The big news this weekend out of the American College of Cardiology’s annual scientific session was the comparison of long-term outcomes for two new (and competing) drugs targeting cholesterol, the injectables known as PCSK9 inhibitors. Regeneron’s (REGN) alirocumab and Amgen’s {AMGN) evolocumab both lowered bad cholesterol meaningfully in large, randomized studies – no surprise – and both appear to have a beneficial effect on cardiovascular outcomes. Observers, however, have been keen to point out that these drugs may have negative neurocognitive effects. Both drugs are expected to be approved later this year, with alirocumab slightly ahead.
Results for alirocumab and evolocumab were published in the New England Journal of Medicine on Sunday.
In the 78-week and 2,341-patient ODYSSEY trial, Regeneron’s alirocumab produced a 62% reduction in cholesterol compared to control at 24 weeks. Alirocumab was linked to an increase in some adverse events, including injection-site reactions (5.9% vs. 4.2%) and neurocognitive events (1.2% vs. 0.5%).
Most importantly, in a post hoc analysis, the rate of major adverse cardiovascular events (death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or hospitalization) was lower with alirocumab than with placebo (1.7% vs. 3.3%) with a hazard ratio of 0.52 – essentially, the risk of an event is reduced by 42% with the new product (95% confidence interval, 0.31 to 0.90; nominal P=0.02).
Meanwhile in two open-label extension studies of evolocumab, 4,465 patients were followed for 11.1 months. Evolocumab reduced LDL cholesterol by 61% compared to placebo (from 120 mg per deciliter to 48 mg per deciliter (P<0.001)). Adverse events were similar between the two groups, though neurocognitive events were reported more frequently in the evolocumab group (.9%) versus the control group (.3%) . The rate of cardiovascular events at 1 year was improved from 2.18% in the standard-therapy group to 0.95% in the evolocumab group (HR of 0.47; 95% confidence interval, 0.28 t o 0.78; P=0.003).
In an NEJM editorial accompanying the publication, Drs. Neil Stone and Donald Lloyd-Jones explain that while PCSK9s are on track to become “important arrows in our quiver” calling for their widespread use would be premature without followup from other ongoing and immense trials.
Reports from several lipid treatment trials provide important object lessons in this regard. Two trials of niacin revealed lower levels of LDL cholesterol and lipoprotein(a) when niacin was added to statin therapy but no net clinical benefit and very worrisome signals of harm.6 A randomized, controlled trial of torcetrapib reminds us that “off-target” effects can scuttle a promising drug.7 And the recent long-awaited presentation of results of a trial in which ezetimibe was added to moderate-intensity statin therapy in high-risk patients showed only modest benefit, though with excellent safety.8
REGN and AMGN both climbed in early trading on Monday.
One or more of PropThink’s contributors are long AMGN or REGN.
