For the second time, the FDA has issued a complete response letter (CRL) to Janssen regarding their supplemental new drug application (sNDA) to market rivaroxaban (Xarelto) for the reduction of the risk of cardiovascular events in acute coronary syndrome (ACS) patients.

The company first filed an NDA in December 2011 and received priority review from the FDA in February 2012. In May 2012, the FDA's Cardiovascular and Renal Drugs Advisory Committee voted six to four against recommending rivaroxaban's approval for ACS. The committee expressed concern about the increased risk of bleeding and raised doubts whether missing data for approximately 1,000 (12%) patients in the Phase III trial, as well as a high dropout rate, may have skewed results in rivaroxaban's favor. Janssen then received the first CRL requesting more data in June 2012. In September 2012, Janssen submitted additional data to support its application. However, this has evidently been deemed insufficient to address the FDA's concerns.

The exact details of the most recent CRL remain unclear, but it undoubtedly relates again to the Phase III ATLAS ACS 2 TIMI 51 trial and the increased bleeding risk. The original application was based on results of the Phase III ATLAS ACS 2 TIMI 51 trial, which met its primary end point of significantly reducing the composite efficacy end point of cardiovascular death, myocardial infarction (MI), and stroke versus placebo, despite an increased risk of bleeding and intracranial hemorrhage. The positive efficacy result was driven by a clinically significant decrease in cardiovascular death in the lower rivaroxaban dose (2.5 mg twice daily), which was not observed in the higher dose (5 mg twice daily).

Given the conflicting effect of the two rivaroxaban doses on ischemic end points, the mortality benefit seen with the lower dose surprised many thought leaders interviewed by Decision Resources, leaving many unsure of the mechanism involved and some recommending further studies.

In a press release issued on March 4th, the company restated that it remains ?confident in the robustness and results of the ATLAS ACS 2 TIMI 51 trial.? They went on to say that they ?will continue to work with the FDA to address their questions."

Rivaroxaban, which is also marketed by Bayer, has already won FDA approval for several clinical uses in the US, including the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and to reduce the risk of stroke in people with non-valvular atrial fibrillation. While an approval for ACS would have boosted overall sales, the changing antithrombotic landscape would have restricted its use in ACS, given the fact there is less need for an adjunct to clopidogrel (Bristol-Myers Squibb/Sanofi's Plavix/Iscover, generics) and aspirin now that ticagrelor (AstraZeneca's Brilinta/Brilique) and prasugrel (Eli Lilly/Daiichi Sankyo's Effient/Efient) are available. Uptake would have been further restricted by increased bleeding concerns, restrictions in patients with a history of stroke or transient ischemic attack (TIA), which were excluded from the Phase III trial, and cost and compliance issues related to adding a third agent.

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