FDA Panel Supports Vorapaxar but Not Extra Indication for Rivaroxaban

Issue: March/April 2014

The FDA’s Circulatory and Renal Drugs Advisory Committee voted 10-1 to recommend the approval of vorapaxar for the reduction of atherothrombotic events in patients with a history of MI, but it voted 0-10, with one abstention, against recommending approval for rivaroxaban for the treatment of ACS over the course of 90 days.

Vorapaxar May Benefit Those Who Have Had MI

FDA staff had recommended approval of vorapaxar as an adjunctive therapy for patients with a history of MI to reduce risks for CV death, MI, stroke and urgent coronary revascularization, and the panel agreed. If approved, vorapaxar will be marketed by Merck Sharp & Dohme under the brand name Zontivity.

“This drug addresses a real unmet clinical need,” said acting panel chairman Philip Sager, MD, of Stanford University School of Medicine. “The benefit-risk ratio is positive and the results are robust.”

However, panel members were split on whether the drug should also be indicated as adjunctive therapy for patients with peripheral arterial disease. While the TRA 2P–TIMI 50 pivotal trial was underpowered for that population, adding the data from those with PAD to those with prior MI did not change the positive results, according to presentations from Merck representatives and FDA personnel.

Panelist Mori J. Krantz, MD, FACC, FACP, of the University of Colorado, Denver, said he cast the lone “no” vote in part to express a “formal dissent to the use of the drug in patients with PAD.” He also said the effect size of the drug for CV events was not large enough to offset concerns about increased risk for bleeding.

Panelists were also undecided on how to caution against use of vorapaxar in patients who weigh <60 kg, in whom the drug did not show a benefit in TRA 2P–TIMI 50. The issue will be worked out between FDA staff and Merck before a final decision on approval, FDA officials said.

Bleeding Risks a Concern with Rivaroxaban

Panel members were less receptive to Janssen Pharmaceuticals’ request for an expanded indication for rivaroxaban (Xarelto) to help prevent CV death, MI or stroke in the first 90 days after ACS.

The vote marked the second time the panel has advised against approval of rivaroxaban in patients with ACS. In May 2012, the panel voted 4-6 against recommending the drug for an expanded indication for patients with ACS, citing a lack of data on early patient withdrawals and deaths.

Panelists said the data presented since the previous hearing were not convincing enough to override concerns that bleeding risks might outweigh benefits in terms of CV death, MI or stroke.

A Janssen executive said in a press release that the firm will continue to address the concerns of the FDA and its advisory panel members.

Janssen based its case for approval on results from the ATLAS ACS 2–TIMI 51 trial (n=15,526). In this trial, rivaroxaban-combined doses were superior to placebo at reducing the risk of achieving the primary, composite efficacy endpoint of CV death, MI or stroke (HR=0.84; 95% CI, 0.74-0.96).

However, patients assigned to 2.5 mg rivaroxaban twice per day (1.3%; HR=3.46; 95% CI, 2.08-5.77) or 5 mg rivaroxaban twice per day (1.6%; HR=4.47; 95% CI, 2.71-7.36) had increased rates of non-CABG TIMI major bleeding vs. placebo (0.4%).

Shortly after the panel’s May 2012 vote, the FDA declined to approve rivaroxaban for the treatment of ACS, citing that there was only one study — which had a P-value >.01 for the primary efficacy analysis — supporting the drug, and that a large number of patients were lost to follow-up.

Steven E. Nissen

While vital status was obtained for 843 of the 1,338 participants for whom it was not available at the end of ATLAS ACS 2–TIMI 51, the new data did not sufficiently strengthen the evidence, panelists said.

“The additional vital status helps a bit, but it is not good enough,” panel member Steven E. Nissen, MD, MACC, chairman of the cardiovascular medicine department at the Cleveland Clinic Foundation, said. “There is a high likelihood of some degree of information censoring.”

The FDA is not required to follow the recommendations of its advisory panels, but it usually does. – by Erik Swain

Disclosure: The panel members report no relevant financial disclosures.