Mipomersen preferentially reduces small low-density lipoprotein particle number in patients with hypercholesterolemia

•The effect of mipomersen on LDL particle subclasses in hypercholesterolemia was evaluated.•Homozygous familial hypercholesterolemia had a greater mean percentage of large LDL particles. Comparison with severe hypercholesterolemia, heterozygous familial hypercholesterolemia with coronary artery disease, and hypercholesterolemia.•Mipomersen consistently reduced all LDL particle numbers in all 4 phase 3 studies.•Mipomersen preferentially reduced the concentration of small LDL particles in all 4 phase 3 studies.

BackgroundBecause of variability in lipoprotein cholesterol content, low-density lipoprotein (LDL) cholesterol frequently underrepresents or overrepresents the number of LDL particles. Mipomersen is an antisense oligonucleotide that reduces hepatic production of apolipoprotein B-100, the sole apolipoprotein of LDL.ObjectiveTo characterize the effects of mipomersen on lipoprotein particle numbers as well as subclass distribution using nuclear magnetic resonance (NMR) spectroscopy.MethodsWe compared the tertiary results for the direct measurement of LDL particle numbers by NMR among 4 placebo-controlled, phase 3 studies of mipomersen that had similar study designs but different patient populations: homozygous familial hypercholesterolemia (HoFH), severe hypercholesterolemia, heterozygous familial hypercholesterolemia with established coronary artery disease, or hypercholesterolemia with high risk for coronary heart disease (HC-CHD).ResultsHoFH patients had the highest median total LDL particles at baseline compared with HC-CHD patients, who had the lowest. At baseline, the HoFH population uniquely had a greater mean percentage of large LDL particles (placebo, 60.2%; mipomersen, 54.9%) compared with small LDL particles (placebo, 33.1%; mipomersen, 38.9%). In all 4 studies, mipomersen was associated with greater reductions from baseline in the concentrations of small LDL particles compared with those of large LDL particles, and both total LDL particles and small LDL particles were statistically significantly reduced.ConclusionsMipomersen consistently reduced all LDL particle numbers and preferentially reduced the concentration of small LDL particles in all 4 phase 3 studies.