Evolocumab Safe and Effective Out to 5 Years: OSLER-1

When given on top of standard of care (SOC), evolocumab (Repatha; Amgen) consistently lowers LDL cholesterol out to 5 years with good safety and tolerance as well as no development of neutralizing antibodies, according to late follow-up from the OSLER-1 trial.

“The final report of the OSLER-1 study adds valuable information about treating patients with hypercholesterolemia using evolocumab over an extended time frame,” lead author Michael Koren, MD (Jacksonville Center for Clinical Research, Florida), and colleagues write. “This consistent efficacy over time provides reassurance, especially given the expressed concerns about overcoming possible tendencies for less aggressive background pharmacotherapy and diet following the initiation of anti-PCSK9 therapy.”

Koren told TCTMD that based on these data, he has “no reservations” about recommending PCSK9 inhibitors to patients with hypercholesterolemia who are not meeting guideline-recommended lipid levels despite maximally tolerated statins. “This class of anti-PCSK9 drugs is extremely safe and can be used over a long period of time without an increasing rate of side effects. In fact some side effects may go down a little bit over the course of extended use. And the lipid results . . . were incredibly steady and impressive,” he said.

The main OSLER-1 trial randomized over 1,000 patients with hypercholesterolemia who were initially enrolled in phase II parent studies of evolocumab to SOC alone or plus evolocumab 420 mg subcutaneously every 4 weeks. At 1 year, the researchers found the study drug reduced LDL-cholesterol levels and showed a trend toward reduced cardiovascular events compared with SOC. After 1 year, all patients were eligible to receive open-label evolocumab.

For this analysis, published in the October 29, 2019, issue of the Journal of the American College of Cardiology, Koren et al followed 1,255 patients who received at least one dose of evolocumab in the original study—881 received their first dose during the SOC control period and 374 during the all-evolocumab phase. Overall, 71% of these patients used statins at the time of receiving their first open-label dose of evolocumab, including 20% at high intensity.

Over approximately 2, 3, 4, and 5 years of exposure, the PCSK9 inhibitor on top of SOC lowered mean LDL-cholesterol levels by 56% (n = 1,071), 57% (n = 1,001), 56% (n = 943), and 56% (n = 803), respectively. Mean baseline LDL cholesterol dropped from 140 to 61 mg/dL on evolocumab. The drug also lowered mean apolipoprotein B, median lipoprotein(a), and median triglyceride levels, and it increased HDL-cholesterol.

Yearly rates of serious adverse events among patients who received evolocumab plus SOC ranged from 6.9% to 7.9%, comparable to the 6.8% rate observed in the SOC group through 1 year. In total, 27% of patients discontinued evolocumab over the 5-year period, which equals a 6.7% annualized discontinuation rate. Also, two patients each in the SOC alone and SOC plus evolocumab groups developed new, transient, binding antidrug antibodies, but the researchers did not identify any neutralizing antibodies or any loss in treatment efficacy.

“Further, the present study showed no clinical evidence of increased hypersensitivity with extended evolocumab treatment,” the authors write. “For example, the rate of possible injection-site reactions (based on MedDRA search strategies) decreased from a 4.1% annualized rate in the first year of exposure to evolocumab to 0.2% annually in year 4 and beyond, a trend that likely reflects both improved injection skills and the absence of immunogenicity.”

Another advantage to these results is that they “extend the safety findings from the FOURIER study,” Koren and colleagues write, acknowledging that while an open-label trial design “does not allow for a vigorous evaluation of cardiovascular outcomes, the continued low rate of adjudicated cardiovascular events in the OSLER-1 study provides reassurance about the persistence of clinical benefits over longer-term anti-PCSK9 therapy.”

Unique Study Design

In an editorial accompanying the study, M. John Chapman, PhD, DSc (Pitié-Salpetriere Hospital, Paris, France), and Henry Ginsburg, MD (Columbia University, New York, NY), highlight the unique design of OSLER-1: patients included in the first year as SOC controls provide a comparator against themselves in years 2-5.

Indeed, “by using this methodology, you get a good sense for whether or not the yearly rates are going up, down, or staying the same,” Koren said. “And we were able to track these rates. . . . This open-label year 1 control group methodology is not a commonly used tool, but I think it's a very powerful one to look at long-term safety.”

“Overall, these findings augur well for the use of PCSK9 inhibitors in the chronic treatment of high and very-high-risk hypercholesterolemic patients, and particularly in those with residual cardiovascular risk whose LDL cholesterol level on treatment with either a statin or statin-ezetimibe combination is not at the guideline-recommended goal of < 70 mg/dL,” Chapman and Ginsburg conclude.

In the future, “we need to look at research that really focuses on the patients who get the most bang for their buck,” Koren argued. “These drugs will cost significantly more than statins, of course, and some people will definitely get benefit from them. The question is: which patients get that benefit?’”

Broadly, patients at the highest risk should derive the most benefit from PCSK9 inhibitors, he said. “But getting more specific, how about patients that can take some statins but can't take enough—is that a good patient population to target for PCSK9 antibodies? What about patients following bypass surgery or other high-risk patients who have other events on statins regardless of LDL-cholesterol levels? . . . [Also], we know that patients that have an acute coronary syndrome are at high risk for complications a year after their acute coronary syndrome, so should we be prescribing anti-PCKS9 drugs for a year after that period of time to allow for plaques to stabilize?”