Bayer/J&J plan to file the first chronic indication for their anticoagulant Xarelto , as well as respond to FDA on the "complete response" letter for their application for acute use in hip and knee replacement surgery, in the second half of 2010, Bayer CEO Werner Wenning announced Feb. 26 during the firm's 2009 year-end report.

It's been nearly a year since FDA levied the "complete response" on the acute indication, but Bayer isn't sweating the lost time. "We see the acute indication simply as a training opportunity for the multi-billion [euro] chronic" market, Bayer HealthCare CEO Arthur Higgins said. The first chronic application will be for prevention of stroke in patients with atrial fibrillation.

Gaining an approval with indications for use in both acute and chronic settings will be a commercial advantage once the drug does reach the market.

Xarelto (rivaroxaban), an oral Factor Xa inhibitor that is already marketed in over 50 countries, brought in €24 million in 2009, and Bayer is projecting between €50 million and €60 million for 2010. So far the approved indication is for prevention of deep vein thrombosis and pulmonary embolism in patients undergoing hip or knee replacement surgery.

Off-label use in other settings is another question, and one that may be at the root of the delay. The issue remaining for FDA may be reluctance to make available a broadly applicable drug for a narrow indication.

"FDA has become very conservative concerning the approval of new chemical entities, particularly if that entity is a first-in-class agent that has potential to be used in large chronic populations off label," said Higgins.

Meanwhile, two of the three remaining Phase III trials for the agent are set to deliver data as soon as May. The EINSTEIN trial in deep vein thrombosis and the ROCKET trial in atrial fibrillation are "neck and neck," Higgins said. The data will be presented at the appropriate medical conference later on this year, he said.

The third trial, MAGELLAN, for prevention of venous thromboembolism in hospitalized acute medically ill patients, also will report this year.

Data Integrity Issues Raised In The "Complete Response" Letter

In the "complete response" letter Johnson & Johnson received last May, 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 studies sites for the four pivotal RECORD studies that formed the basis of the orthopedic use application ('The Pink Sheet' DAILY, May 28, 2009).

Bayer/J&J are working with FDA to satisfy their concerns regarding clinical trial sites, Higgins said. "This is an iterative process." FDA has every right to continue to ask for additional information and for additional approaches, and "we do have the challenge that they also know that they are going to see chronic data very, very shortly," he said.

FDA has increased its scrutiny of "every single filing," not just the Xarelto application, Higgins maintained. The agency also has increased its scrutiny of trial sites, "so rest assured that with the chronic studies, we are going back and making sure that we ... are confident that we don't have issues,"

The medical community is eager for more convenient anticoagulants. Besides warfarin, the only other approved products are injectables, like GlaxoSmithKline's Arixtra (fondaparinux) and Sanofi-Aventis' Lovenox (enoxaparin), used as a comparator in Xarelto trials.

Boehringer Ingelheim's oral direct thrombin inhibitor candidate Pradaxa (dabigatran) also is already on the market in Europe, and a U.S. submission is in the offing. Dabigatran has the advantage of having data already in hand for chronic application (Pharmaceutical Approvals Monthly, December 2009).

Upon Xarelto's U.S. approval, Johnson & Johnson's Ortho-McNeil division, which submitted the rivaroxaban NDA, would commercialize the product in the U.S., though Bayer reps would support the J&J force by detailing rivaroxaban in designated hospital accounts. Bayer is exclusively responsible in countries outside the U.S.

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

Bayer/J&J Will Resubmit Xarelto For Acute Indication In Second Half Along With New Application For Chronic Use

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