OSLER Results Offer Early Encouragement on Longer-Term Safety and Efficacy of PCSK9 Inhibitor

The first event-related outcomes for the PCSK9 inhibitor evolocumab (Repatha, Amgen) are an encouraging step in the right direction but are not the final word on the investigational lipid-lowering therapy. So says a Cleveland Clinic cardiologist involved in studies of the agent.

The results, from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) program, were presented as a late-breaking trial at the American College of Cardiology’s 64th Annual Scientific Session and simultaneously published in the New England Journal of Medicine. They showed that evolocumab plus standard therapy reduced LDL cholesterol by 61 percent after 11 months of use compared with standard therapy alone. An exploratory analysis found that evolocumab also was associated with significantly reduced rates of adjudicated cardiovascular events.

“This was only a one-year follow-up and was not a blinded study, so some questions about long-term safety and efficacy remain,” says Michael Rocco, MD, Medical Director of Cardiac Rehabilitation and Stress Testing in Cleveland Clinic’s Section of Preventive Cardiology. He adds that a slightly increased incidence of neurocognitive events in the evolocumab group relative to the control group needs to be explored more fully, although the absolute rate of such events was low.

“The overall results provide strong encouragement that we are on the right track with the PCSK9 inhibitors and that they may well lead to further improvements in cardiovascular health,” notes Dr. Rocco, who is Cleveland Clinic’s site principal investigator for the OSLER program. “They consistently lower LDL cholesterol in a broad range of patients while demonstrating a very acceptable safety profile. We need to continue looking at how the low LDL levels achieved with these agents affect cardiovascular health over the long term.”

OSLER program at a glance

The reported data come from an analysis combining patients who completed short-term studies of evolocumab and were allowed to enroll in one of two longer-term extension trials. OSLER-1 included 1,324 patients who completed one of five phase 2 parent studies. OSLER-2 included 3,141 patients who completed one of seven phase 3 parent studies.

Participants were randomized to standard therapy alone (N = 1,489) or standard therapy plus evolocumab (N = 2,976) for approximately one year. Evolocumab was given via subcutaneous injection at a dosage of 140 mg every two weeks or 420 mg once monthly. Standard therapy was based on local guidelines for treatment of LDL cholesterol; 85 percent of patients in the standard therapy group were taking a statin or ezetimibe.

Essentials of safety and efficacy outcomes

The primary end point was incidence of treatment-related adverse events, which generally occurred at similar frequencies in the two treatment groups, although the rate of neurocognitive adverse events was slightly higher in the evolocumab group (0.9 percent) vs. the standard therapy group (0.3 percent).

Secondary end points included percentage change in mean LDL cholesterol, which declined in the evolocumab group from 120 mg/dL at baseline to 48 mg/dL within the first 12 weeks of treatment — a 61 percent reduction (P < .001) — and was sustained at that level up to 48 weeks.

Exploratory analysis showed that 0.95 percent of the evolocumab group suffered some type of adjudicated cardiovascular event (death, a coronary event, a cerebrovascular event or heart failure requiring hospitalization) vs. 2.18 percent of the standard therapy group — a 53 percent reduction (P = .003).

Only time can answer remaining questions

Dr. Rocco notes that evolocumab and other PCSK9 inhibitors are potent monoclonal antibodies that have consistently lowered LDL cholesterol by 50 to 60 percent.

The question now, he says, is what happens with these agents over time. “Will these drugs remain safe over the long term, and will they reduce adverse cardiovascular events in various populations of patients? OSLER looked at about 4,500 individuals and found the same robust 60 percent LDL cholesterol reduction we’ve seen in short-term trials, but it also found greater than 50 percent reduction in events such as heart attack, stroke, need for bypass surgery and death from cardiovascular causes.”

More event studies of other PCSK9 inhibitors

Similar reductions in LDL cholesterol and cardiovascular events reported for another PCSK9 inhibitor (alirocumab) in the newly published ODYSSEY LONG TERM trial provide additional support for a benefit from further reductions in LDL cholesterol.

Three large ongoing trials are continuing to address these questions with various PCSK9 inhibitors in patients over three to five years, Dr. Rocco points out. “Up to 60,000 individuals are likely to be included in these trials cumulatively,” he says. “We expect results at the end of 2017 or in 2018, and I think they will provide the definitive answer.”

These trials are being conducted in a blinded fashion, in contrast to the open-label aspect of the OSLER extension studies, which Dr. Rocco cites as a weakness of the new OSLER report, along with the short-term follow-up and low numbers of events. “Without blinded randomization, knowledge of what the patient was receiving may subtly influence patient management decisions or reporting of adverse events and side effects,” he says.