 200 mg dose of mipomersen or placebo weekly for 26 weeks. The primary endpoint will be percent reduction in LDL cholesterol, and data are expected to be available in 2010. The initial indication to be sought for mipomersen will be for patients with homozygous FH, and enrollment in a phase III trial in this patient population is expected to be completed by the end of this year. Data are expected to be available in mid-2009 and a U.S. filing for this indication is anticipated during the second half of 2010.

Genzyme and Isis plan to begin three additional trials evaluating mipomersen's safety and efficacy in reducing LDL cholesterol in high-risk patients during the second half of 2008. These trials will include one for apheresis-eligible patients, and two for high-risk high cholesterol patients. All three have anticipated trial designs that include a 2:1 randomization ratio of a 200 mg dose of mipomersen or placebo weekly for 26 weeks. Data from the trials will inform the design of the morbidity and mortality outcome study for potential expansion of mipomersen's label to include a broader group of at-risk, high cholesterol patients on maximally tolerated, currently available therapies. Following the finalization in June of the mipomersen license and collaboration agreement between Genzyme and Isis, the mipomersen IND and all regulatory authority has been transferred to Genzyme. Genzyme plans to begin discussions with the FDA and regulatory authorities in Europe.