Abstract 14725: Effect of SAR236553/REGN727 Fully Human Monoclonal Anti-Proprotein Convertase Subtilisin/Kexin Type 9 Antibody on Plasma Lipoprotein(a) Concentrations: Pooled Analysis from Three Phase 2 Studies (NCT:01266876; 01288469; 01288443)

Abstract

Background: Lipoprotein (a) [Lp(a)], an LDL-like lipoprotein with apolipoprotein (a) covalently bound to the existing apoB protein, increases the risk of CV disease. Only apheresis and high- dose niacin reduce Lp(a). SAR236553/REGN727 (SAR236553) is a fully human monoclonal antibody to PCSK9 that has recently completed phase 2 clinical trials. The effects of SAR236553 on Lp(a) were analyzed as a prespecified secondary endpoint in these studies.

Methods: We pooled results from three SAR236553 double-blind, randomized, placebo-controlled phase 2 studies consisting of 352 hypercholesterolemic (heterozygous familial hypercholesterolemia [HeFH] and non-FH) patients, 77 on placebo and 275 on doses of SAR236553, ranging from 50-300 mg, administered SC either Q2W or Q4W. All participants were on background statin or statin + ezetimibe 10 mg. Across all study arms, median baseline Lp(a) levels ranged from 15-32 mg/dL.

Results: On top of background lipid-lowering therapy, significant reductions in Lp(a) were observed across the doses and regimens with SAR236553; median changes ranged from -7.5% to -34.7% with SAR236553 versus 0% to -3.9% for placebo. SAR236553 resulted in incremental reductions in LDL-C; changes ranged from -28.9% to -72.4% (LS means) depending upon the dose and regimen. The 150 mg Q2W dose (utilized in all 3 trials) had the greatest effect on LDL-C and Lp(a) reduction. Results of the pooled 150 mg Q2W dose group (N=102) revealed that Lp(a) median change from baseline to week 8/12 for SAR236553 versus placebo was -30.3% versus -0.3%, respectively and -28.3% versus -4.4%, respectively, for patients with baseline Lp(a) >30 mg/dL. A correlation between the percentages of decrease from baseline in Lp(a) and LDL-C was identified (Pearson correlation coefficient=0.4) but less than 5% of the variance in Lp(a) reduction was explained by the percentage decrease in LDL-C, suggesting the effect of SAR236553 on Lp(a) did not only depend on its effect on LDL-C. The effect of SAR236553 on Lp(a) was observed in HeFH and non-FH patients. The most common adverse event was mild injection-site reactions of short duration.

Conclusions: Treatment with SAR236553 significantly decreased plasma Lp(a) concentration and may provide another avenue for lipid management.