A phase 3 trial published Oct. 11 in Circulation found that mipomersen, an antisense oligonucleotide designed to inhibit synthesis of apolipoprotein B-100 protein in the liver and the subsequent release of lipoproteins that contain apolipoprotein B-100, can significantly reduce levels of LDL cholesterol (LDL-C ) in subjects with heterozygous familial hypercholesterolemia (HeFH).

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The study, based on a total of 124 patients with HeFH and coronary artery disease (CAD) who were randomized to either mipomersen (83 patients) or placebo (41 patients) across 26 centers in the United States and Canada, found that mipomersen produced a mean 28 percent reduction in LDL-C in the treatment arm compared to a 5.2 percent increase in LDL-C in the placebo arm (p<0.001). A total of 37 patients (45.1 percent) achieved LDL-C of less than 100 mg/dL compared to two patients (4.9 percent) on placebo. LDL-C changes were seen by week five with near maximal effects by week 21. The LDL-C lowering effect of mipomersen was independent of baseline LDL-C and age, but there was a greater effect in women (-40.6 percent) than in men (-20 percent).

Mipomersen also showed a significant advantage in reducing apolipoprotein B (-26.3 percent vs. +7 percent, p<0.001), total cholesterol (-19.4 percent) non-HDL cholesterol (-25 percent), lipoprotein(a) (-21.1 percent) and the LDL:HDL ratio (-29.2 percent) compared to placebo (p<0.001).
 
There were serious adverse events (CAD, supraventricular tachycardia) in 4.9 percent of the placebo group and 7.2 percent of the treatment group (basal cell carcinoma, angina, acute myocardial infarction, acute and non-acute chest pain, pulmonary embolism), but none of the acute events were associated with the study medication. Common adverse events included injection site reactions (92.8 percent treatment vs. 41.5 percent placebo) and flu-like symptoms (49.4 percent and 31.7 percent).
 
Alanine-aminotransferase (ALT) levels >1.5 times the upper limit of normal (ULN) were seen in 14.5 percent of mipomersen patients vs. 2.4 percent of placebo patients. There were no violations of Hy’s Law and patients with more than three times the ULN for ALT were among those with the greatest reduction in apolipoprotein B. Mipomersen also was associated with elevated hepatic fat (6.2 percent vs. 0.5 percent, p<0.001). Regression analysis showed a significant correlation between maximum ALT levels and the change in hepatic fat content.
 
"Weekly mipomersen 200 mg provided a significant additional 28 percent decrease from baseline in LDL cholesterol in HeFH patients with CAD who could not achieve optimal LDL cholesterol despite stable maximally tolerated lipid lower therapy," said lead author Evan Stein, MD, PhD, Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio. "Mipomersen is an effective therapy to further reduce apolipoprotein B-containing lipoproteins, including LDL and lipoprotein(a) in HeFH patients with CAD on statins and other lipid lowering therapy."
 
Moving forward, Stein said that longer-term studies are needed to further clarify the clinical implications of such increases in hepatic fat, transaminase elevations, and overall safety. "Mipomersen provided significant additional reductions in apolipoprotein B associated atherogenic lipoproteins in a difficult-to-treat HeFH population with CAD already maximally treaded with current lipid-lowering drugs," he said. "While clinical benefits of these additional reductions in apolipoprotein B and associated atherogenic lipids remain to be proven, mipomersen may fill an unmet medical need in HeFH."

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