NEW ORLEANS – In patients with hypercholesterolemia and high cardiovascular risk, the novel agent mipomersen administered as add-on therapy led to robust reductions in LDL cholesterol, based on the results of a double-blind, phase III study presented at the annual scientific sessions of the American College of Cardiology.
"In high-risk patients refractory to maximally tolerated statin therapy, the addition of mipomersen significantly reduced LDL-C and other atherogenic lipids and lipoproteins," said Dr. William C. Cromwell of the Presbyterian Cardiovascular Institute in Charlotte, N.C.
Mipomersen is the first of a new class of agents called apolipoprotein B (apoB) synthesis inhibitors. In the study, the drug was administered subcutaneously once a week. Among its side effects were injection site reactions, increases in alanine aminotransferase (ALT) levels, and steatosis.
The study included 158 patients at high risk for cardiovascular events who were unable to achieve target LDL-C levels with statins, bile-acid sequestrants, and niacin. At baseline, all patients were on maximally tolerated doses of a statin; 63 were on the maximal approved dose, and 25 were also receiving ezetimibe.
All subjects had LDL-C levels of at least 100 mg/dL and triglycerides below 200 mg/dL. They were randomized 2:1 to 200 mg subcutaneous mipomersen or placebo weekly for 26 weeks. The primary end point was percent change in LDL-C from baseline at week 28 or 2 weeks after the last dose if treatment was not completed.
LDL-C levels of less than 100 mg/dL were achieved by 77 (76%) mipomersen-treated patients, compared with 19 (38%) placebo-treated patients. LDL-C levels of less than 70 mg/dL were achieved by 51 (50%) and 4 (8%), respectively.
The percent reduction in LDL cholesterol from baseline to the primary efficacy time point was a 37% drop in the mipomersen arm and a 5% drop in the placebo arm, a significant difference.
"LDL-C levels decreased through the first 17 weeks of treatment and remained relatively low through week 28," Dr. Cromwell observed. "Mipomersen’s lipid-lowering effects were independent of baseline LDL-C or race, and were similar for patients with and without diabetes."
The effect of the drug in the diabetic subset was robust. In the diabetes cohort, the mean decline in LDL-C from baseline was 51% for the 56 patients on mipomersen and 32% for the 29 on placebo.
Dr. Cromwell noted that the drug had a more pronounced effect in females and in patients whose age was above the median. However, mipomersen’s effects in males and in younger persons were still statistically significant and clinically meaningful.
Mipomersen also was associated with significant reductions from baseline values in apoB (38%), total cholesterol (26%), non-HDL cholesterol (36%), and lipoprotein(a) (24%). HDL-C levels did not change significantly from baseline.
Sixty of the 105 mipomersen-treated patients (57%) and 44 of 52 placebo patients (85%) completed treatment. A total of 26 mipomersen-treated patients and 2 placebo-treated patients discontinued due to on-treatment adverse events. Of the mipomersen noncompleters, seven discontinued due to a liver enzyme-related adverse event, and seven stopped because of an injection site reaction.
Injection site reactions were the most common adverse event, occurring in 78% of the mipomersen group and 31% of the placebo group. Flu-like symptoms occurred in 34% and 21%, respectively.
"Injection site reaction is the biggest side effect with this drug. This ranges from induration to redness, and some patients have skin discoloration. It’s real, and it does have to be managed," Dr. Cromwell acknowledged.
ALT elevations at least 3 times the upper limit of normal were observed in 14% of patients on mipomersen, versus none receiving placebo, but this occurred without concomitant significant bilirubin elevations, he said. For 10% of patients, ALT elevations occurred on consecutive measurements at least 7 days apart. One patient had an ALT of at least 10 times the upper limit of normal.
"We don’t see this as a huge ALT signal," Dr. Cromwell pointed out. "This is against the backdrop of a statin, which is already sensitizing the liver. We think it’s reassuring."
Approximately one-third of patients had an increase in steatosis, defined as liver fat increasing by at least 5%; median percent change from baseline was 15%. "This does not represent a huge accumulation of fat. Instead, it is a signal that it’s there at 28 weeks, and it is not particularly worrying. In a series of patients with much longer exposures, there is a plateau in this increase."
Dr. Patrick Moriarty, a lipid specialist who is assistant professor of medicine at the University of Kansas, Kansas City, commented, "We treat many refractory patients, and I can tell you that a drug of this class is very much needed in this patient population. It will help get their lipid numbers down."