Data from Mipomersen Phase 3 Trial in heFH Patients Presented at ESC
Study Meets Primary Endpoint with 28 Percent LDL-C Reduction
CAMBRIDGE, Mass. & CARLSBAD, Calif.--(BUSINESS WIRE) -- 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 today 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."
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.
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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 www.isispharm.com.
Genzyme Safe Harbor Statement
This press release contains forward-looking statements regarding Genzyme's business plans and strategies regarding mipomersen including, without limitation, statements about its potential uses, its safety profile, the expected timing of regulatory filings in the U.S. and E.U., and the studies that are expected to form a basis of the regulatory filings. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those forecasted. These risks and uncertainties include, among others: that regulatory authorities determine additional clinical studies of mipomersen are needed to support a 2011 filing; that Genzyme is unable to continue to support its clinical and other development efforts related to mipomersen; that regulatory authorities determine mipomersen's safety profile does not support approval for treatment of any or all of the targeted population; the actual efficacy and safety of mipomersen including, without limitation, the effects of elevations in liver transaminases; and the risks and uncertainties described in Genzyme's SEC reports filed under the Securities Exchange Act of 1934, including the factors discussed under the caption "Risk Factors" in Genzyme's Quarterly Report on Form 10-Q for the period ended June 30, 2010. Genzyme cautions investors not to place undue reliance on the forward-looking statements contained in this press release. These statements speak only as of the date of this press release and Genzyme undertakes no obligation to update or revise the statements.
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Isis Safe Harbor Statement
This press release includes forward-looking statements regarding Isis' collaboration with Genzyme Corporation, its financial and business development activities, and the development, activity, therapeutic potential and safety of mipomersen in treating patients with high cholesterol. Any statement describing Isis' goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs. Isis' forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Isis' forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Isis. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Isis' programs are described in additional detail in Isis' annual report on Form 10-K for the year ended December 31, 2009 and its most recent quarterly report on Form 10-Q, which are on file with the SEC. Copies of these and other documents are available from the Company.
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