Evolocumab (AMG 145), a fully human monoclonal antibody to PCSK9, effectively reduced LDL cholesterol and decreased the incidence of cardiovascular (CV) events when added to standard therapy, according to data presented at the American College of Cardiology (ACC) Scientific Sessions 2015.
The results were from the latest analysis of the phase 2 (OSLER-1) and phase 3 (OSLER-2) open-label extension studies of evolocumab. The findings were simultaneously published in the New England Journal of Medicine.
Combined data from the OSLER-1 and OSLER-2 studies showed this investigational agent plus standard of care treatment reduced adjudicated CV events, including death, myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack and heart failure, by more than 50% (rate, 0.95% in the evolocumab group vs. 2.18% in the standard therapy group; HR=0.47; 95% CI, 0.28-0.78).
Additionally, evolocumab plus standard of care treatment was found to reduce LDL cholesterol levels by 61%, from a median of 120 mg/dL to 48 mg/dL, compared with standard of care alone.
The OSLER-1 and OSLER-2 trials are ongoing open-label extension studies designed to characterize long-term effects of evolocumab. The trials enrolled 4,465 patients who had completed one of 12 phase 2 and phase 3 studies.
In the studies, a total of 2,976 patients were randomly assigned to subcutaneous evolocumab 140 mg every 2 weeks or 420 mg monthly plus standard of care therapy and 1,489 were randomly assigned to standard of care alone.
Adverse events occurred in 2,060 of 2,976 patients (69.2%) in the evolocumab group and 965 of 1,489 patients (64.8%) in the standard therapy group. These events were considered serious in 222 patients (7.5%) assigned evolocumab and 111 patients (7.5%) assigned standard therapy.
Though the rate of neurocognitive adverse events was low overall, they were reported more frequently among patients assigned evolocumab. Incidence of these events, however, did not seem to be associated with LDL level during treatment, the researchers noted.
Other reported adverse events included arthralgia, limb pain, headache, injection site reaction (evolocumab group only) and fatigue.
The researchers noted, however, that few CV outcomes occurred, which limited the study results. An ongoing trial of 27,500 patients to evaluate the effect of evolocumab on CV outcomes, with data expected in 2017.
Even so, the OSLER-1 study showed that this agent maintained its efficacy over a 2-year period and indicated that safety risks were balanced between the two treatment groups. Additionally, Michael Koren, MD, who is an investigator for the OSLER-1 study and CEO of the Jacksonville Center for Clinical Research in Florida, said that over a period of 24 months, evolocumab showed a safety and efficacy profile in patients with hypercholesterolemia consistent with what was seen in previous studies.
Kim Eagle, MD, who is a professor of internal medicine and director of the Cardiovascular Center at the University of Michigan Health System in Ann Arbor, said PCSK9 inhibitors like evolocumab could make a significant difference in high-risk patients who cannot tolerate statins due to their side effects. Another benefit with this class of drugs may be compliance, and investigators are currently studying monthly or bimonthly injections.
“The big issue will be cost,” said Dr. Eagle in an interview with Endocrinology Advisor. “Drugs in this class change how cholesterol is synthesized and metabolized. Most of the studies have looked at these drugs in patients who are intolerant or fail statins. It appears that the PCSK9 inhibitors appear to be well tolerated and at first glance appear to have fewer side effects than statins.”
This study was supported by Amgen, a manufacturer of the drug.
- Sabatine MS et al. Late-Breaking Clinical Trial: Effect of the PCSK9 Inhibitor Evolocumab on Cardiovascular Outcomes. Presented at: American College of Cardiology (ACC) 64th Annual Scientific Session & Expo; March 14-16, 2015; San Diego.
- Sabatine MS et al. N Engl J Med. 2015; doi:10.1056/NEJMoa1500858.