Abstract 12729: Comparisons of Peak LDL-C Reduction and Duration of Effect With Lower or Higher Dosing Regimens of the PCSK9 Inhibitor Evolocumab
Introduction: Recent studies of anti-PCSK9 antibodies have established this new class as highly effective in lowering LDL-C and well tolerated with or without background statins. Because peak LDL-C responses to anti-PCSK9 antibodies are not linearly dose-proportional, understanding the pharmacodynamic profile of the therapy can help select optimal dosing. Consequently, we assessed the peak LDL-C effects of 3 evolocumab doses during ongoing therapy and the persistence of effects after 2 weeks when the next dose would be due.
Methods: In the 12 week Phase 2 LAPLACE-TIMI 57 study 107 patients underwent assessments at weeks 9 and 11 in addition to the usual biweekly lipid measurements at weeks 8 and 10. We analyzed data from patients who received evolocumab 70 or 140 mg Q2W or 420 mg QM for PCSK9 suppression and peak LDL-C effectiveness estimated to occur 1 week post dosing. Persistence of the LDL-C lowering effect over the next week was also assessed.
Results: The Figure shows PCSK9 and LDL-C over the analyzed interval. Mean baseline LDL-C in these groups was about 130 mg/dL. Week 8 LDL-C representing steady state trough effects were 85.4 mg/dL (35% below baseline), 47.1 mg/dL (62% below baseline) and 52.8 mg/dL (52% below baseline) for 70 and 140 mg Q2W and 420 mg QM, respectively. Week 9 LDL-C for the 70 and 140 mg doses reflected reductions from baseline of 55% and 70%, respectively and an additional -29% and -22% from trough levels. The offset from maximum LDL-C lowering at week 9 to week 10 for Q2W regimens showed mean LDL-C increases of 25.4 mg/dL in the 70 mg group and 6.3 mg/dL in the 140 mg group. No offset was seen in the 420 mg group during weeks 9-10. LDL-C variability was greatest for 70 mg Q2W over the studied dosing interval.
Conclusions: During steady state dosing of evolocumab on stable statin therapy, dose escalations affect the duration of the LDL-C lowering response more than the peak effect. Higher doses result in less fluctuation in LDL-C response, which may be a goal of therapy.
Author Disclosures: M.J. Koren: Research Grant; Modest; Amgen, Inc., Pfizer, Regeneron, Roche, and Sanofi. S. Doshi: Employment; Significant; Amgen, Inc. R. Castro: Employment; Significant; Amgen, Inc. J.P. Gibbs: Employment; Significant; Amgen, Inc. M.G. Emery: Employment; Significant; Amgen, Inc. R. Somaratne: Employment; Significant; Amgen, Inc. S.M. Wasserman: Employment; Significant; Amgen, Inc..
- © 2015 by American Heart Association, Inc.