BACKGROUND Evolocumab and other anti-PCSK9 antibodies reduced adverse cardiovascular outcomes in clinical trials
of high-risk patients over <3 years median treatment duration. OBJECTIVES The OSLER-1 trial (Open Label Study of Long Term Evaluation Against LDL-C Trial) evaluated longer-term effects of evolocumab during open-label hypercholesterolemia treatment for up to 5 years. METHODS Patients randomized to standard of care (SOC) or evolocumab 420 mg monthly (evolocumab þ SOC) for year 1. After year 1, patients could enter the all-evolocumab period and receive evolocumab þ SOC for an additional 4 years. The authors analyzed the persistence of lipid effects and exposure-dependent safety focusing on yearly rates of adverse events (AEs) and anti-drug antibodies over 4.951 patient-years of observation. RESULTS A total of 1,255 patients (safety analysis population) randomized into the year 1 SOC-controlled period and received $1 evolocumab dose (mean SD age 57 12 years; 53% female). A total of 1,151 patients (efficacy analysis population) progressed to the all-evolocumab period (year 2 and beyond). Evolocumab þ SOC persistently lowered mean SE low-density lipoprotein cholesterol (LDL-C) by 56% 0.6% (n ¼ 1,071), 57% 0.8% (n ¼ 1,001), 56% 0.8% (n ¼ 943), and 56% 0.8% (n ¼ 803) after approximately 2, 3, 4, and 5 years, respectively, from randomization. Mean baseline LDL-C decreased from 140 to 61 mg/dl on treatment. Yearly serious AE rates during evolocumab þ SOC ranged from 6.9% to 7.9%, comparable to the 6.8% rate in SOC patients during year 1. Evolocumab discontinuation due to AEs occurred in 5.7% of patients. Two SOC and 2 evolocumab þ SOC patients developed new, transient, binding anti-drug antibodies; no neutralizing antibodies were observed. CONCLUSIONS The OSLER-1 trial demonstrated consistently excellent LDL-C–lowering efficacy, tolerance, and safety of evolocumab, with no neutralizing antibodies detected, throughout the longest-duration study of a PCSK9 inhibitor reported to date. (Open Label Study of Long Term Evaluation Against LDL-C Trial [OSLER-1]; NCT01439880) (J Am Coll Cardiol 2019;74:2132–46) © 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.