Mipomersen Phase 3 trial in heFH meets primary, secondary and tertiary endpoints

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.

“Having these data presented is a great milestone for the mipomersen program”

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."