Merck makes it official: excess bleeding doomed trial

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Merck confirmed that excess bleeding was the reason one of two big clinical trials of experimental blood-thinning agent vorapaxar was stopped.
Even without official details, analysts had been speculating that increased hemorrhaging was the reason the trial, called TRACER, was halted. And now vorapaxar's once blockbuster commercial prospects have moderated as the investment community assesses Merck's chances of salvaging research into whether the drug can prevent heart attacks, not in acute coronary syndrome (ACS) as TRACER was designed to do, but in the remaining study population—secondary prevention.
The firm announced last week that TRACER, a 13,000-patient Phase III study, was being terminated and that a second trial, the TRA-2P study evaluating vorapaxar in secondary prevention of heart attacks, would continue but without the roughly 6,000 patients who had a stroke before entry into the study.
In a Merck statement, issued late yesterday, the chairman of TRA-2P, Dr. Eugene Braunwald, reported that the Data and Safety Monitoring Board (DSMB), which had recommended the study changes, “observed an increase in intracranial hemorrhage in patients with a history of stroke that is not outweighed by their [the DSMB's] considerations of potential benefit.”
Among patients without a history of stroke, of which there are more than 20,000 with myocardial infarction or peripheral arterial disease, the DSMB recommended that the trial continue.
Merck's statement didn't come as a shock to analysts. In a note to investors last Friday, Sanford Bernstein's Tim Anderson wrote that, “In all likelihood, it was excessive bleeding that caused the problem,” based on which he modeled a delay in the launch of vorapaxar from 2012 to 2013, and a decrease in its 2015 sales forecast from $1.2 billion to $300 million—a 75% decline—equating to a decline in EPS of 4%.
“At this point, it seems prudent to eliminate (or nearly eliminate) vorapaxar from investor models,” wrote Anderson. That seemed to be what investors were thinking; Merck stock sunk 7% on the day the study changes were announced.
But this reaction may have been overstated, observed Barclays Capital's Tony Butler, based on his own EPS estimates. Even in what Butler calls the “bear-case scenario,” should the agent fail both indications in ACS and secondary prevention in the setting of atherosclerosis, he estimated a top-line impact in 2015 of $400-500 million and an EPS impact of 3-4%.
Should vorapaxar succeed in secondary prevention—Butler's bull case, and the one he expects to happen—“we note the loss of TRACER has very limited impact for the company's 2015 outlook: $100-150M on top line or <1% impact on EPS.”
Others seem to feel that it may be premature to rule out vorapaxar. Credit-Suisse's Catherine Arnold revised her Merck estimates to reduce vorapaxar's probability of success from 65% (secondary prevention) and 75% (ACS) to 35%, leading to a new 2016 global vorapaxar sales forecast of $800 million.
“Vorapaxar may have no role in patients with acute coronary syndrome (ACS), especially those who are given a stent and receive a number of other anti-thrombotic drugs as well,” she wrote this week after meeting with a cardiologist to assess the agent's prospects. “Vorapaxar may still prove to be a useful drug, however, in the roughly 1/3 of ACS patients who are treated medically and in longer-term secondary prevention based on 2P.”
And data from TRA-2P should be sufficient for filing purposes, despite the elimination of the 6,000 patients without a history of stroke, Arnold added. “Our expert feels that the remaining 20,000 patients should be sufficient to see an impact on heart attacks and coronary revascularization, but likely not on overall cardiac mortality.”
Especially if past is precedent. In the Jupiter trial, a study involving AstraZeneca's Crestor, Arnold noted, “18,000 patients was sufficient to see a difference in cardiovascular morbidity and mortality in patients at a much lower risk for future events than those in [Merck's] 2P.”
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