FDA Advisory Panel Recommends Approving Vorapaxar

January 15, 2014

SILVER SPRING, MD (updated) — A Food and Drug Administration advisory committee voted overwhelmingly in favor of approving vorapaxar (Zontivity, Merck Sharpe & Dohme), a novel protease-activated receptor 1 (PAR-1) inhibitor that targets thrombin-induced platelet activation, for treatment in the post-MI setting.

The Cardiovascular and Renal Drugs Advisory Committee voted 10 to 1 in favor of approving vorapaxar for the treatment of patients who had an MI. The drug would be contraindicated in those with a history of stroke or transient ischemic attack (TIA) because of an increased risk of bleeding in these patients.

The basis for approval is from the TRA 2°P TIMI-50 clinical trial. Reported by heartwire when it was presented in 2012 at the American College of Cardiology Scientific Sessions , the 26 499-patient study met its primary end point. Patients enrolled in TRA 2°P TIMI-50 had at least one of three atherosclerotic conditions (prior MI, prior stroke, or established peripheral arterial disease), but those with a prior MI made up 70% of the trial population.

The primary end point of the trial was the time to cardiovascular death, MI, stroke, or urgent coronary revascularization. Among those treated with vorapaxar 2.5 mg, there was a 13% reduction in the primary end point. When coronary revascularization was excluded, the secondary end point of cardiovascular death, MI, or stroke was also significantly reduced.

On the downside, moderate or severe bleeding occurred in 4.2% of patients treated with vorapaxar compared with 2.5% in the placebo-treated patients, a statistically significant 66% increase. As TRA 2°P investigator Dr Eugene Braunwald (Brigham and Women's Hospital, Boston, MA) pointed out during his presentation of the data, "there is no free lunch" when it comes to treatment with these types of medications, as they all are associated with risks.

As reported previously by heartwire , vorapaxar in particular increased the risk of intracranial hemorrhage (ICH), and this led to changes in the study design. Patients with a prior history of stroke/TIA were excluded from the trial after recommendations from the data safety and monitoring board were approved by the clinical investigators.

Good Risk/Benefit Profile With Vorapaxar

On the whole, the advisory panel believed the benefit/risk profile of vorapaxar in the overall patient population, excluding stroke and TIA patients, was very favorable.

"I currently feel that the benefit/risk ratio is one that is acceptable, where we're overall going to be helping more people, in ways that they would care about, than we are going to be harming," said committee member Julia Lewis (Vanderbilt University School of Medicine, Nashville, TN).

End points that patients care about, as well as their physicians, are cardiovascular death and stroke, noted Lewis, but these, individually, were not significant in the TRA 2°P trial. There were trends toward a reduction in cardiovascular death and ischemic stroke that did not reach statistical significance, but treatment with vorapaxar did reduce the combined secondary end point of cardiovascular death and MI by 14% (p=0.002) and MI alone by 17% (p=0.001). Lewis, while voting for approving, said that the effect size on primary composite end point was significant and clinically meaningful.

Dr Mori Krantz (University of Colorado, Denver), the lone vote against approval, took the opposite opinion, saying that he worried about the size of the clinical benefit, particularly with regard to harder end points such as cardiovascular death. He noted that nearly 1000 patients would need to be treated to prevent one cardiovascular death. He also said he worried about the amplification of the bleeding signal once this drug is available in the real world.

Speaking during the daylong session, advisory-panel chairperson Dr Philip Sager (Stanford University School of Medicine, CA) said there is an unmet clinical need in the post-MI patient population, with a lack of therapies shown to be beneficial. "While there certainly is some bleeding risk, the benefits, including the primary end point and key secondary end points, clearly outweigh those risks," said Sager. "The risk/benefit ratio is positive."

Similarly, Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA) echoed the sentiments of the other panelists, saying that he believes the reduction in cardiovascular events outweighs the bleeding risks, but he said there is still a need for a better understanding of that reduction in risk. For example, he would have liked to have seen more "granularity" in the data, such as the clinical consequences of the MIs observed in the trial. "But with the data, as presented to us, yes, the benefits outweigh the risks."

Other Deliberations

Throughout the day, the panel debated whether or not patients who weighed less than 60 kg should be treated with vorapaxar, as there was a signal of increased bleeding in this subgroup. The panel, however, felt there weren't enough data to make a definitive statement on the risks in this particular subgroup. In the end, panel members would like to see the decision to use vorapaxar in those <60 kg in the hands of the treating physician, leaving them to decide on the overall trade-offs between risk and benefit.

In addition, the panel noted there is very limited evidence supporting use of vorapaxar in post-MI patients treated with antiplatelet agents other than clopidogrel plus aspirin. They suggested that any label for vorapaxar point out the drug has not been studied in post-MI patients concomitantly treated with prasugrel (Effient, Lilly/Daiichi-Sanyo) plus aspirin or ticagrelor (Brilinta, AstraZeneca) plus aspirin.

"I wouldn't want to go toward urging people away from using more effective antiplatelet drugs, but on the other hand it hasn't been studied. We don't have data," said Sager.

As noted, the TRA 2°P trial included patients with peripheral artery disease (PAD), but treatment with vorapaxar in this subgroup did not significantly reduce the risk of cardiovascular death, MI, stroke, or coronary revascularization. Although Merck selected not to seek an approval for this subgroup, aiming only for the post-MI patient, panel members had some difficulty determining what to do with these patients and the label. In the end, although some panelists felt the indication should reflect the study population, which would include PAD patients, others were more comfortable leaving treatment with post-MI patients alone.

The advisory committee's endorsement of vorapaxar is in line with the opinions of the FDA reviewers. As reported by heartwire , in documents published prior to the panel meeting, the FDA review stated that vorapaxar should be approved as an "adjunctive therapy in patients with a history of MI to reduce the risk of cardiovascular death, myocardial infarction, stroke, and urgent coronary revascularization."

Despite the positive vote this week from the advisory committee, the ultimate decision for approval rests with the FDA. The agency typically follows the advice of the advisory committee, although it does not have to.

In the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial with vorapaxar, adding the PAR-1 inhibitor to standard therapy significantly raised the risk of major bleeding complications, including ICH, over two years. Merck discontinued the study and is not seeking an ACS approval, nor are the FDA reviewers recommending it.

Merck sponsored the TRA 2°P and TRACER trials.

CORRECTION: The newsletter sent to members alerting them to the result of the vorapaxar advisory committee erroneously stated that vorapaxar had received a positive vote for ACS. This error was not part of our news coverage.


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