FDA Refuses ACS Indication for Rivaroxaban--for Now

June 22, 2012

June 22, 2012 (Raritan, New Jersey) — The US FDA has failed to approve the new anticoagulant rivaroxaban (Xarelto, Bayer Healthcare/Janssen Pharmaceuticals) for the additional indication of use in patients with acute coronary syndrome (ACS) [1].

The agency has decided to follow the advice of its Cardiovascular and Renal Drugs Advisory Committee on this, which narrowly voted against recommending approval four weeks ago, based on concerns about missing data from the ATLAS ACS 2 TIMI 51 trial of the factor Xa inhibitor. Instead, the FDA has issued a "complete response letter," requesting more data to help it with its decision. In a press release, Janssen says it is "evaluating" the situation and "will respond to the agency's questions as quickly as possible."

Rivaroxaban looked like it might succeed where other new oral anticoagulants had failed in gaining the ACS indication. While these agents have all shown good results as an alternative to warfarin in patients with atrial fibrillation, their use in patients with ACS has been fraught with difficulty, because in this situation they are added to several other anticlotting agents, and therefore the bleeding risk is very high.

All the phase 2 studies of these drugs in ACS showed problems with bleeding when given with dual antiplatelet therapy, and the first phase 3 trial of one of these agents in this indication (the APPRAISE-2 trial with apixaban) was stopped early because of bleeding. But ATLAS-ACS 2 TIMI 51 was not stopped early, so the hope was that rivaroxaban had hit the sweet spot.

ATLAS-ACS 2 TIMI 51 Generated Great Excitement

Bayer/Janssen first revealed that rivaroxaban had significantly reduced the primary composite efficacy end point of cardiovascular death, MI, and stroke vs placebo in ACS patients in ATLAS-ACS 2 TIMI 51 last September. But they said at the time that the drug was also associated with a significant increase in the primary safety end point: major bleeding events not associated with coronary artery bypass surgery. Experts said at the time they would need to see the full results to properly evaluate the trade-off between efficacy and bleeding.

The trial was fully presented in a late-breaking clinical trial session at the AHA meeting in Orlando last November and simultaneously published in the New England Journal of Medicine. There, it was reported that the lower of the two doses of rivaroxaban tested, 2.5 mg twice daily, had the better benefit/risk balance, due to a lower bleeding risk than the higher 5-mg twice-daily dose.

At the time, doctors were split as to what they thought. Many observed that this was the first time that an antithrombotic had shown a reduction in deaths when added to dual antiplatelet therapy in ACS and that this was impressive and likely primarily due to a reduction in sudden cardiac death with rivaroxaban. And the 2.5-mg twice-daily dose is only a quarter of that employed in atrial fibrillation, proponents said, adding that the fact that it showed benefit despite not being added into therapy until a few days after the index ACS event was also notable.

Others, however, were concerned that the trial did not enroll enough patients at high risk of bleeding, such as the elderly, and that there were some seemingly odd results--such as the fact that stroke was not reduced by rivaroxaban, nor was there a reduction in MI with the 2.5-mg dose. Added to this, the bleeding hazard with rivaroxaban in ATLAS-ACS 2 TIMI 51 was "unprecedented," one expert observed.

Company Hopeful of Gaining ACS Indication

Despite these concerns, Janssen--which holds US marketing rights to rivaroxaban--pressed ahead with filing, submitting the supplementary US new drug application (sNDA) for use of rivaroxaban in ACS at the end of December. In February, the FDA assigned this as a priority review.

An FDA advisory committee meeting date was set for May 23. In documents posted a couple of days before this, the agency looked to be favoring approval of rivaroxaban for this indication. However, it did ask the advisory panel to discuss a number of issues relating to data quality--specifically "substantial missing data."

Ultimately, it was this that led the majority of panel members to a negative decision last month. The committee voted six to four (with one abstention) against recommending that the FDA approve rivaroxaban for ACS.

Rivaroxaban is already approved in the US for the prevention of stroke in patients with AF and to prevent thromboses in people undergoing hip and knee replacement.