Time-Averaged LDL-C Lowering with Evolocumab: Pooled Analysis of Phase 2 Trials

Abstract

<h3>Lead Author's Financial Disclosures</h3> B.S. is an employee of Amgen and owns Amgen stock. <h3>Study Funding</h3> Amgen, Inc. <h3>Background/Synopsis</h3> LDL-C is a causal risk factor for atherosclerotic cardiovascular disease, and the clinical benefit from LDL-C lowering is proportional to the magnitude of reduction. Clinical trials have consistently shown that evolocumab reduces LDL-C levels by approximately 60%; however, this value is based on measurements at the trough of drug effect on LDL-C. Time-averaged methods that include LDL-C measurements throughout the dosing interval may better assess the true magnitude of cumulative LDL-C exposure. <h3>Objective/Purpose</h3> We analyzed pooled data from multiple studies of evolocumab with weekly LDL-C assessments to enable a time-averaged analysis including both peaks and troughs of drug effects on LDL-C. <h3>Methods</h3> Individuals from the pharmacokinetics substudies of five phase II evolocumab trials (LAPLACE-TIMI 57: combination therapy with statins; YUKAWA: combination therapy with statins in a Japanese population; RUTHERFORD: heterozygous familial hypercholesterolemia; GAUSS: statin-intolerant; or MENDEL: monotherapy) were included in the analysis if they had both a baseline LDL-C and ≥1 weekly LDL-C measurement at weeks 9-12. Evolocumab dosing was 140mg every two weeks (Q2W) or 420mg monthly (QM). Percent change from baseline in LDL-C (and in free serum PCSK9) was averaged across weeks 9-12 for evolocumab versus placebo. <h3>Results</h3> The overall pooled analysis included 399 individuals who were randomized and dosed; 66% were receiving statin therapy and 10% were receiving ezetimibe at baseline. A total of 371 individuals received treatment at weeks 8 and 10, had a baseline LDL-C measurement, and ≥1 weekly LDL-C measurement at weeks 9-12. At week 9 (peak reduction), the placebo-adjusted LDL-C reductions were 71.5% (95% confidence interval: 66.5, 76.6) and 69.8% (65.3, 74.3) for Q2W and QM dosing, respectively. The time-averaged percent reduction in LDL-C with evolocumab versus placebo across weeks 9-12 was 68.8% (65.0, 72.7) with the Q2W dose and 66.9% (62.6, 71.3) with the QM dose (figure). Time-averaged percent reduction in serum free PCSK9 with evolocumab versus placebo across weeks 9-12 was 81.9% (76.1, 87.8) with the Q2W dose and 77.4% (72.5, 82.4) with the QM dose. <h3>Conclusions</h3> In this pooled analysis of 5 trials with weekly LDL-C assessments (weeks 9-12), evolocumab treatment (Q2W or QM) produced time-averaged LDL-C reductions of 67-69% and maximal reductions of 70-72% versus placebo. Time-averaged methods that include both peaks and troughs of drug effect may better reflect cumulative LDL-C-lowering capability. The intensive and consistent LDL-C-lowering effects of evolocumab demonstrated in this time-averaged analysis likely contribute to its clinical benefits.