A Phase 3 Study of Evolocumab (AMG 145) in Statin-Treated Japanese Patients at High Cardiovascular Risk

Abstract

Evolocumab (AMG 145), a fully human monoclonal antibody against PCSK9, significantly reduced low-density lipoprotein cholesterol (LDL-C) levels in phase 2 and 3 studies. This phase 3 study evaluated the efficacy and safety of evolocumab plus atorvastatin in Japanese patients with hyperlipidemia or mixed dyslipidemia and high cardiovascular risk. Patients were randomized to atorvastatin 5 or 20 mg/day for 4 weeks. Subsequently, patients underwent second randomization to evolocumab 140 mg biweekly (Q2W) or 420 mg monthly (QM) or placebo Q2W or QM. Coprimary end points were % change from baseline in LDL-C at week 12 and mean of weeks 10 and 12. Secondary end points included change and % change in other lipids and proportion of patients reaching LDL-C <70 mg/dl. Adverse events and laboratory values were recorded. Four hundred four patients were randomized to study drug. At baseline, the mean (SD) age was 61 (10) years (placebo) and 62 (11) years (evolocumab); 39% and 40% were women; 14% and 12% had cerebrovascular or peripheral arterial disease; and 51% and 47% had diabetes. At entry, mean (SD) calculated LDL-C was 128 (23) mg/dL; after stabilization on atorvastatin 5 and 20 mg/day, baseline LDL-C levels were 118 (35) and 94 (24) mg/dL, respectively. Mean LDL-C reductions at week 12 for evolocumab versus placebo ranged from 67% to 76%. No imbalances were observed in adverse events between treatment groups. Efficacy and safety for Q2W or QM evolocumab dosing were similar. In conclusion, in high-risk Japanese patients receiving stable statin therapy, evolocumab markedly reduced LDL-C and was well tolerated.

Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta‐Analysis of 35 Randomized Controlled Trials

“…A total of 138 study arms from 35 studies were analyzed, comprising 45 539 patients (Table S1). 5, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 Alirocumab was used in 18 studies (28 treatment arms), and evolocumab was used in 17 studies (39 treatment arms; Figure 1); placebo was the most common control used (52 control arms), with ezetimibe used in 17 arms, and standard therapy in 2 arms. Eight studies were of an exclusively FH population, and 5 studies included only patients intolerant to statins.…”

“…Intensive background statin therapy was defined as daily use of atorvastatin ≥40 mg, rosuvastatin ≥20 mg, simvastatin ≥80 mg, or any statin plus ezetimibe. For studies in Japanese populations,11, 12, 13, 14 a modified definition of intensive background statin therapy was used (atorvastatin ≥10 mg, pitavastatin ≥2 mg, rosuvastatin ≥5 mg, simvastatin ≥20 mg, lovastatin ≥40 mg, fluvastatin ≥80 mg, pravastatin ≥40 mg, or any statin plus ezetimibe). Studies were classified as familial hypercholesterolemia (FH) studies if inclusion criteria required diagnosis of FH by genotyping or clinical criteria.…”

One-Year Efficacy and Safety of Evolocumab in Japanese Patients ― A Pooled Analysis From the Open-Label Extension OSLER Studies ―

“…6 YUKAWA-2 was a 12-week, phase 3 study evaluating the efficacy and safety of evolocumab along with lowdose or high-dose atorvastatin in Japanese patients with hyperlipidemia or mixed dyslipidemia and high CV risk. 7 Patients eligible for the YUKAWA studies were ≥20 years old, had stable statin therapy prior to screening, and triglycerides ≤400 mg/dL. Additionally, YUKAWA-1 patients were required to have LDL-C ≥115 mg/dL plus any statin at screening, while patients in YUKAWA-2 were required to have LDL-C ≥100 mg/dL and were also required to be on atorvastatin 5 or 20 mg daily.…”

“…6, 7 Here, we report 1-year efficacy and safety data from an analysis of Japanese patients who completed a 12-week phase 2 or 3 evolocumab clinical trial in Japan (YUKAWA-1 or YUKAWA-2, respectively), and continued into 1 of 2 ongoing evolocumab open-label extension (OLE) studies (OSLER-1 and OSLER-2). C ardiovascular (CV) disease-related deaths from heart disease and stroke are the second and third highest causes of death in Japan.…”

Evolocumab: rising momentum as novel antidyslipidemic drug

“…25 In total, 507 patients were screened for the study and 409 were randomized to 5mg/day or 20mg/day atorvastatin doses. Subsequently, patients underwent the second randomization to evolocumab 140mg biweekly (Q2W) or 420 mg monthly (QM) or placebo Q2W or QM.…”