PCSK9, a novel target for lowering LDL cholesterol: promise and progress

Evaluation of: Stein EA, Gipe D, Bergeron J et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a Phase 2 randomised controlled trial. Lancet 380(9836), 29-36 (2012). Elevated levels of LDL cholesterol (LDL-c) are associated with an increased risk of cardiovascular events. PCSK9 is a protein that promotes degradation of the LDL receptor and, thus, inhibition of PCSK9 is an attractive drug target for reducing LDL-c levels. Monoclonal antibodies to PCSK9 have been shown to dramatically lower LDL-c in primates and humans. Phase 1 clinical trials using the Sanofi-Aventis/Regeneron SAR236553/REGN727 antibody to PCSK9 were the first studies reporting its safety and LDL-lowering efficacy in humans. Stein et al. have recently extended these findings by publishing the results of a multicenter, randomized, placebo-controlled Phase II trial designed to examine the safety and efficacy of repeated subcutaneous injections of the specific monoclonal antibody against human PCSK9 (REGN727/SAR236553) in 77 patients with heterozygous familial hypercholesterolemia. The injection of REG727 was well tolerated and dramatically lowered LDL-c (50-70%) in patients with heterozygous familial hypercholesterolemia also receiving statin alone or with ezetimibe. Injection of 150 mg every 2 weeks was more effective in attaining low stable LDL-c levels than higher doses given every 4 weeks. These results support the safety and efficacy of using monoclonal antibodies to human PCSK9 to lower LDL-c and pave the way for Phase III clinical trials.