Caution in First PCSK9 Inhibitor Vote Reflects Sentiment of Earlier Reviews

Editorials that appeared during the run-up to the FDA advisory committee meetings noted the lack of long-term cardiovascular data and the need to be cautious about lowering cholesterol at any cost.

The caveats in Tuesday’s 13-3 vote from the FDA advisory panel reviewing alirocumab, the first of 2 PCSK9 inhibitors facing deadlines for action, have the potential to take huge potential markets for the drug off the table. But for anyone following editorials in leading journals, the ambivalence shouldn’t have come as a surprise.

FDA’s 16-member Endocrinologic and Metabolic Drugs Advisory Committee found that manufacturer, Sanofi-Regeneron, had “sufficiently established that the LDL cholesterol—lowering benefit of alirocumab exceeds its risks,” and to “support approval in one or more patient populations.” That’s the question the panel must answer.

But in doing so, panel members addressed the same concerns that were raised during a press conference at this year’s meeting of the American College of Cardiology (ACC), and in editorials in the New England Journal of Medicine and Annals of Internal Medicine. Overall, those voting in favor said these powerful, cholesterol-fighting medications may be of benefit for patients who have very high cholesterol levels and other risk factors who have failed other therapy, or have a history of familial hypercholesterolemia.

Several panel members made it clear, however, that alirocumab should not be viewed as a routine substitute for statins, the stand-bys that most patients rely upon. Patients who cannot tolerate statins were a point of contention, although they have been viewed by the drugmakers as prime candidates for PCSK9 inhibitors. The sentiments echoed the editorial that appeared in Annals on April 28, 2015, which said while the drugs hold promise, long-term data on cardiovascular risks will not be known for some time.

“Confirmation of these findings in long-term, ongoing, pivotal trials with prespecified CVD end points and monitoring of a range of adverse events will help establish the role of these novel agents in CVD risk management,” the writers said at the time.

In March, when cardiovascular benefits of rival drug evolocumab were presented at ACC and published in NEJM, the opinion was “not-so-fast,” in contrast with the intense marketing present at that conference. “The evidence-driven cholesterol guidelines did not endorse the concept that lower LDL cholesterol levels are better at all costs,” the writers said, adding that “how you get there” matters, and risks to patients must be assessed. Evolocumab, made by Amgen, faces its advisory panel discussion today.

PCSK9 inhibitors have been touted as revolutionary in that they can reduce cholesterol by as much as 60%, while also reducing the number of cardiovascular events. However, it has been noted that the cardiovascular evidence has come from small trials with short-term follow-up.

FDA’s concern about long-term cardiovascular effects is rooted in the experience of the last decade, when the diabetes drug rosiglitazone became a blockbuster, only to be linked in an NEJM meta-analysis to increased heart attack risk. While a later study caused FDA to reverse restrictions it put on the drug, the episode changed the way the regulators do business, as seen by 2 giant trials evaluating cardiovascular risk on diabetes drugs that were presented this past weekend at the 75th Scientific Sessions of the American Diabetes Association.

If an FDA approval reflects the advisory committee sentiments, it will be welcome to pharmacy benefit managers and health plans who have been bracing themselves for the “next Sovaldi,” as prices for the PCSK9 inhibitors have been estimated at about $10,000 a year. While that is not as expensive as the high-priced cure for hepatitis C virus, the prospect of waves of patients switching from low cost statins to a costly, branded drug had many nervous.