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Evolocumab shows promise in GAUSS-2, LAPLACE-2 trials
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WASHINGTON — Findings from two trial demonstrate that evolocumab, a PCSK9 inhibitor, lowered LDL in statin-intolerant patients as well as in patients taking concomitant statin therapy.
In the GAUSS-2 and LAPLACE-2 trial, patients assigned evolocumab, an investigational fully human monoclonal antibody in development by Amgen, had lower LDL levels at the end of the study compared with patients assigned ezetimibe (Zetia, Merck).
GAUSS-2
In the GAUSS-2 trial, researchers evaluated whether evolocumab would lower LDL compared with ezetimibe in patients with hypercholesterolemia and statin intolerance (n=307). The study had two primary endpoints: mean percentage change from baseline in LDL at 10 and 12 weeks and percentage change from baseline in LDL at 12 weeks.
Randomization occurred on a 2:2:1:1 basis as follows: subcutaneous evolocumab 140 mg biweekly plus daily oral placebo; subcutaneous evolocumab 420 mg monthly plus daily oral placebo; subcutaneous placebo biweekly plus daily oral ezetimibe 10 mg; or subcutaneous placebo monthly plus daily ezetimibe 10 mg.
Erik S.G. Stroes
Patients assigned the biweekly dose of evolocumab had a treatment difference in LDL reduction vs. ezetimibe of –37% at a mean of 10 weeks and 12 weeks and a difference of –38% at 12 weeks, while those assigned a monthly dose of evolocumab had a treatment difference in LDL reduction vs. ezetimibe of –39% at a mean of 10 weeks and 12 weeks and a difference of –38% at 12 weeks (P<.001 for all comparisons), Erik S.G. Stroes, MD, from Academic Medical Center, Amsterdam, said at a press conference.
Adverse event rates were very low, he said, and the evolocumab group had a lower rate of myalgia than the ezetimibe group (8% vs. 18%).
Evolocumab is “clinically efficacious whether you [take] it biweekly or monthly, it’s better than ezetimibe, it’s well-tolerated in a difficult high-risk patient population with a clinically unmet need,” Stroes said. “We hope this will be a very good option for these patients.”
LAPLACE-2
In the LAPLACE-2 trial, researchers assessed the efficacy of evolocumab in patients with hypercholesterolemia and mixed dyslipidemia also taking a statin (n=2,067). The primary outcome was mean percentage change from baseline in LDL at 10 and 12 weeks.
Participants were randomly assigned to one of five statin regimens: atorvastatin 10 mg; atorvastatin 80 mg; rosuvastatin (Crestor, AstraZeneca) 5 mg; rosuvastatin 40 mg; or simvastatin 40 mg. They were then randomly assigned to evolocumab, ezetimibe or placebo.
Jennifer G. Robinson
Patients assigned evolocumab had LDL reductions of 63% to 75% compared with placebo at a mean of weeks 10 and 12, while those assigned ezetimibe had LDL reductions of 19% to 32% compared with placebo (P>.001 for all comparisons), Jennifer G. Robinson, MD, MPH, from the College of Public Health at University of Iowa, said at the press conference.
There was no difference in adverse event rates between the groups.
“[Evolocumab] really seems to have quite a clean profile,” she said. – by Erik Swain
For more information:
Robinson J. Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials.
Stroes ESG. Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials. Both presented at: American College of Cardiology Scientific Sessions; March 29-31, 2014; Washington, D.C.
Disclosure: The studies were funded by Amgen. Robinson reports financial ties with Amarin, Amgen, AstraZeneca, Daiichi Sankyo, Genentech, GlaxoSmithKline, Hoffman-LaRoche, Pfizer, Sanofi-Aventis, Sanofi/Regeneron and Takeda. Stroes reports financial ties with Merck, Novartis and Sanofi.
Perspective
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Peter Libby, MD
The results of the ensemble of studies — not just with this agent, but other agents with similar approaches — are not surprising based on what we know from the human genetics. I think it is very important for planning phase 3 mega-trials to know the best dose regimen and drug interactions, as explored in these smaller studies. You need to do these investigations to understand the ABCs of these agents. I think these results certainly indicate a green light to go ahead with the large-scale endpoint trials, which are the ultimate proof.
Perspective
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Roger S. Blumenthal, MD
The action of the PCSK9 inhibitors seems clean and the results seem reproducible, no matter whether it is given alone, on top of a moderate- or high-dose statin, or on top of ezetimibe. We learned from the latest set of [ACC/American Heart Association] guidelines that numbers don’t necessarily translate into things that we have to do as cardiologists. The bar has been raised so high that for widespread use we are going to need to see still longer term safety and more events. But, I think there is a possibility that if 2- or 3-year follow-up data don’t show any safety signals, then the PCSK9 inhibitors could get approved for select very-high-risk groups. Of interest, only about 8% of patients in the GAUSS-2 trial had symptoms of myalgia. Evolocumab is a subcutaneous injection; it can’t be administered orally because the monoclonal antibody will get broken down in the stomach and intestine. But, for example, diabetics routinely give themselves subcutaneous injections; I think the high-risk individuals could certainly do this if there aren’t other good options available.
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