Xarelto should not be approved in ACS says FDA panel

An FDA advisory committee has voted against approval of Bayer and Johnson & Johnson's (J&J) anticoagulant Xarelto in the treatment of acute coronary syndrome (ACS) until further data is available.

By 10 votes to zero, with one abstention, the panel agreed that J&J and Bayer had failed to provide enough information in the application dossier for Xarelto (rivaroxaban) to support approval in ACS patients.

The FDA has already turned down Xarelto in ACS twice, with the same panel voting against approval in 2012, although Bayer did manage to convince the European Commission (EC) that the drug should be approved in ACS patients with elevated cardiac biomarkers last year.

In the US, Xarelto is already approved for use in atrial fibrillation (AF), patients undergoing hip or knee replacement surgery and those at risk of venous thromboembolism (VTE), but approval in ACS would help it to compete with other new anti-clotting agents such as AstraZeneca's Brilinta (ticagrelor) and Lilly's Effient (prasugrel).

J&J and Bayer are seeking approval of Xarelto as a 90-day treatment regimen intended to reduce the risk of thrombotic cardiovascular events based on the results of the ATLAS ACS TIMI 51 trial.

This study showed that adding a 2.5mg dose of Xarelto to standard antiplatelet therapy significantly reduced cardiovascular death, myocardial infarction or stroke in patients after a recent ACS compared to those who received standard antiplatelet therapy alone.

One of the key areas of concern for the FDA committee meeting is that the ATLAS ACS trial looked at chronic Xarelto therapy rather than a defined 90-day course. J&J and Bayer had conducted re-analyses of the trial data in order to support the new indication but did not carry out any new trials, which could set a worrying precedent, said panellist Sanjay Kaul of Cedars-Sinai Medical Center in Los Angeles.

Moreover, follow-up data is still missing on around 400 patients in the trial, albeit down from the 1,300 patients missing when the panel first conducted its review. Given that Xarelto is known to increase the risk of bleeding complications the quality of the data is critical to make a judgment, added the Cleveland Clinic's Steven Nissen.

The overarching conclusion was that the two companies were trying to redefine the parameters of the trial to suit the new regimen, but panellists want a new study to prove the drug's worth.

Bayer's head of global development Kemal Malik said the company would work with J&J so that the FDA could "finalise its review" of the application.

While Brilinta and Effient are available to ACS patients, Xarelto's closest rivals - Bristol-Myers Squibb and Pfizer's Eliquis (apixaban) and Boehringer Ingelheim's Pradaxa (dabigatran) - have not been approved in this indication in the US.

Regardless of the ACS verdict Xarelto continues to grow strongly in its approved indications, with Bayer reporting sales leaped to €633m ($860m) in the first nine months of 2013, more than three times the tally in the same period of 2012.

Meanwhile, J&J sales of $593m in the first three quarters of 2013, up from $144m a year earlier, putting the drug firmly on track to meet Bayer's expectations of €2bn-plus in peak sales. That said, analysts have estimated that ACS could represent an additional $1bn market opportunity for the drug.