Need proof that CV outcomes are make-or-break? See Merck's reaction to anacetrapib trial win

Few thought Merck & Co.’s cholesterol-fighting candidate anacetrapib would hit its phase 3 trial goals. After all, three other drugs in the CETP inhibitor class failed dismally. But anacetrapib pulled it off, and the med might just join other new therapies vying for patients who’ve failed on standby statin drugs.

A big question mark remains—will Merck actually file for approval?—and the data released Tuesday are broad-brush only. The drug met its primary endpoint in the Reveal trial, full stop. Details won’t be available till the European Society of Cardiology meeting in August.

As always, it’s the details that will tell. Merck itself said in announcing the results that it’s weighing an FDA filing, not planning one, so the data likely aren’t clear cut.

Whatever Merck decides, its initial uncertainty illustrates just how important cardiovascular outcomes trials have become for new drugs in that field. And given the lukewarm response to Amgen’s PCSK9 outcomes trial, Fourier, it appears doctors and payers don’t just want proof that these drugs do deliver benefits—they want those benefits to be hefty.

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Here’s one difference, though. Merck’s Reveal used a composite endpoint that comprised heart-related death, heart attack and coronary bypass surgery. Unlike some outcomes trials, including Amgen’s Repatha test, Reveal’s composite goal didn’t include stroke. Leerink Partners analyst Seamus Fernandez pointed out that fact in a Tuesday note, adding that the Merck trial also bore out a previously disclosed risk—anacetrapib accumulated in trial patients’ fatty tissue—and that’s a potential safety worry.

Given that, the drug would probably need to deliver a “very robust” CV benefit—particularly a reduction in risk of cardiovascular death—to be worth the trouble of a launch, the analyst said. Leerink’s team has discussed the issue with cardiologists before, and some said they’d be comfortable with using the med, so far as it hit its goals in Reveal.

Others, however, said they’d be more cautious. “[G]iven multiple other oral and injectable therapies being available for treating hyperlipidemia,” Fernandez wrote Tuesday, those cardiologists “feel it would take a long time for them to incorporate anacetrapib into their practice in any meaningful way.”

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In fact, the company said it’s consulting with external experts about the possible filing, and Barclays Capital analysts say Merck is likely looking for feedback from the medical community. “We got the sense ... that Merck is waiting for the reaction from leading KOLs and CV trial groups like TIMI and the Cleveland Clinic to get a better sense in which the direction the winds are blowing with regard to anacetrapib’s benefit/risk profile before proceeding with a filing,” Barclays’ Geoff Meacham wrote in a Tuesday note.

And prescribers are only one group of partners Merck would need to make anacetrapib a success. As Amgen has seen with Repatha—and fellow PCSK9 drugmakers Sanofi and Regeneron have experienced with Praluent—reluctant payers can put the brakes on a seemingly certain trip to blockbusterdom.

Of course, payers had been citing a lack of CV outcomes data as reason to be wary of adopting the PCSK9s more broadly. Amgen now has its Repatha outcomes data, and the reaction to that study may be a cautionary tale for Merck with anacetrapib. Industry watchers leapt on Repatha’s failure to deliver a big decrease in cardiovascular death, and though the drug showed some dramatic long-term effects on heart attack and stroke risk, percentagewise, analysts totted up the absolute numbers and said they weren’t too impressed.

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Amgen, for its part, says it’s negotiating with payers and hurdles to Repatha use are coming down. For example, the California-based drugmaker recently inked a deal with Harvard Pilgrim Healthcare that gives the insurer a refund if a Repatha patient suffers a heart attack.

If doctors and payers aren’t loudly applauding Repatha’s 33% cut to heart attack and stroke risk after a year’s therapy, then Merck would logically have to beat Repatha’s results to get the market excited. Hence the discussions with outside experts.

Bernstein analyst Tim Anderson cited the drug’s long half-life—and consequent accumulation in the body—as one reason for Merck’s reluctance to commit to filing for approval, despite obvious safety effects in previous trials. Second possibility “the effect size (meaning the magnitude of heart attack reduction) may not be very clinically meaningful,” Anderson wrote Tuesday.

If that’s the case, then anacetrapib may never make its way to store shelves, partly because of other alternatives already on the market, including generic statins and Merck’s newly generic Zetia. “[T]he company might reason that the commercial case to file for approval is a weak one,” Anderson said. We’ll likely have to wait till ESC rolls around to find out for sure.