More Promising Results for PCSK9 Inhibitors

March 15, 2015

More Promising Results for PCSK9 Inhibitors

  1. Harlan M. Krumholz, MD, SM

A pair of randomized trials found significant reductions in LDL cholesterol for the drugs versus placebo, with similar rates of adverse events.

  1. Harlan M. Krumholz, MD, SM

Interest in the proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors is intensifying as large phase 3 trials move toward completion and anticipation builds about FDA rulings. Meanwhile, smaller industry-sponsored trials continue to offer hints of how the drugs may affect outcomes.

The ODYSSEY LONG TERM trial, a phase 3 randomized, double-blind, placebo-controlled study of alirocumab, enrolled 2341 patients with heterozygous familial hypercholesterolemia or established coronary disease from 320 sites in 27 countries. Patients had LDL cholesterol levels of 70 mg/dL or higher and were receiving a statin at the maximally tolerated dose. The drug was discontinued in 28% of the alirocumab group and 25% of the placebo group. At 24 weeks, the mean percentage change in LDL, the primary endpoint, was −61% in the alirocumab group and +0.8% in the placebo group. Cardiovascular events occurred in 4.6% of the alirocumab group and 5.1% of the placebo group.

The OSLER long-term follow-up trial enrolled patients who had completed one of 12 open-label, randomized trials of evolocumab. The parent studies had different entry criteria, but the follow-up trial required that patients had not experienced an adverse event leading to discontinuation of the medication, were stable, and did not need unblinded lipid measurements. They were randomized to evolocumab with standard therapy or to standard therapy alone. At 12 weeks, evolocumab was associated with a 61% reduction in LDL compared with standard therapy. Serious adverse effects were similar in the two groups; rates of cardiovascular events at 1 year were 0.95% in the evolocumab group and 2.18% in the standard-therapy group.

Comment

The news from the early trials of PCSK9 drugs continues to be encouraging. With large phase 3 trials in progress, these latest findings should raise hopes but shouldn't yet be considered definitive demonstration of the benefit and risk profile of these drugs. The authors are careful to note that these trials were not designed to assess long-term clinical outcomes.

Editor Disclosures at Time of Publication

  • Disclosures for Harlan M. Krumholz, MD, SM at time of publication Consultant / Advisory board United Healthcare; VHA, Inc.; Premier, Inc. Equity ImageCor Grant / Research support FDA; NIH-NHLBI; Commonwealth Fund; The Catherine and Patrick Weldon Donaghue Medical Research Foundation; Robert Wood Johnson Foundation; Medtronic Editorial boards BMJ.com/us; American Journal of Managed Care; American Journal of Medicine; Archives of Medical Science; Central European Journal of Medicine; Critical Pathways in Cardiology; Current Cardiovascular Risk Reports; JACC: Cardiovascular Imaging; Journal of Cardiovascular Medicine; Circulation: Cardiovascular Quality and Outcomes Leadership positions in professional societies American Board of Internal Medicine (Chair, Assessment 2020 Task Force)

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