PCSK9 Inhibitors Show Promise Where Statins Fall Short

A new class of LDL-lowering drugs—human monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PSCK9)—was a highlight at the American College of Cardiology 2014 Scientific Sessions.

In multiple clinical trials, PSCK9 inhibitors demonstrated the ability to lower LDL cholesterol in patients with hypercholesterolemia for whom therapy with statins or ezetimibe was not very effective or well tolerated.

“This is the most powerful LDL-lowering therapy ever discovered. Although we don’t yet know the effect of these drugs on long-term outcomes, they appear to be safe and effective at lowering LDL-C in patients who can’t tolerate statins,” says Steven Nissen, MD, Chairman of the Department of Cardiovascular Medicine at Cleveland Clinic.

Unlike existing oral cholesterol-lowering agents, PCSK9 inhibitors are administered subcutaneously. Administration every two weeks or monthly dosing are being evaluated.

The largest evidence came from five trials of Amgen’s evolocumab. However, trials of Sanofi/Regeneron’s alirocumab and Pfizer’s bococizumab were also presented.

DESCARTES randomized 901 patients to diet alone, atorvastatin 10 mg/day, atorvastatin 80 mg/day or atorvastatin 80 mg/day plus ezetimibe 10 mg/day. Patients who reached an LDL of 75 mg/dL or higherwere randomized to evolocumab 420 mg/monthly or a placebo every 4 weeks. By week 12, evolocumab had reduced LDL a mean of 57 percent, compared with placebo.

MENDEL-2 randomized 614 hypercholesterolemic patients to evolocumab, ezetimibe or placebo. Evolocumab given biweekly at 140 mg or monthly at 420 mg lowered LDL 55 to 57 percent over placebo and 38 to 40 percent over ezetimibe.

RUTHERFORD-2 evaluated the safety, tolerability and efficacy of evolocumab in 331 patients with heterozygous familial hypercholesterolemia taking statins and/or ezetimibe. Participants were randomized to one of three doses of the drug or placebo given biweekly or monthly. The evolocumab dosing regimens proved equivalent and effective at lowering LDL 61 to 63 percent in 10 to 12 weeks.

LAPLACE-2 randomized patients with primary hypercholesterolemia and mixed dyslipidemia to a daily statin for four weeks, then to treatment with various doses and regimens of evolocumab. In all cases, the new drug was highly effective in reducing LDL, with as many as 95 percent of patients in the high-intensity group achieving an LDL of less than 70 mg/dL. Adding the new agent to ezetimibe reduced LDL levels to levels as low as 33 mg/dL. Additionally, evolucumab significantly reduced non-LDL cholesterol, apolipoprotein B and lipoprotein (a) levels.

GAUSS-2 included 307 patients with a mean LDL of 193 mg/dL who had shown intolerance to two or more statins: the majority had failed four or more statins. The patients were randomized to evolocumab biweekly or monthly plus oral placebo, or to ezetimibe daily plus monthly subcutaneous placebo. Compared with ezetimibe, evolocumab had nearly twice the LDL-lowering power, reducing LDL by 53 to 56 percent versus 37 to 39 percent. More than 75 percent of high-risk patients treated with the monoclonal antibody achieved an LDL less than 100 mg/dL—an accomplishment reached by less than 10 of ezetimibe patients.

ODYSSEY is a program of six trials evaluating alirocumab in more than 22,000 patients. Results of two of the trials were presented at ACC. In the first, patients with elevated LDL levels at moderate risk for cardiovascular disease were randomized to the study drug at 75 mg given every two weeks or to ezetimibe 10 mg. At 24 weeks, alirocumab had reduced LDL levels 54.1 percent, while ezetimibe produced a drop in LDL of 17.2 percent.

In the second study, which compared alirocumab with statins and ezetimibe in patients with heterozygous familial hypercholesterolemia, the study drug lowered LDL levels by 60 percent.

Trials of bococizumab lag behind those of alirocumab and evolocumab. In a randomized, placebo-controlled, dose-ranging study of the drug in statin-treated hypercholesterolemic patients, researchers reported that the addition of bococizumab produced significant reductions in LDL cholesterol.

Despite these impressive short-term findings, the long-term effects of PCSK9 inhibitors still need to be evaluated. More information will be available in 2018, when the FOURIER study is completed, although the FDA may approve one or more of these drugs before cardiovascular outcome trials are finished. The Fourier study is 22,500-patient trial is evaluating evolocumab versus statin therapy in high-risk patients with a composite endpoint of cardiovascular death, myocardial infarction and hospitalization for revascularization, unstable angina or stroke. The other makers of PCSK9 inhibitors are conducting similar studies.