FDA Panel Will Have To Resolve Bleeding Risk With Merck’s Vorapaxar
This article was originally published in The Pink Sheet Daily
Executive Summary
Novel antiplatelet product has suffered from excess bleeding rates in clinical trials and is searching for an appropriate patient population, after initial hopes of being a blockbuster.
Advisory committee members will have to grapple with bleeding risks associated with Merck & Co. Inc.’s platelet inhibitor vorapaxar, a product once thought to be a potential blockbuster, but now likely searching for an ideal population for use.
Vorapaxar, proposed trade name Zontivity, will go before the Cardiovascular and Renal Drugs Advisory Committee Jan. 15 as part of a three-day meeting; Chelsea Therapeutics International Ltd.’s Northera (droxidopa) and Johnson & Johnson’s Xarelto (rivaroxaban) will also be reviewed on the 14th and 16th, respectively (Also see "Acceptability Of Revised Study Expected To Be On Agenda For Northera Advisory Panel" - Pink Sheet, 10 Oct, 2013.).
The novel protease activated receptor-1 (PAR-1) antagonist has a proposed indication of reduction of atherothrombotic events in patients with a history of myocardial infarction. Merck also proposed that the product has been shown to reduce the rate of a combined endpoint of cardiovascular death, MI, stroke and urgent coronary revascularization, according to a Federal Register notice expected to be published Dec. 17.
Bleeding Risk Clouds Potential Use
Vorapaxar was once considered a highlight of Merck’s merger with Schering-Plough (Also see "Merck R&D: A Jam-Packed Pipeline But Much Of It Wait-And-See" - Pink Sheet, 11 May, 2010.). However, bleeding issues seen in vorapaxar’s clinical trials have tempered expectations for the drug’s use.
It was thought that the thrombin receptor antagonist could create a new class of antiplatelet agents to compete with Eli Lilly & Co./Daiichi Sankyo Co. Ltd.’s Effient (prasugrel) in the antithrombotic market.
Effient has had its own problems with increased bleeding, which were also discussed by the Cardio-Renal advisory committee. The drug was cleared with a “black box” warning on bleeding risk (Also see "Effient Approval Shows Mark Of FDA Controls" - Pink Sheet, 15 Jul, 2009.). AstraZeneca PLC’s Brilinta (ticagrelor) was subsequently approved with a less extensive class warning on bleeding risk for antiplatelet agents (Also see "Brilinta Approval Shows AstraZeneca's Success With Aspirin Theory, But Can It Change The Market?" - Pink Sheet, 25 Jul, 2011.).
Merck announced in 2011 it was stopping the Phase III TRACER trial of vorapaxar early due to excess bleeding rates. Nearly 13,000 patients with acute coronary syndrome were part of the trial, whose primary endpoint was time to first occurrence of CV death, heart attack, stroke or recurrent ischemia with re-hospitalization or urgent coronary revascularization.
Merck said patients with a high risk of stroke were taken out of the trial after the data safety monitoring board found increased risk of intracranial hemorrhage in that population (Also see "Intracranial Hemorrhage The Culprit In Merck's Vorapaxar Trial" - Pink Sheet, 20 Jan, 2011.).
The even larger TRA-2P TIMI 50 study showed vorapaxar helped prevent additional cardiovascular events as add-on therapy following a heart attack. But it also found a heightened risk of major bleeding.
The study included 26,449 patients in stable condition after a heart attack, stroke or peripheral arterial disease and on a range of medications, including aspirin, a thienopyridine (mostly clopidogrel), statins and blood pressure medications. The primary composite endpoint – death from cardiovascular causes, MI or stroke – at three years was reduced 13% compared to placebo.
But the benefit came with a statistically significant increase in moderate to severe bleeding. The treatment group saw a 4.2% increase compared to a 2.5% increase in the placebo group. Intracranial hemorrhage rates also were higher among those on vorapaxar compared to placebo; the rate of intracranial hemorrhage was significantly lower in patients with no history of stroke. [Editor’s note: This sentence has been corrected to note that the incidence of intracranial hemorrhage was lower, not higher, in patients with no history of stroke.]
The results met with a cool reception, with investors downgrading estimates and leading cardiologists speculating that the drug may have a future in a subpopulation but should not have widespread use (Also see "Bleeding Rates In TRA-2P Further Dim Outlook For Merck’s Vorapaxar" - Pink Sheet, 1 Apr, 2012.).
FDA’s estimated goal for a decision on vorapaxar is mid-2014.