Initial filing for mipomersen will cover homozygous familial hypercholesterolemia.
Genzyme and Isis Pharmaceuticals reported positive Phase III results from two studies of mipomersen in patients who had high cholesterol levels while on maximally tolerated lipid-lowering therapy. With these studies, the companies have completed the four Phase III trials that are planned to be included in the initial U.S. and EU regulatory filings.
Expected in the first half of 2011, these filings will seek approval for the treatment of patients with homozygous familial hypercholesterolemia (hoFH) and may also include patients with severe hypercholesterolemia.
The two previous Phase III studies of mipomersen, which focused on patients with homozygous and heterozygous FH (heFH), also met their primary and secondary endpoints. In November 2009, Genzyme and Isis said that mipomersen decreased LDL-C in hoFH patients by 25%. Then in February of this year, the companies reported that the drug reduced LDL-C in heFH patients by 28%.
Mipomersen is an apo-B synthesis inhibitor 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.
In the studies being reported today, patients with severe hypercholesterolemia getting mipomersen demonstrated 36% reduced LDL-C, the primary endpoint, compared with a 13% increase in those receiving placebo. In patients with high cholesterol and high cardiovascular risk, mipomersen reduced LDL-C by 37% compared with a 5% reduction in the placebo group.
Both studies met all their secondary endpoints as well, according to Genzyme and Isis. Frequently observed adverse events were injection site reactions, flu-like symptoms, and elevations in liver transaminases.
One of the studies was a double-blind, placebo-controlled trial that included 58 patients with severe hypercholesterolemia. Severe hypercholesterolemia patients were defined as those who have LDL-C levels ≥200 mg/dL with baseline cardiovascular disease (CVD) or LDL-C levels ≥300 mg/dL without CVD. Patients were randomized 2:1 to receive a 200 mg dose of mipomersen or placebo weekly for 26 weeks. This study was conducted at 26 sites in North America, Europe, and South Africa.
Besides reducing LDL-C from the average baseline level of 276 mg/dL to 175 mg/dL, the drug also met each of its three secondary endpoints with statistically significant reductions in apo-B, non-HDL-cholesterol, and total cholesterol, the companies report.
Of the 39 patients treated with mipomersen, 27 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, state Genzyme and Isis. There was one death in the study due to acute coronary syndrome in a patient treated with mipomersen that was reported as unrelated to treatment.
Elevations in liver transaminases (ALTs) in patients treated with mipomersen were generally similar to those seen in other studies, the companies add. Fifteen percent of patients had persistent ALT elevations above three times the upper limit of normal (3X ULN) during the treatment period.
The second study reported today was conducted in 158 hypercholesterolemic patients at high risk of developing coronary heart disease. It was a double-blind, placebo-controlled trial, and patients were taking a maximally tolerated dose of a statin. Patients were randomized 2:1 to receive a 200 mg dose of mipomersen or placebo weekly for 26 weeks. This study was conducted at 43 sites in the U.S. and Canada. This was the first study of mipomersen designed to evaluate patients with diabetes. More than 50% of patients in the study had type 2 diabetes.
Patients treated with mipomersen had an average LDL-C at baseline of 123 mg/dL. At the end of the study, these patients had an average LDL-C level of 75 mg/dL. The trial also met each of its three secondary endpoints with statistically significant reductions in apo-B, non-HDL-cholesterol, and total cholesterol.
Of the 105 patients treated with mipomersen, 60 completed treatment. Twenty-six of the discontinuations in the mipomersen group were reported as being related to adverse events, which Genzyme and Isis believe are similar to previous studies.
As with the study in patients with severe hypercholesterolemia, elevations in ALTs were observed that were similar to those seen in other trials. Ten percent of patients had persistent ALT elevations above 3X ULN during the treatment period.