Long-term Low-Density Lipoprotein Cholesterol-Lowering Efficacy, Persistence, and Safety of Evolocumab in Treatment of Hypercholesterolemia: Results Up to 4 Years From the Open-Label OSLER-1 Extension Study

Abstract

Importance: The Open-Label Study of Long-term Evaluation Against LDL-C (OSLER-1) evaluated the durability of long-term efficacy and safety during long-term therapy with evolocumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9).

Objective: To determine whether LDL-C level reductions with evolocumab persist across different populations. Secondary objectives included assessment of adverse events, antidrug antibodies, and factors contributing to treatment discontinuation.

Design, setting, and participants: This ongoing, randomized open-label extension trial (OSLER-1) was conducted at 192 sites in 18 countries. A total of 1324 of 1666 patients randomized into 1 of 5 12-week double-blind phase 2 parent studies completed a parent study and chose to participate in OSLER-1; 1255 received 1 or more evolocumab doses. As of August 2016, 812 of 1324 (61%) had 208 weeks of follow-up. This current study was conducted from October 2011 to August 2016, with a data cutoff of August 26, 2016.

Interventions: During year 1, patients were randomized to evolocumab, 420 mg, plus standard of care (SOC) or SOC alone. After year 1, all patients continuing the study received evolocumab, 420 mg, plus SOC.

Main outcomes and measures: Lipids, safety, and tolerability every 12 weeks. A multivariate model identified factors associated with discontinuation of evolocumab.

Results: At parent study baseline, the mean (SD) age of the population was 57.1 (11.6) years, with 52.9% being women. The median LDL-C level was 133 mg/dL (to convert to millimoles per liter, multiply by 0.0259). After 52 weeks, evolocumab plus SOC was associated with a significant reduction in LDL-C level by 61% (95% CI, -63% to -60%) vs 2% (95% CI, -5% to -0.2%) with SOC alone (P < .001). At approximately 2, 3, and 4 years of study follow-up, the median LDL-C level was reduced by 59% (95% CI, -60% to -57%), 59% (95% CI, -61% to -58%), and 57% (95% CI, -59% to -55%), respectively, from parent study baseline. For patients receiving statin therapy unchanged from baseline, at week 208, the median LDL-C level reduction was 58%. No neutralizing antibodies to evolocumab were detected. The annualized incidence of new-onset diabetes was 4% in the SOC alone group and, adjusting for duration of evolocumab exposure, 2.8% in the evolocumab plus SOC group. Neurocognitive event rates were 0% (SOC alone) and 0.4% (evolocumab plus SOC). A total of 79% of patients persisted with evolocumab treatment, with a mean exposure duration of 44 months.

Conclusions and relevance: In the longest clinical trial exposure to a PCSK9 inhibitor to date, evolocumab produced sustained reductions in LDL-C levels. The annual frequency of adverse events did not occur more frequently with cumulative exposure during open-label observation.

Trial registration: clinicaltrials.gov Identifier: NCT01439880.

Figure 1.. Patient Disposition in Open-Label Study of Long-term Evaluation Against LDL-C (OSLER-1)

Patients enrolled into OSLER-1 from 1 of 5 phase 2 parent studies. Patients were randomized 2:1 to receive evolocumab plus standard of care (SOC) or SOC alone for the first 52 weeks during the SOC-controlled period. Subsequently, all patients were eligible to receive 420 mg of evolocumab in addition to SOC every month. A total of 812 patients had 4 or more years of follow-up; the persistence rate was 79%. GAUSS-1 indicates Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects; LAPLACE-TIMI, LDL-C Assessment With Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined With Statin Therapy–Thrombolysis in Myocardial Infarction 57 Trial; MENDEL-1, Monoclonal Antibody Against PCSK9 to Reduce Elevated Low-Density Lipoprotein Cholesterol in Adults Currently Not Receiving Drug Therapy for Easing Lipid Levels; RUTHERFORD-1, Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder; and YUKAWA-1, Study of LDL-Cholesterol Reduction Using a Monoclonal PCSK9 Antibody in Japanese Patients With Advanced Cardiovascular Risk.

Figure 2.. Effects of Evolocumab on Low-Density Lipoprotein Cholesterol (LDL-C) Level Over 4 Years

Calculated LDL-C percentage change from the phase 2 parent study baseline to week 208 of the Open-Label Study of Long-term Evaluation Against LDL-C (OSLER-1). The error bars represent SEs. Plot is based on observed data with no imputation for missing values. The median baseline LDL-C level was 133 mg/dL. The median week 208 on-treatment LDL-C level was 60 mg/dL. The key shows parent study assignment/year 1 assignment/long-term open-label assignment. To convert LDL-C to millimoles per liter, multiply by 0.0259. SOC indicates standard of care.