Genzyme (GENZ) and Isis Pharma (ISIS) Announce Phase 3 Data from Mipomersen Study

November 17, 2009 9:38 AM EST

Genzyme Corp. (NASDAQ: GENZ) and Isis Pharmaceuticals Inc. (NASDAQ: ISIS) announced that data from the phase 3 study of mipomersen in patients with homozygous familial hypercholesterolemia (hoFH) were presented today at the American Heart Association's Scientific Sessions. The study met its primary endpoint in an intent-to-treat analysis, with a 25 percent reduction in LDL-cholesterol after 26 weeks of treatment, vs. 3 percent for placebo (p<0.001) which constitutes an average reduction greater than 100 mg/dL. The trial also met each of its secondary endpoints.

This phase 3 study in hoFH patients, one of the largest trials to date in this rare population, was designed to test the efficacy and safety of adding mipomersen to substantial lipid-lowering therapy. Patients' average LDL-C at baseline was greater than 400 mg/dL. All but one of the patients were being treated with lipid-lowering therapy (50/51, 98 percent), of whom 11 (22 percent) were taking a statin alone and 39 (78 percent) were taking a statin in combination with at least one other lipid-lowering agent, most commonly ezetimibe (37/50, 74 percent). The LDL-C reductions observed in the study were in addition to those achieved with the patients' existing therapeutic regimen.

The trial met all of its secondary and tertiary endpoints, suggesting that mipomersen may offer potential benefits to patients beyond LDL-C reduction. Patients treated with mipomersen experienced a 27 percent reduction in apolipoprotein B vs. 3 percent for placebo; a 21 percent reduction in total cholesterol vs. 2 percent for placebo; and a 25 percent reduction in non-HDL cholesterol vs. 3 percent for placebo (all p<0.001).

Reductions were observed in other atherogenic lipids, including: Lp(a) by 31 percent and VLDL-C by 17 percent (both p<0.01 vs. placebo); and triglycerides by 18 percent (p=0.013 vs. placebo). Apo B, Lp(a) and triglycerides are all generally accepted risk factors for cardiovascular disease.

Mipomersen patients' HDL-C levels increased 15 percent (p=0.035 vs. placebo), which combined with the LDL-C reductions observed, resulted in improved LDL/HDL ratios, a ratio considered an important measure of cardiovascular risk. Mipomersen patients' LDL/HDL ratios decreased by 34% (p<0.001 vs. placebo).

Consistent with previous studies evaluating mipomersen, the most commonly observed adverse events were injection site reactions (77 percent for mipomersen vs. 24 percent for placebo), flu-like symptoms (29 percent for mipomersen vs. 24 percent for placebo) and elevations in liver transaminases (12 percent >= 3 X ULN for mipomersen vs. none for placebo.)

Of the 34 patients treated with mipomersen, 28 completed the study. Reasons for withdrawal from the mipomersen group were: injection site reactions (2), elevations in liver transaminases (1), rash (1), personal reasons (1), and non-compliance (1).

Four patients had elevations in liver transaminases above 3 X ULN (three times the upper limit of normal), three of whom reached between 5 and 8 X ULN. None of these patients, including the patient who discontinued the study, had changes in other laboratory tests to indicate hepatic dysfunction, i.e., Hy's Law. In all cases, transaminases returned to entry criteria by the end of planned clinical observations.

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