Efficacy and Safety of Longer-Term Administration of Evolocumab (AMG 145) in Patients With Hypercholesterolemia

BACKGROUND: Evolocumab (AMG 145), a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein cholesterol (LDL-C) in phase 2 studies of 12 weeks' duration. The longer-term efficacy and safety of PCSK9 inhibition remain undefined. METHODS AND RESULTS: Of 1359 randomized and dosed patients in the 4 evolocumab phase 2 parent studies, 1104 (81%) elected to enroll into the Open-Label Study of Long-term Evaluation Against LDL-C (OSLER) study. Regardless of their treatment assignment in the parent study, patients were randomized 2:1 to receive either open-label subcutaneous evolocumab 420 mg every 4 weeks with standard of care (SOC) (evolocumab+SOC, n=736) or SOC alone (n=368). Ninety-two percent of patients in the evolocumab+SOC group and 89% of patients in the SOC group completed 52 weeks of follow-up. Patients who first received evolocumab in OSLER experienced a mean 52.3% SE, 1.8% reduction in LDL-C at week 52 (P<0.0001). Patients who received 1 of 6 dosing regimens of evolocumab in the parent studies and received evolocumab+SOC in OSLER had persistent LDL-C reductions (mean reduction, 50.4% SE, 0.8% at the end of the parent study versus 52.1% SE, 1.0% at 52 weeks; P=0.31). In patients who discontinued evolocumab on entry into OSLER, LDL-C levels returned to near baseline levels. Adverse events and serious adverse events occurred in 81.4% and 7.1% of the evolocumab+SOC group patients and 73.1% and 6.3% of the SOC group patients, respectively. CONCLUSION: Evolocumab dosed every 4 weeks demonstrated continued efficacy and encouraging safety and tolerability over 1 year of treatment in the largest and longest evaluation of a PCSK9 inhibitor in hypercholesterolemic patients to date. CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov. Unique identifier: NCT01439880.