New information emerged today about two new cholesterol-lowering drugs that have been attracting a lot of attention. Data about the PCSK9 inhibitors-- evolocumab, under development by Amgen, and alirocumab, under development by Sanofi and Regeneron-- were published in the New England Journal of Medicine.
The effects of the two drugs appeared to be broadly consistent. Both lowered LDL cholesterol powerfully, which is what the drugs were designed to do. The situation is less clear regarding the more difficult to ascertain safety and tolerability of the drugs and their long-term clinical effects. On the one hand the very early data suggests that the LDL lowering effect may result in a substantial cardiovascular benefit. On the other hand, early signs hinting at adverse neurocognitive and other effects may put a brake on the so far unimpeded progress of the drugs through the FDA approval process.
Evolocumab
Investigators presented combined results from 2 open-label randomized extension studies of evolocumab comparing 2 regimens of the injectable monoclonal antibody (140 mg every 2 weeks or 420 mg every month) to standard therapy. 4,465 patients were followed for 11.1 months. The trials were designed to obtain longer-term information about the safety and side effect profile of the drug, and also to obtain a "prespecified exploratory analysis" of cardiovascular events.
As expected, evolocumab resulted in a large 61% reduction in LDL, from 120 mg/dl to 48 mg/dl. Overall there was a similar rate of serious adverse events (7.5% in each group) but there was a small increase in neurocognitive events (0.9% versus 0.3%). The investigators noted that these events did not appear to be related to the reduction in LDL and further pointed out that the open-label design and the greater number of visits in the treatment group might have played a role. (However, one observer, Sanjay Kaul, said that it is also possible that these events are indicative of an off-target effect.)
The rate of cardiovascular events at 1 year was 0.95% in the evolocumab patients versus 2.18% in the control group (HR 0.47, CI 0.28-0.78, p=0.003). It should be noted, however, that this analysis contained only 60 total events. But, the investigators cautioned, the cardiovascular outcomes of the drug can not be fully determined until the completion of the ongoing 27,500 patient FOURIER trial. In a presentation of the results at the American College of Cardiology meeting in San Diego, principal investigator of the trial Marc Sabatine said that FOURIER will include a formal assessment of neurocognitive side effects.
Alirocumab in ODYSSEY
ODYSSEY offered a similar look at the long term effect of alirocumab. The trial was designed to assess the LDL lowering effect and the long term safety of alirocumab on 2,341 patients. In line with expectations, treatment with a 1 ml injection of alirocumab every two weeks resulted in a large 62% reduction compared to placebo. Overall there were a similar number of adverse events in both groups but alirocumab was linked to an increase in some adverse events, including injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%).
The investigators also reported a post hoc analysis of major adverse cardiovascular events, consisting of cardiac death, nonfatal MI, stroke, or unstable angina requiring hospitalization. At 78 weeks the event rate was 1.7% in the alirocumab group versus 3.3% in the placebo group (HR 0.52, CI 0.31-0.90, p=0.02).
Editorial
In an accompanying editorial, Neil Stone and Donald Lloyd-Jones, both of whom served as e co-authors of the recent cholesterol guidelines, write that the reduction in cardiovascular events with both drugs "whet our appetites for further results that show cardiovascular benefit and documented safety." They express hope that, like statins, the beneficial effect will continue to grow over time.
But, they state, "it would be premature to endorse these drugs for widespread use before the ongoing randomized trials... are available." Until these trials are finished they say that use of the drugs should fit within the recent guidelines which recommend non-statin therapy in high-risk patients with persistently high LDL levels despite statin therapy or in people who are unable to tolerate statins.
Click here for a fuller discussion about the neurocognitive findings.
