Abstract 19931: Mipomersen, An Apolipoprotein B Synthesis Inhibitor, Reduces Small LDL Particle Number and Increases LDL Particle Size in Patients with Heterozygous Familial Hypercholestrolemia and Coronary Artery Disease
Apolipoprotein B (apo B) is the main structural component of the atherogenic lipoprotein particles VLDL, IDL, LDL and Lp(a). Elevated levels of these particles are associated with an increased risk for CVD, mainly by arterial wall interactions of one or more of these lipoproteins in the atherogenic process. The effects of mipomersen (ISIS 301012), an investigational apo B synthesis inhibitor, was evaluated in a multi-centre Phase 3 study of 124 patients with heterozygous familial hypercholesterolemia (FH) and CAD on stable lipid-lowering therapy with LDL-C ≥100 mg/dL. Patients were randomized to 26 weeks placebo (n=41) or mipomersen 200 mg/wk (n=83) s.c.. Mipomersen produced a 28% mean reduction in LDL-C (p<0.001) and similar reductions in apo B, non-HDL-C, and TC (p<0.001). Herein, we report lipoprotein particle numbers (lipoprotein-P) and subclass distributions based on NMR. Baseline total LDL-P and VLDL-P were in range of other CAD populations, e.g. Framingham Offspring and EPIC-Norfolk. Mipomersen produced a substantial and statistically significant reduction in total LDL-P from baseline at Week 28 or 2 weeks after last dose compared to placebo (p<0.001, see Table). Total VLDL-P number was also reduced, but to a lesser extent. Reductions in total LDL and VLDL particle number were primarily due to decreases in the small particle subclasses. Modest, but statistically significant reductions in large LDL-P and IDL-P also occurred. LDL size increased, whereas VLDL size was unchanged. Mipomersen produced a similar effect on atherogenic lipoprotein particles in the 26-week Phase 3 study involving homozygous FH patients (Raal et al. Lancet 2010). Collectively, these results suggest that mipomersen may represent an effective modality for reduction of LDL particle number. Further studies are needed to determine if the results differ depending on the nature of the dyslipidemia. This study was sponsored by Genzyme Corporation and Isis Pharmaceuticals, Inc.
- © 2010 by American Heart Association, Inc.