Original Investigation
Long-Term Efficacy and Safety of Evolocumab in Patients With Hypercholesterolemia

https://doi.org/10.1016/j.jacc.2019.08.1024Get rights and content
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Abstract

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 + SOC) for year 1. After year 1, patients could enter the all-evolocumab period and receive evolocumab + 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 + SOC persistently lowered mean ± SE low-density lipoprotein cholesterol (LDL-C) by 56% ± 0.6% (n = 1,071), 57% ± 0.8% (n = 1,001), 56% ± 0.8% (n = 943), and 56% ± 0.8% (n = 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 + 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 + 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)

Key Words

evolocumab
LDL-cholesterol
lipoproteins
PCSK9
randomized controlled trial

Abbreviations and Acronyms

ADA
anti-drug antibody
AE
adverse event
ApoB
apolipoprotein B
LDL-C
low-density lipoprotein cholesterol
Lp(a)
lipoprotein(a)
PCSK9
proprotein convertase subtilisin/kexin type 9
SAE
serious adverse event

Cited by (0)

Amgen (Thousand Oaks, California) provided funding for the study, and was responsible for the design and conduct of the study; conducted collection and management of data; participated in the analysis and interpretation of the data in partnership with independent authors; and participated in the preparation, review, or approval of the manuscript in partnership with the independent authors. Dr. Koren is employed by Jacksonville Center for Clinical Research, a company that has received research funds and consulting fees from Amgen, Pfizer, Regeneron, Sanofi, and The Medicines Company. Dr. Sabatine has received institutional research grant support from Abbott Laboratories, Amgen, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Gilead, GlaxoSmithKline, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, Novartis, Poxel, Pfizer, Quark Pharmaceuticals, Roche Diagnostics, and Takeda; and has received consulting fees from Alnylam, Amgen, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, DalCor, Dyrnamix, Esperion, IFM Therapeutics, Intarcia, Ionis, Janssen Research and Development, The Medicines Company, MedImmune, Merck, MyoKardia, and Novartis. Dr. Giugliano has received research grant support from Amgen; has received honoraria from Amgen, Amarin, Daiichi-Sankyo, Akcea, Bristol-Myers Squibb, CVS Caremark, and Pfizer. Dr. Langslet has received lecture and Advisory Board fees from Amgen, Sanofi, and Boehringer Ingelheim. Dr. Wiviott has received institutional grants from Amgen, Arena, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Eisai, Eli Lilly, Janssen, Merck, and Sanofi; has received consulting fees from Angel Medical Systems, ARENA, AstraZeneca, Allergan, Boehringer Ingelheim, Boston Clinical Research Institute, Bristol-Myers Squibb, Daiichi-Sankyo, Eisai, Eli Lilly, ICON Clinical Research, Janssen, Lexicon, Merck, St. Jude Medical, Servier, and Xoma; and his spouse is an employee of Merck. Drs. Ruzza and Hamer are employees of and own stocks/stock options in Amgen. Dr. Ma is employed as a contractor on behalf of Amgen. Dr. Wasserman is an employee of and holds stocks/stock options in Amgen; and appears on a number of pending patents owned by Amgen relating to evolocumab and PCSK9 inhibition. Dr. Raal has received research grants, honoraria, or consulting fees for professional input and/or delivered lectures from Sanofi, Regeneron, Amgen, and The Medicines Company.

Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.