The oral anticoagulants market could be one of the most competitive for new drug launches in 2011, and partners Bristol-Myers Squibb and Pfizer could see regulatory action on their entrant apixaban - to be marketed as Eliquis - in the second half of 2011, earlier than anticipated.

FDA has agreed to review the oral 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 cannot take warfarin, Bristol confirmed during the company's third-quarter sales and earnings call Oct. 26.

The news means Bristol and Pfizer have a shot at a faster route to market in a competitive area of drug development. Previously, it was uncertain whether FDA would agree to review the application based on AVERROES or if the agency would require data from an ongoing Phase III study, ARISTOTLE, comparing apixaban to warfarin in atrial fibrillation patients. Data from ARISTOTLE aren't expected until mid-2011.

"Our understanding is that this will be an AVERROES filing, and there will be a decision to be made upon filing on whether or not this is a priority review," Bristol's R&D President Elliott Sigal explained. However, it is entirely possible that FDA could still require the ARISTOTLE data during the review process, he cautioned.

Bristol and Pfizer already have initiated a rolling NDA submission for apixaban. The filing is expected to be complete in the first quarter of 2011. The firms previously had suggested they would pursue the early filing opportunity after stopping AVERROES early because apixaban reduced the relative risk of a composite stroke or systemic embolism by 54% compared with aspirin - without a significant increase in major bleeding (Also see "Apixaban Impresses At ESC, Leading To Speculation About An Early Filing" - Pink Sheet, 31 August, 2010.).

If all goes smoothly with the filing based on AVERROES and FDA agrees to a priority review, it would position Bristol/Pfizer in a tight race with Bayer Healthcare/Johnson & Johnson to be the second to market with a novel oral anticoagulant. Bayer and J&J were the first to file their oral factor Xa inhibitor, Xarelto (rivaroxaban), but FDA issued a "complete response" letter for the application in May 2009, and the companies have been awaiting data from the ROCKET-AF study, comparing Xarelto to warfarin in atrial fibrillation patients, before refilling. Those data are scheduled to be presented at the American Heart Association scientific sessions in Chicago, Nov. 13-17.

Boehringer Ingelheim already has won the first-to-market title with its oral direct thrombin inhibitor Pradaxa (dabigatran), which was approved by FDA Oct. 19 as the first new anticoagulant since warfarin (Bristol's Coumadin and generics) was approved in the 1950s (Also see "FDA Pradaxa Approval Balances Efficacy And Bleeding Risk" - Pink Sheet, 25 October, 2010.).

Apixaban Could Find Sizeable Market Niche

But with its strong safety profile thus far and unique clinical trial program, apixaban could address an interesting niche in the market. Of the three lead programs, Pfizer/Bristol are the only companies that chose to study their candidate compared to aspirin in patients who are not able to take warfarin - a sizeable patient population. Some 40% to 50% of patients who are at moderate to severe risk of stroke do not receive warfarin for various reasons, including safety, monitoring requirements and lifestyle, according to Bristol.

As the clinical profiles of the three lead drugs become clearer, apixaban's bleeding profile will be an important advantage. The drug makers are planning to differentiate apixaban from the competition on safety. "Coumadin-like efficacy with increased safety should be a powerful message," Sigal said during the conference call. In contrast, Pradaxa was approved with a superiority claim compared to warfarin, but with serious risk of major bleeding.

And, as Sigal said, Bristol/Pfizer have a chance to own the market for patients who aren't able to use warfarin. "No one will be able to do a study comparing [against] aspirin if apixaban is approved. They will have to do non-inferiority studies against apixaban," he said.

Bristol has several other near-term regulatory milestones approaching as well. The firm said it remains on track to file the first-in-class SGLT-2 inhibitor dapagliflozin with partner AstraZeneca in the U.S. and Europe by the end of 2010 or early 2011. The FDA action date for the cancer immunotherapy ipilimumab in second-line metastatic melanoma is Dec. 25. And the company expects to hear back from FDA on filings for Sprycel (dasatinib) for front-line chronic myeloid leukemia and on a fixed-dose combination of Onglyza (saxagliptin) with metformin by the end of October.

Despite the pipeline progress, new drugs won't make up for the lost revenues Bristol is expected to see after 2011 when Plavix (clopidogrel) goes off patent. And that remains the big overhang for Bristol.

The company reported net sales of $4.8 billion, flat against the year-ago third quarter. Lower sales of Abilify, Avapro and Erbitux and the impact of health care reform offset gains by Plavix, Baraclude and Orencia. Net income was $949 million, versus $966 million in the year-ago period, although the 2009 quarter included $75 million related to discontinued operations. Net earnings from continuing operations were higher - $949 million in the 2010 quarter versus $892 million last year.

-Jessica Merrill (j.merrill@elsevier.com)

Bristol/Pfizer's Apixaban Gets A Chance At The Inside Track

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