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Long-Term Efficacy and Safety of Evolocumab in Patients With Hypercholesterolemia
Michael J Koren1, Marc S Sabatine2, Robert P Giugliano2
1Jacksonville Center for Clinical Research, Jacksonville, Florida.
Insights
Evolocumab (a PCSK9 inhibitor) demonstrated sustained LDL-C reduction and a favorable safety profile in high-risk patients over 5 years. This long-term study confirmed its efficacy and tolerability in managing cholesterol levels.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Clinical Trials
Background:
- Anti-PCSK9 antibodies, including evolocumab, have shown efficacy in reducing cardiovascular events in high-risk patients.
- Previous trials demonstrated benefits with a median treatment duration of under 3 years.
Purpose of the Study:
- To evaluate the long-term effects of evolocumab on lipid levels and safety.
- To assess the persistence of lipid-lowering effects and exposure-dependent safety over up to 5 years.
Main Methods:
- The OSLER-1 trial involved patients receiving standard of care (SOC) or evolocumab + SOC.
- Patients transitioned to an all-evolocumab period for up to 4 additional years.
- Analysis focused on lipid changes, adverse events (AEs), and anti-drug antibodies over 4.951 patient-years.
Main Results:
- Evolocumab + SOC consistently lowered LDL-C by approximately 56% over 5 years.
- Mean LDL-C decreased from 140 mg/dl to 61 mg/dl.
- Serious AE rates were comparable to SOC, and no neutralizing antibodies were detected.
Conclusions:
- The OSLER-1 trial provides the longest safety and efficacy data for a PCSK9 inhibitor to date.
- Evolocumab demonstrated sustained LDL-C reduction and excellent tolerance.
- No neutralizing antibodies were observed, supporting the long-term safety of evolocumab.
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).
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