DUBLIN – The FDA issued Merck & Co. Inc. a complete response letter to its supplemental new drug applications for cholesterol-lowering drugs Zetia (ezetimibe) and Vytorin (ezetimibe and simvastatin), which sought to add claims that they reduced the risk of cardiovascular events, including death, to existing label claims on lowering low-density lipoprotein cholesterol (LDL-C).

Merck, of Kenilworth, N.J., said it “is reviewing the letter and will determine next steps.” With patent expirations for both products looming in April 2017 – and an “authorized” generic version of ezetimibe due to appear by the end of 2016 – Merck appears to have few options available to it that would reverse the decision in a time frame that would be commercially meaningful. Moreover, the emergence of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor class raises further questions about Vytorin’s clinical utility.

Vytorin has long been a lucrative hedge for Merck against the genericization of its statin franchise, which went off patent in mid-2006. The drug, which gained approval in 2004, has delivered blockbuster revenues for all but a couple of years since – sales declined during 2008 and 2009 on concerns, later dismissed, that it caused cancer. Most of those sales were gained in the absence of any direct evidence that Vytorin had any effect on cardiovascular mortality or morbidity, however. Its effects on LDL-C alone – a surrogate endpoint – drove its aggressive and successful marketing efforts for many years.

The Enhance (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) study, which investigated its effects on arterial plaque buildup in patients with familial hypercholesterolemia, failed to show that adding Zetia to simvastatin had any benefit. The failure – and the failure to communicate the study’s outcome in a timely fashion – triggered a class action suit, which eventually resulted in a $688 million settlement. The mammoth Improve-IT trial (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) sought to settle the long-running controversy over the drug’s ambiguous clinical benefits. (See BioWorld Today, Nov. 18, 2014.)

That study, which appeared in the June 18, 2015, issue of The New England Journal of Medicine, gained emblematic status on the basis of being the first cardiovascular outcomes trial to establish there was an additive benefit from taking two cholesterol-lowering drugs, acting through different mechanisms. It was held up as further evidence in support of the LDL hypothesis – that reducing LDL-C by any means (Zetia reduces intestinal absorption of cholesterol by inhibiting the Niemann-Pick C1-like 1 protein) – is beneficial.

The scale of that benefit was modest, however, and critics consider its clinical significance to be marginal at best. The issue had become evident during the early years of the study, when Schering-Plough – which developed Zetia and which jointly marketed Vytorin with Merck until they joined forces following a $41 billion takeover of Schering-Plough in 2009 – increased its recruitment target from 12,500 to 18,000 patients to boost its chances of detecting an efficacy signal. When the data were eventually unveiled, the necessity of that move became obvious. There was little to separate the two treatment arms: 32.7 percent of those on Vytorin experienced either cardiovascular death, a major coronary event or nonfatal stroke vs. 34.7 percent of those in the control arm, who received simvastatin only.

The writing was on the wall for the application since December, when the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 10-5 against the application, on the grounds that the effect was too small to be clinically meaningful. One of the dissenters argued that the FDA’s task was to assess the statistical significance of the data – determining the clinical merits or demerits of a drug was the job of payers. The agency has the last word, however, and has the luxury of having never to apologize or explain.

The present refusal does not signify the immediate end of the road for Vytorin, however, as the drug retains its existing label, that it can lower LDL-C in patients. Moreover, the IMPROVE-IT investigators found that patients older than 75, as well as those with diabetes, obtained most benefit from Vytorin therapy. And Zetia continues to clock up large sales among the substantial subgroup of patients with cardiovascular disease who are intolerant to statins, even if it has never shown clear evidence that it has any benefit as a monotherapy. Merck has not yet published the individual sales figures for the two products in 2015, but together they pulled in $3.777 billion, down from $4.166 billion in 2014.

The first cardiovascular outcomes data for a PCSK9 inhibitor – Repatha (evolocumab), marketed by Thousand Oaks, Calif.-based Amgen Inc. – are due in the second half of this year. Paris-based Sanofi SA and Tarrytown, N.Y.-based Regeneron Pharmaceuticals Corp. are expected to unveil data for their rival product, Praluent (alirocumab), in 2017. Although one expert in cardiovascular genomics told this writer there is “an irrational exuberance” driving expectations for those drugs, their superior activity in lowering LDL-C is expected to result in a significant drop in the rate of cardiovascular events. He put it at no more than 25 percent, however. Even so, that is a lot more than 2 percent – and if payers can stomach the pricing, it will soon be harder than ever to make a clinical case for Vytorin.