Data from Mipomersen Phase 3 Trial in heFH Patients Presented at ESC

Genzyme Corp.Genzyme Corp. (NASDAQ: GENZ) and Isis Pharmaceuticals Inc. (NASDAQ: ISIS) announced that data from the phase 3 study of mipomersen in patients with heterozygous familial hypercholesterolemia (heFH) were presented at the European Society of Cardiology's Congress 2010 in Stockholm, Sweden. The study met its primary endpoint with a 28 percent reduction in LDL-cholesterol, compared with an increase of 5 percent for placebo (p<0.001). The trial also met all of its secondary and tertiary endpoints. Frequently observed adverse events were injection site reactions, flu-like symptoms and elevations in liver transaminases, as seen in other mipomersen studies.

This double-blind, placebo-controlled phase 3 study was designed to test the efficacy and safety of adding mipomersen to stable lipid-lowering therapy. Patients were randomized 2:1 to receive a 200 mg dose of mipomersen or placebo weekly for 26 weeks. The trial included 124 adult heFH patients at 26 sites in the United States and Canada. All of the patients had pre-existing coronary artery disease and LDL-C levels greater than 100 mg/dL, and were taking a maximally tolerated dose of a statin, as well as additional lipid-lowering drugs in most cases. Prior to study enrollment, 78 percent of patients had previously experienced at least one cardiovascular event and 49 percent had more than one previous cardiovascular event.

Patients treated with mipomersen had an average LDL-C at baseline of 150 mg/dL. These patients had an average LDL-C level of 104 mg/dL at the end of the study. Forty-five percent of the mipomersen-treated patients achieved LDL-C levels of less than 100 mg/dL, a recognized treatment goal for high-risk patients. The reductions observed in the study were in addition to those achieved with the patients’ existing therapeutic regimens.

The trial met all of its secondary and tertiary endpoints. Patients treated with mipomersen experienced a 26 percent reduction in apolipoprotein B compared with a 7 percent increase for placebo; a 19 percent reduction in total cholesterol compared with a 4 percent increase for placebo; and a 25 percent reduction in non-HDL cholesterol compared with a 4 percent increase for placebo (all p<0.001).

Reductions were observed in other atherogenic lipids, including Lp(a) by 21 percent compared with no change for placebo (p<0.001). Apo B and Lp(a) are both generally accepted risk factors for cardiovascular disease. Study results are based on an intent-to-treat analysis (full analysis set).

"Having these data presented is a great milestone for the mipomersen program," said Paula Soteropoulos, vice president and general manager of Genzyme's cardiovascular business. "The data underscore our belief that mipomersen has the potential to help those familial hypercholesterolemia patients who are 'left behind' by current therapies, and are in need of new treatment options."

As seen in other mipomersen studies, the most commonly observed adverse events were injection site reactions (93 percent for mipomersen compared with 42 percent for placebo) and flu-like symptoms (49 percent for mipomersen compared with 32 percent for placebo).

All 41 patients treated with placebo completed treatment. Of the 83 patients treated with mipomersen, 73 completed treatment; nine of the discontinuations were related to adverse events, the nature of which was generally similar to previous studies. Reasons for withdrawal from the mipomersen group were: elevations in liver transaminases (3), injection site reactions (2), non-cardiac chest pain (2), injection site reactions and flu-like symptoms (1), and constipation (1).

In this study, elevations in liver transaminases (ALTs) in patients treated with mipomersen were observed that were generally similar in character with those seen in other studies. Six mipomersen-treated patients (7 percent) had persistent ALT elevations above 3X ULN during the treatment period. Persistent is defined as consecutive elevations at least one week apart. As measured by MRI, mipomersen-treated patients had a modest change in liver fat from baseline (median increase of 4.9 percent), compared with the placebo-treated patients (median increase of 0.4 percent). In general, increases in liver transaminases and liver fat appeared to be associated with the greatest reductions of LDL cholesterol. No patients, including those who discontinued the study, had changes in other laboratory tests to indicate hepatic dysfunction, and there were no Hy's Law cases.

