Date: 2011-04-05
Type of information: Results
phase: 3
Announcement: results
Company: Genzyme (USA - MA), a Sanofi company (France)
Product: mipomersen
Action
mechanism: apo-B synthesis inhibitor
Disease: heterozygous familial hypercholesterolemia
Therapeutic area: Cardiovascular diseases - Genetic diseases - Rare diseases
Country: North America, Europe and South Africa
Trial
details: This double-blind, placebo-controlled trial included 58 patients with severe heterozygous familial hypercholesterolemia, who were already taking maximally tolerated lipid-lowering medications. Severe heFH patients were defined as those who had LDL-C levels ? 300 mg/dL or those who had LDL-C levels ? 200 mg/dL with coronary heart disease (CHD) or other forms of clinical atherosclerotic disease. Patients were randomized 2:1 to receive a self-administered 200 mg subcutaneous injection of mipomersen or placebo weekly for 26 weeks. This study was conducted at 26 sites in North America, Europe and South Africa.
Latest
news: Genzyme and Isis have now completed the four phase 3 studies that are planned to be included in the initial U.S. and EU filings for marketing approval of mipomersen. As previously reported, the phase 3 study of mipomersen in homozygous (ho) FH patients met its primary endpoint with 25 percent LDL-C reduction, and the phase 3 study in heFH patients met its primary endpoint with a 28 percent LDL-C reduction.
Genzyme expects to file for EU marketing approval of mipomersen for the treatment of patients with hoFH and severe heFH in the first half of this year. Genzyme also expects to file for U.S. approval for the hoFH indication in the second half of this year.
Genzyme announced that data from two phase 3 studies of mipomersen in patients who had high cholesterol levels while on lipid-lowering therapy were presented at the American College of Cardiology’s 60th Annual Scientific Session.
In the study in patients with severe heterozygous familial hypercholesterolemia (heFH), mipomersen reduced LDL-C, the primary endpoint, by 36 percent compared with a 13 percent increase for placebo (p<0.001). This study, which was presented today by Jean-Claude Tardif, M.D., of the Montreal Heart Institute, Montreal, Canada, also met each of its secondary endpoints. Patients treated with mipomersen had an average LDL-C at baseline of 276 mg/dL. At the end of the trial, these patients had an average LDL-C level of 175 mg/dL, representing an average LDL-C reduction of 101 mg/dL (36 percent). The reductions observed in the study were in addition to those achieved with the patients’ existing maximally tolerated lipid-lowering regimens.
Patients treated with mipomersen also experienced reductions in other atherogenic lipids, including: a 36 percent reduction in apolipoprotein B (apo-B) compared with an 11 percent increase for placebo; a 33 percent reduction in lipoprotein a (Lp(a)) compared with a 1 percent reduction for placebo; a 34 percent reduction in non-HDL-cholesterol compared with a 14 percent increase for placebo; and a 28 percent reduction in total cholesterol compared with an 11 percent increase for placebo (all p<0.001). Study results are based on an intent-to-treat analysis (full analysis set).
Of the 39 patients treated with mipomersen, 27 completed treatment; of the 19 patients treated with placebo, 18 completed treatment. Eight of the discontinuations in the mipomersen group were reported as being related to adverse events, the nature of which was generally similar to previous studies. The placebo discontinuation was reported as being related to an adverse event. The most common adverse events were injection site reactions (90 percent mipomersen; 32 percent placebo) and flu-like symptoms (46 percent mipomersen; 21 percent placebo.) There was one death in the study due to acute coronary syndrome in a patient treated with mipomersen.
Elevations in liver transaminases (ALTs) in patients treated with mipomersen were observed that were generally similar in character with those seen in other studies. In this study, 15 percent of mipomersen patients had persistent ALT elevations above 3X ULN (three times the upper limit of normal) during the treatment period. Persistent is defined as consecutive elevations at least one week apart. No patients had changes in laboratory tests indicative of clinically significant hepatic dysfunction, and there were no Hy’s Law cases. In general, increases in ALT levels appeared to be associated with rapid and larger drops in LDL-C.
