Merck & Co. revealed Jan. 19 that patients at high risk for stroke were removed from a Phase III trial of anti-clotting agent vorapaxar due to findings by the data safety monitoring board of increased intracranial hemorrhage in that population. The risk of bleeding greatly diminishes the prospects for the drug, one of the key pipeline products Merck acquired through its purchase of Schering-Plough last year.

The announcement came about one week after Merck reported that it was ending the Phase III TRACER study of vorapaxar - also known as TRA (Thrombin Receptor Antagonist) -in patients with acute coronary syndrome and removing patients who experienced a stroke before or during the trial from the TRA-2P study, based on DSMB guidance (Also see "Phase III Setback For Merck's Antithrombotic Damages One Of The Key Assets Of The Schering Merger" - Pink Sheet, 13 January, 2011.).

At the time the trial changes were announced, Merck was blinded to the study results and did not know why the DSMB recommended the changes. Industry analysts widely speculated, however, that an excess bleeding risk was likely observed. Merck has still has not seen the data from either trial and does not know how the changes will affect its plans to file an NDA for the compound later this year, a spokesperson said.

Merck reportedly had hoped to position vorapaxar in competition with Eli Lilly's Effient (prasugrel), which carries a black box warning for bleeding risk.

The decision to shut down TRACER concludes a trial in which enrollment of nearly 13,000 patients was completed in June 2010, with about 10,000 patients having reached the minimum follow-up requirement of one year. The primary endpoint of the study is time to first occurrence of events including cardiovascular death, heart attack, stroke or recurrent ischemia with re-hospitalization, or urgent coronary revascularization. Enough events occurred to power the trial for efficacy, although many remaining patients will not meet the minimum follow-up.

The removal of about 6,000 patients from the TRA-2P secondary prevention trial still leaves about 20,000 patients in the study - those with prior heart attack or peripheral arterial disease. The DSMB recommended that the trial continue in those patients, Merck noted Jan. 19.

In a letter to Merck, TRA-2P study chairman Eugene Braunwald wrote that the DSMB has "observed an increase in intracranial hemorrhage in patients with a history of stroke that is not outweighed by [its] considerations of potential risk."

Braunwald added, "in contrast ... the DSMB recommended to us that it is important that the trial continue to completion in the more than 20,000 patients who qualified for the trial with myocardial infarction or peripheral arterial disease who have not had a stroke." He cited the compound's remaining potential to reduce death and ischemic events in such patients.

Analysts Not Optimistic About Benefit-To-Risk Ratio

Analysts, however, suggest that the chances of vorapaxar producing a good enough benefit-to-risk ratio in the remaining trial is slight.

In an interview, Barclays Capital analyst Tony Butler said he is not optimistic about the future of vorapaxar. "Importantly, [the finding is] bleeding in a certain population ... but I think this notion of bleeding brings to bear the idea that risk for this product is extraordinarily high and, therefore, the net present value of this particular product diminishes substantially. I think most individuals have effectively written it off as a failure."

Even the ongoing findings from the TRA-2P trial might be more of an academic exercise at this point, he added.

"From a scientific or medical perspective, it might be interesting to see what happens with the rest of the 20,000 patients in TRA-2P, but the risk that that trial is successful is extraordinarily high," Butler said. "I'm not saying it's a failure, but it does make you wonder what was the impetus for continuing the study."

In a Jan. 19 note, UBS Investment Research analyst Marc Goodman concurred, predicting a finding of clinical efficacy in TRA-2P but only to a degree that would be more than offset by excess bleeding risk. The study is still powered to demonstrate a 10% efficacy difference between vorapaxar and placebo, he wrote. However, he estimated that a 2% to 3% excess bleeding risk in heart attack and PAD patients will culminate in a negative clinical profile.

"Thus, while TRA-2P can be statistically positive, we believe both its regulatory and commercial prospects are low," Goodman said, lowering vorapaxar's chance of regulatory success to 15%.

Beyond the risk of bleeding, he said another problem is that while the PAD market is large - maybe 12% to 14% of the U.S. population - about 75% of patients go untreated because there is little to no reimbursement for testing for PAD.

As in TRA-2P, Goodman expects vorapaxar to demonstrate efficacy but poor benefit-to-risk in the TRACER study. "Given that the trial was not stopped at the interim analysis (50% of the required events), the negative profile did not appear until after most of the patients (about 77%) had been on vorapaxar for over a year," he said. "Therefore, we would assume that the intracranial hemorrhage signal is severe and related to duration of treatment."

-Joseph Haas (j.haas@elsevier.com)

Intracranial Hemorrhage The Culprit In Merck's Vorapaxar Trial

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