Caution in PCSK9 Inhibitor Votes Reflects Sentiment of Earlier Reviews

July 28, 2015
Mary K. Caffrey

Evidence-Based Diabetes Management, July 2015, Volume 21, Issue SP11

A review published before FDA's vote on alirocumab outlines how editorials in 2 major journals were reflected in subsequent votes by advisory panels.

In separate votes in June, an FDA advisory panel recommended approval for the first 2 PCSK9 inhibitors, a powerful new class of drugs that has been shown to lower cholesterol by as much as 60% in clinical trials. However, the 13-3 vote to recommend alirocumab, which came on June 9, 2015, followed by the 11-4 vote to recommend evolocumab on June 10, 2015, showed a cautious approach on the part of the FDA’s Endocrinologic and Metabolic Drug Advisory Committee (which had slightly different makeup over the 2 days).

As the panel discussed alirocumab, a drug from Sanofi-Regeneron that will be marketed as Praluent, advisory committee members expressed concern that patients might abandon statins, which are cheap and have a proven safety record, for these lesser-known newcomers. Fewer than half the panel members taking part in the alirocumab vote were on board with approving the drug for patients who cannot tolerate statins— which had to unsettle drug makers, since statin-intolerant patients have been viewed as an important market for this drug class.1

In fact, when Amgen made its presentation the next day on evolocumab, to be marketed as Repatha, the company brought in Marc Sabatine, MD, MPH, to make the case for why patients who cannot tolerate statins should have access to the therapy. But when the vote came, only 4 panel members were satisfied that evolocumab should be approved for patients who were statin-intolerant; a slim majority voted for its use in patients who have high cholesterol and high cardiovascular (CV) risk.2

The PCSK9 inhibitors nearing FDA approval are monoclonal antibodies that have been touted as a revolutionary way to lower cholesterol. They target a protein in the liver, the proprotein convertase subtilisin kexin 9, inactivating it to dramatically lower low-density lipoprotein (LDL), or “bad,” cholesterol. Their development is based on the discovery of a genetic mutation among groups of pa-tients with very low levels of cholesterol.3

FDA advisory committee members agreed that both drugs are worthwhile and much-needed solutions for patients who suffer from a genetic disorder, familial hypercholesterolemia. Voting on alirocumab also seemed likely to extend access to younger patients who have extremely high cholesterol levels, who have been unable to control cholesterol with other therapy, or who have uncontrolled cholesterol coupled with a high risk of heart attack or stroke.

Beyond that, the split votes over the 2 days make it hard to say who else will gain access, and what restrictions the FDA will include on the label.

The caveats concerning both votes have the potential to take significant markets for the drug off the table. But for anyone who’s been following editorials in leading journals, the ambivalence shouldn’t have come as a surprise.

In discussing both drugs, panel members addressed the same concerns that were raised during a press conference at the March meeting of the American College of Cardiology (ACC) and in editorials in the New England Journal of Medicine and Annals of Internal Medicine.4-6 FDA panel members made it clear that PCSK9 inhibitors should not be viewed as a routine substitute for statins, the standbys on which most patients rely. Their sentiments echoed the editorial that appeared in Annals on April 28, 2015, which said while the drugs hold promise, long-term data on CV risks will not be available until at least 2017.6

“Confirmation of these findings in long-term, ongoing, pivotal trials with pre-specified CVD [cardiovascular disease] 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 the CV benefits of rival drug evolocumab were presented at ACC and published in NEJM, the reaction was “not so fast,” in contrast to the in-tense 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, add-ing that “how you get there” matters, and risks to patients must be assessed.5

The FDA’s concern about long-term CV 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-anal-ysis to increased heart attack risk. The FDA now requires CV outcomes trials for all new diabetes drugs. While there have been some promising CV results for PCSK9 inhibitors, it has been noted that the evidence has come from small trials with short-term follow-up.3

If an FDA approval reflects the advi- sory 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.7 RefeRences

1. Herper M. Federal panel recommends approv-ing high powered cholesterol shot with cautions. Forbes website. matthewherper/2015/06/09/federal-panel-recommends-approving-high-powered-cholester-ol-shot-with-cautions/. Published June 9, 2015. Accessed June 20, 2015.

2. Herper M. Live blog: FDA panel for Amgen’s cholesterol drug Repatha. Forbes website. Published June 10, 2015. Accessed June 22, 2015.

3. Curfman G. PCSK9 inhibitors a major advance in cholesterol lowering therapy. Harvard Health Blog. pcsk9-inhibitors-a-major-advance-in-cholesterol-lowering-drug-therapy-201503157801. Published March 15, 2015. Accessed June 9, 2015.

4. Caffrey MK. Cholesterol fighting evolocumab also reduced cardiovascular events, study finds. Am J Manag Care. 2015; 21(SP7):SP232-SP233.

5. Stone NJ, Lloyd-Jones DM. Lowering LDL cholesterol is good, but how and in whom [published online March 15, 2015]. N Engl J Med. doi:10.1056/NEJMe1502192.

6. Cainzos-Achirica M, Martin SS, Cornell JE, et al. PCKS9 inhibitors: a new era in lipid-lowering treatment? [published online April 28, 2015]. Ann Intern Med. doi:73226/M15-0920.

7. Caffrey MK. The formularies fight back: AJMC panelists discuss how discounts, exclusivity deals should expand HCV treatment. Am J Pharm Ben. 2015;7(2):107-108.