FDA Again Seeks More Info on Rivaroxaban in ACS

Shelley Wood

March 05, 2013

RARITAN, NJ — Rivaroxaban (Xarelto, Bayer Healthcare/Janssen Pharmaceuticals) will not be getting the much-hoped-for approval in patients with ACS this week [1]. The FDA has issued a complete response letter (CRL) to Janssen regarding the company's supplemental new drug application for rivaroxaban in patients with ACS.

This is the second CRL the company has received from the FDA; the last was in June 2012.

"We remain confident in the robustness and results of the ATLAS ACS 2 TIMI 51 trial, evidenced by a significant reduction in cardiovascular events, including a clinically important decrease in cardiovascular death, as published in the New England Journal of Medicine. While we saw an increase in major bleeding, there was no increase in fatal bleeding," Dr Christopher Nessel, vice president at Janssen, said in a press statement late Monday. "We will continue to work with the FDA to address their questions."

In May 2012, the FDA's Cardiovascular and Renal Drugs Advisory Committee narrowly voted against recommending approval, based on concerns about missing data from the ATLAS ACS 2 TIMI 51 trial of the factor Xa inhibitor.

Between the first CRL and Monday's announcement, the sponsor submitted new data to the FDA in September 2012, addressing the question of missing data on patients who had withdrawn from the trial. "To compile these data, the company undertook a global effort and was able to confirm the vital-status information for 843, or 63%, of the 1338 trial participants who previously had unknown vital status," Monday's press release noted. "The mortality benefit observed during the treatment phase of the study was maintained. These new events were distributed equally between the three treatment groups (2.5 mg, 5 mg, and placebo) of patients who were alive (806) and those who had died (37). After these efforts, follow-up data were not available on only 2.4% of patients."

Commenting on the news for heartwire Monday, Dr Sanjay Kaul (University of California, Los Angeles), who was one of the FDA advisors who voted against the expanded indication last May, said he was "not surprised" to hear of the CRL from the FDA.

He notes that while the sponsor should be commended for confirming the vital-status rate in so many patients, the overall rate of unknown vital status in the trial, at 3.2%, was "still much higher than the rates reported in contemporary trials TRITON TIMI-38 (0.12%), PLATO (0.01%), and TRACER (1.9%)."

Kaul also took issue with other trial findings, including the lack of an expected dose response (the 5-mg dose did not have greater efficacy compared than the 2.5-mg dose), the divergent impact of the two doses on ischemic end points, and the "lack of a statistically persuasive efficacy benefit" for the primary adjudicated efficacy end point.

Rivaroxaban has 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 antiplatelet agents, and therefore the bleeding risk is very high.

ATLAS-ACS 2 TIMI 51, however, met its primary end point of significantly reducing the primary composite efficacy end point of cardiovascular death, MI, and stroke vs placebo in ACS patients. 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.

Kaul, however, sees other major trial results as clues to the fact that this may not be the way forward. "Supportive external evidence for incremental benefit associated with novel oral anticoagulants in ACS beyond standard dual antiplatelet therapy [DAPT] is currently lacking," he said in an email to heartwire . "On the contrary, there is evidence for unfavorable benefit/risk balance with DAPT plus dabigatran ( REDEEM ), apixaban (APPRAISE 2), and vorapaxar (TRACER)."

Rivaroxaban is already approved by the FDA for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), to reduce the risk of recurrences following initial treatment, to reduce the risk of DVT and PE after knee- or hip-replacement surgery, and to reduce the risk of stroke in people with nonvalvular atrial fibrillation.

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