Johnson & Johnson and Bayer HealthCare may gain a market advantage if regulators grant an approval with indications for both chronic and acute use of its anticoagulant rivaroxaban, based on regulatory filings the co-development partners announced Jan. 5.

In the U.S., J&J both submitted an NDA for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and answered the "complete response" letter FDA issued in 2009 on its NDA for prevention of deep vein thrombosis and pulmonary embolism in patients undergoing knee and hip replacement surgery. The surgical indication involves short-term, acute treatment, whereas the A-Fib indication entails chronic use.

In Europe, Bayer submitted applications to the European Medicines Agency for antithrombotic indications in atrial fibrillation, deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism. Bayer already markets it there as Xarelto for deep venous thromboembolism prevention in adult patients following elective hip or knee replacement surgery.

Answering The "Complete Response"

Since the "complete response," Bayer/J&J have said they would wait for data to make the chronic and acute filings at the same time (Also see "Bayer/J&J Will Resubmit Xarelto For Acute Indication In Second Half Along With New Application For Chronic Use" - Pink Sheet, 26 February, 2010.). Having both indications on its label would distinguish Xarelto from other anticoagulants on the market.

In the letter, FDA asked for additional data from completed and ongoing studies, market surveillance data from ex-U.S. countries where the drug was already sold (to further assess the risk-benefit profile), and additional information on study sites for the four pivotal RECORD studies included in the orthopedic use application.

"Specific information requested by the FDA" is included in the submission, which is supported primarily by the Phase III RECORD clinical trial program, J&J said.

But FDA also is looking for long-term safety data, particularly on hepatotoxicity. Six-month data from the ATLAS study, conducted to assess the safety and efficacy of rivaroxaban in secondary prevention of acute coronary syndrome, could complete the picture. The resubmission also almost certainly contains a REMS proposal.

J&J used top-line data from the ATLAS study in its 2009 presentations to an FDA advisory committee, which voted in support of the application, but the agency's review is restricted to data in the NDA package, and it didn't include that data ([A#1490528007]).

Supporting The Chronic Use Claim

Meanwhile, results from the 14,000-patient pivotal Phase III ROCKET AF study were presented in November at the American Heart Association meeting.

The headline news was that in a pre-specified analysis of patients who actually received treatment per protocol, rivaroxaban was shown to be superior to warfarin, with a 21% reduction in relative risk for stroke and non-CNS systemic embolism.

However, the intent-to-treat analysis - the more conservative option generally preferred by regulators that considers all patients randomized into the trial - found the Factor Xa inhibitor to have comparable and not superior efficacy to warfarin.

That difference is important because labeling for Boehringer Ingelheim's anticoagulant Pradaxa (dabigatran) includes language acknowledging the drug performed significantly better than warfarin. Pradaxa was approved, with the atrial fibrillation indication, in October (Also see "FDA Plays It Safe With Boehringer Ingelheim's Pradaxa By Approving A Single Dosing Option" - Pink Sheet, 20 October, 2010.).

In Europe, Bayer's submission for treatment of deep vein thrombosis and prevention of pulmonary embolism is based on data from the Phase III EINSTEIN-DVT study and the EINSTEIN-extension. Those data, supporting the use of rivaroxaban in the prophylactic indication, showed it to be non-inferior to treatment with subcutaneous Lovenox (enoxaparin) followed by a vitamin K antagonist, either warfarin or acenocoumarol. The research was published in the December New England Journal of Medicine ('Study Shows Rivaroxaban Valid For VTE Prophylaxis,' Health News Daily, Dec. 7, 2010).

Bristol-Myers Squibb and Pfizer's competing anticoagulant apixaban suffered a setback in December, when the Phase III APPRAISE-2 study in acute coronary syndrome was terminated due to increased bleeding. Bristol maintained the bleeding occurred in only the high-risk patients in the study, one of nine in the anticoagulant's development program (Also see "Apixaban Study Halted – But It May Not Cause Much Damage To The Program" - Pink Sheet, 1 December, 2010.).

Those results notwithstanding, apixaban, which would be marketed as Eliquis, has a chance to catch up in the race to market. Bristol said in October that FDA has agreed to review the Factor Xa inhibitor based on Phase III data from the AVERROES trial, a study comparing apixaban to aspirin for the prevention of stroke in patients with atrial fibrillation who can't take warfarin. Data from the ARISTOTLE study, comparing apixaban to warfarin in that indication are not due until mid-2011. With AVERROES data, the rolling NDA could be completed in the first quarter (Also see "Bristol/Pfizer's Apixaban Gets A Chance At The Inside Track" - Pink Sheet, 26 October, 2010.).

J&J/Bayer's resubmission of the chronic use claim puts Xarelto back ahead, however, and should the acute indication receive priority review, it too could clear FDA before other applications. Priority review was granted for Boehringer Ingelheim's direct thrombin inhibitor Pradaxa (dabigatran) and Lilly/Daiichi's antiplatelet agent Effient (prasugrel), though AstraZeneca's Brilinta (ticagrelor), another antiplatelet agent, received standard review. But the actual review times for the approved drugs have far exceeded the target 6 or 10 months.

-Shirley Haley (s.haley@elsevier.com)

Xarelto Back On Track: J&J Answers "Complete Response" Letter And Files For Atrial Fibrillation

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