Genzyme Corp. and Isis Pharmaceuticals Inc. 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 per cent reduction in LDL-cholesterol, compared with an increase of 5 per cent 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 per cent 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 per cent reduction in apolipoprotein B compared with a 7 per cent increase for placebo; a 19 per cent reduction in total cholesterol compared with a 4 per cent increase for placebo; and a 25 per cent reduction in non-HDL cholesterol compared with a 4 per cent increase for placebo (all p<0.001).

Reductions were observed in other atherogenic lipids, including Lp(a) by 21 per cent 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 per cent for mipomersen compared with 42 per cent for placebo) and flu-like symptoms (49 per cent for mipomersen compared with 32 per cent 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 per cent) 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 per cent), compared with the placebo-treated patients (median increase of 0.4 per cent). 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 US and EU 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 US and EU 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.

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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