"In all four of the phase 3 studies we have completed, we have seen consistent and robust reductions in LDL cholesterol and other atherogenic lipids that support our plan to initially target homozygous and severe heterozygous familial hypercholesterolemia patients," said Isis Pharmaceuticals Chairman and CEO Stanley T. Crooke. "We are excited by these positive phase 3 results and look forward to working with Genzyme to bring mipomersen to patients who are in need of a new and novel lipid-lowering agent."

About Mipomersen
Mipomersen is a first-in-class apo-B synthesis inhibitor currently in late-stage development. It is intended to reduce LDL-C by preventing the formation of atherogenic lipids. It acts by decreasing the production of apo-B, which provides the structural core for all atherogenic lipids, including LDL-C, which carry cholesterol through the bloodstream.

Genzyme's initial U.S. and E.U. regulatory filings for mipomersen will seek marketing approval for the treatment of patients with homozygous FH (hoFH). These initial filings may also include patients with severe heFH. In the first half of 2011, Genzyme expects to submit the initial U.S. and E.U. filings, and to have made progress toward filing in other major international markets.

Genzyme and Isis have completed all four phase 3 studies planned to support the initial filings. As previously reported, the phase 3 study of mipomersen in hoFH patients met its primary endpoint with 25 percent LDL-C reduction, and results were presented at last year's American Heart Association meeting. Genzyme and Isis announced top-line results of the phase 3 study in heFH patients in February. The companies last month reported that the phase 3 studies of mipomersen in severe hypercholesterolemia and high-risk patients met their primary endpoints with 36 and 37 percent LDL-C reductions. These four studies will be included in the initial filings. In addition, studies are ongoing and planned to evaluate alternative dosing regimens.

About Familial Hypercholesterolemia
FH is one of the most common genetic disorders, and results in elevated LDL cholesterol levels. FH patients have inherited abnormalities in liver cells that are responsible for clearing LDL-C from the blood. These patients experience a markedly increased risk of premature cardiovascular disease (CVD) and CVD-related death.

There are two forms of FH: homozygous (hoFH), where a defective gene is inherited from both parents, or heterozygous (heFH), where a defective gene is inherited from only one parent. HoFH is a very rare condition estimated to affect approximately one in a million people worldwide. HeFH is a more common form of the disorder, with a prevalence of approximately one in 500.

About Genzyme
One of the world's leading biotechnology companies, Genzyme is dedicated to making a major positive impact on the lives of people with serious diseases. Since 1981, the company has grown from a small start-up to a diversified enterprise with more than 12,000 employees in locations spanning the globe and 2009 revenues of $4.5 billion. In 2010, Genzyme was named to the Fortune 500.

With many established products and services helping patients in 100 countries, Genzyme is a leader in the effort to develop and apply the most advanced technologies in the life sciences. The company's products and services are focused on rare inherited disorders, kidney disease, orthopaedics, cancer, transplant, and immune disease. Genzyme's commitment to innovation continues today with a substantial development program focused on these fields, as well as cardiovascular disease, neurodegenerative diseases, and other areas of unmet medical need.

Genzyme's press releases and other company information are available at

About Isis
Isis is exploiting its expertise in RNA to discover and develop novel drugs for its product pipeline and for its partners. The Company has successfully commercialized the world's first antisense drug and has 23 drugs in development. Isis' drug development programs are focused on treating cardiovascular, metabolic, and severe neurodegenerative diseases and cancer. Isis' partners are developing antisense drugs invented by Isis to treat a wide variety of diseases. Isis and Alnylam Pharmaceuticals are joint owners of Regulus Therapeutics Inc., a company focused on the discovery, development and commercialization of microRNA therapeutics. Isis also has made significant innovations beyond human therapeutics resulting in products that other companies, including Abbott, are commercializing. As an innovator in RNA-based drug discovery and development, Isis is the owner or exclusive licensee of approximately 1,600 issued patents worldwide. Additional information about Isis is available at