Results of a Phase 3 trial showed that in patients with severe heterozygous familial hypercholesterolemia (heFH), mipomersen reduced LDL-C levels by 36 percent, according to a study presented at the annual meeting of the American College of Cardiology in New Orleans.
Jean-Claude Tardif, MD, of the Montreal Heart Institute in Montreal, presented the study, which enrolled 58 patients with severe heFH who were taking maximally tolerated lipid-lowering medications. These patients had LDL-C levels that were greater than or equal to 300 mg/dL or those with coronary heart disease or atherosclerosis who had LCL-C levels greater than or equal to 200 mg/dL.
The researchers randomized patients at a 2:1 ratio to receive either a 200 mg self-administered subcutaneous injection of mipomersen (39 patients) or a weekly placebo for 26 weeks (19 patients). At the start of the trial patients treated with mipomersen had an average LDL-C level of 276 mg/dL By the end of follow-up these patients’ average LDL-C levels were 175 mg/dL, a reduction of 36 percent.
Eight patients in the mipomersen arm discontinued treatment due to adverse events. These events included injection site reactions and flu-like symptoms. One death occurred in the study that the researchers attributed to acute coronary syndrome.
Tardif also offered that patients treated with mipomersen experienced reductions in atherogenic lipids including a 36 percent reduction in apolipoprotein B (apo-B) compared with an 11 percent increase for placebo. In addition, the researchers reported a 33 percent reduction in lipoprotein a compared with a 1 percent reduction for placebo; a 34 percent reduction in non-HDL-C compared with a 14 percent increase for placebo; and a 28 percent reduction in total cholesterol compared with an 11 percent increase for placebo.
Tardif and colleagues studied elevations in liver transaminases (ALTs) in patients treated with mipomersen and found that 15 percent of mipomersen patients had persistent ALT elevations above three times the upper limit of normal. The researchers noted that increases in ALT levels are associated with rapid and larger drops in LDL-C.
In a second study presented at ACC, William Cromwell, MD, of the Presbyterian Cardiovascular Institute in Charlotte, N.C., and colleagues reported data on mipomersen in patients with high cholesterol who were also at a high risk for CHD. The researchers found that mipomersen reduced LDL-C by 37 percent compared with a 5 percent reduction in the placebo arm.
The study included 158 hypercholesterolmeia patients with LDL-C levels equal to or above 100 mg/dL who were at a high risk of developing CHD taking a tolerated dose of a statin. The patients were randomized at a 2:1 ratio to receive a self-administered 200 mg subcutaneous injection of mipomersen (105 patients) or placebo for 26 weeks (53 patients).
The patients treated with mipomersen had an average LDL-C at baseline that was 123 mg/dL. The average LDL-C levels at the end of the study was 75 mg/dL, a reduction of 37 percent. Cromwell et al reported that half of the mipomersen-treated patients achieved LDL-C levels that were below 70 mg/dL.
The patients treated with mipomersen also had reduced levels of apo-B and Lp (a). In this study, 26 patients were unable to continue on mipomersen therapy due to adverse events.
While mipomersen is in its late-stage development phase, makers of the drug (Genzyme, in collaboration with Isis) said that they expect to file for EU approval for for the drug for indication in patients with hoFH and severe heFH in the first half of this year. The company expects to file for U.S. approval in the second half of this year.