Merck's Frontrunner Antiplatelet Hits Brick Wall

Yesterday Merck announced major changes to 2 mammoth, placebo-controlled phase 3 trials of its novel antiplatelet agent,* which the company acquired by way of its famous merger with Schering-Plough. The use of vorapaxar,** specifically a thrombin-receptor antagonist, will be discontinued completely in the TRACER study, a hospital-based study of patients with acute coronary syndrome, and discontinued partly in the TRA-2P (or TIMI-50) study, a trial enrolling patients with prior MI, stroke, or peripheral artery disease. In the TRA-2P study, the drug will be stopped in stroke patients only, which make up about 25% of the study population, says the company's press release.

Reasons for the trial changes, which were made on the basis of a review by the Data and Safety Monitoring Board, are speculative; but the logical conclusion is that bleeding events were substantially greater in patients receiving the investigational drug. An article describing the TRA-2P study, published last year in the American Heart Journal by the TIMI Study Group, suggested that bleeding risks might be (relatively) reduced with varapaxar, because it "does not interfere with other pathways for hemostasis." (The standard, comparator antiplatelet would be aspirin, which acts fairly high up in the clotting cascade.)

Analysts' responses to Merck's news were cautious (which can be interpreted as extremely bearish). The company's share value was (probably overly) slammed on the news, by losing about 6% of its value.

Others are questioning whether the Merck-Schering merger was worth it, given the latest performance of this frontrunner compound—on which Merck (and others) placed high blockbuster-like hopes.

* Not to be confused with an anticoagulant and the developing market for this class of compounds.

** Aka SCH 530348.

01/20/11 update: In yesterday's press release, Merck reveals that, yes indeed, the reason that stroke patients are being removed from the TRA-2P study is because of an increased risk of hemorrhage—specifically an increased risk of intracranial hemorrhage. Patients with MI or peripheral vascular disease will continue on in the secondary-prevention* study of the company's novel antiplatelet agent.

According to the venerable Eugene Braunwald, Harvard cardiologist and chairman of the study, the Data and Safety Monitoring Board "observed an increase in intracranial hemorrhage in patients with a history of stroke that is not outweighed by their considerations of potential benefit."

Although TRA-2P is placebo controlled, all enrollees are receiving standard of preventive care in the form of aspirin or clopidogrel. The design of the trial is such that patients are undergoing (or underwent) randomization to treatment on the basis of their vascular disease and whether they were to receive clopidogrel. (So as far as I can tell, the study is one of really dual-antiplatelet therapy—in patients assigned to the investigational drug.)

* Or tertiary prevention, depending on how you define the term.