Pooled Safety Analysis of Evolocumab

Study Questions:

What is the safety and tolerability of evolocumab, a PCSK9 antibody, in a pooled safety analysis of controlled trials and the first year of open-label extension (OLE) trials that included a standard-of-care control group?


Analysis included adverse event (AE) data from 6,026 patients in 12 phase 2 and 3 parent trials with a median exposure of 2.8 months, and of those patients, from 4,465 patients who continued with a median follow-up of 11.1 months in two OLE trials. AEs were analyzed separately for the parent and OLE trials. Overall AE rates, serious AEs (SAEs), laboratory assessments, and AEs of interest were evaluated.


Overall AE rates were similar between evolocumab and control in the parent trials (51.1% vs. 49.6%) and in year 1 of OLE trials (70.0% vs. 66.0%), as were those for SAEs. Elevations of serum transaminases, bilirubin, and creatine kinase were infrequent and similar between groups. Muscle-related AEs were similar between evolocumab and control. Neurocognitive AEs were infrequent and balanced during the double-blind parent studies (5 events [0.1%], evolocumab groups vs. 6 events [0.3%], control groups). In the OLE trials, 27 patients (0.9%) in the evolocumab groups and 5 patients (0.3%) in the control groups reported neurocognitive AEs. No neutralizing anti-evolocumab antibodies were detected.


Overall, this integrated safety analysis of 6,026 patients pooled across phase 2/3 trials and 4,465 patients who continued in open-label extension trials for 1 year supports a favorable benefit-risk profile for evolocumab.


Importantly, AE rates did not increase among patients attaining very low levels of low-density lipoprotein cholesterol (LDL-C) (<25 mg/dl) compared to LDL-C levels ≥40 mg/dl. The results of the very large (>25,000 patients) long-term prospective randomized outcome trial of evolocumab versus placebo in high-risk patients with atherosclerotic cardiovascular disease (press release reportedly positive), will be presented at the American College of Cardiology Annual Scientific Session. Among the major issues remaining is whether there is evidence for neurocognitive changes over the long-term.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Antibodies, Monoclonal, Atherosclerosis, Bilirubin, Cholesterol, LDL, Creatine Kinase, Drug-Related Side Effects and Adverse Reactions, Dyslipidemias, Myalgia, Primary Prevention, Proprotein Convertases, Transaminases

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