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FDA approval of an antidote for Factor Xa novel anticoagulants would further drive the already strong uptake of J&J/Bayer's Xarelto and Bristol/Pfizer's Eliquis, analysts say.






Sponsors of oral Factor Xa anticoagulants may breathe a sigh of relief with news of the US FDA's acceptance of Portola Pharmaceuticals Inc.'s revised application for the accelerated approval of AndexXa (andexanet alfa) antidote.



Portola announced Aug. 15 that FDA accepted its resubmission of a BLA for AndexXa for use as a reversal agent in patients who have uncontrolled or life-threatening bleeding while taking the two leading Factor Xa inhibitors – Bristol-Myers Squibb Co./Pfizer Inc.Eliquis (apixaban) and Johnson & Johnson/Bayer AG's Xarelto (rivaroxaban). The user fee date for the resubmitted filing is Feb. 2, 2018.



Five novel oral anticoagulants (NOACs) are now FDA-approved. Boehringer Ingelheim GMBH's direct thrombin inhibitor Pradaxa (dabigatran) was the first on the market in 2010 and took the brunt of bad publicity over excess bleeding. The other four are all Factor Xa inhibitors. In addition to Eliquis and Xarelto, FDA has cleared Daiichi Sankyo Co. Ltd.'s Savaysa (edoxaban) and Portola's Bevyxxa (betrixaban), which was just approved in June for a niche indication for patients hospitalized for acute medical illness and at risk of thromboembolic events. (Also see "Portola's Bevyxxa Poised To Capture Niche Novel Anticoagulant Market" - Scrip, 26 Jun, 2017.)



"The lack of a reversal agent for these drugs is a current concern for physicians, as they are unable to reverse the anticoagulation effects of these medications in cases of emergency bleeding or surgery. This concern is thought to have hindered the uptake of Factor Xa inhibitors, Xarelto and Eliquis," Datamonitor analyst Jack Allen commented to Scrip.



Portola initially was aiming for accelerated approval for the product in reversing anticoagulant effects of all approved Factor Xa inhibitors, including Sanofi's indirect, injectable Factor Xa inhibitor Lovenox (enoxaparin), which is now generic. However, Portola received a complete response letter (CRL) for the antidote in August 2016. FDA cited a range of problems in the letter, including manufacturing issues, the need for time to review amendments to the ANNEXA-4 confirmatory study, and insufficient data supporting approval for use. (Also see "Portola Seeks Narrower Label For AndexXa Antidote After FDA Rebuff" - Scrip, 18 Aug, 2016.)



At the time of the CRL, the company had Phase III data in healthy volunteers for Xarelto and Eliquis, but not the other agents, and the company said it was shifting its regulatory focus to securing approval for these two anticoagulants specifically.



The resubmission includes supplemental information primarily related to analytics and manufacturing, as requested by the FDA in the complete response letter, Portola said. It also includes additional data from the ANNEXA-4 study of patients with Factor Xa inhibitor-related bleeding. Portola plans to submit a supplemental BLA covering use in reversing effects of betrixaban, edoxaban and enoxaparin in the next 12 to 18 months, as well as use in urgent surgery.



Portola also noted that in 2016, 90,000 US patients treated with Factor Xa inhibitors were subsequently admitted to the hospital due to bleeding. CEO Bill Lis said during the company's Aug. 9 earnings call that the company expects this figure to grow to 150,000 in the next decade.



Some 10 million patients are on oral Factor Xa inhibitors in the G7 countries, 95% of whom are on apixaban and rivaroxaban, the exec noted.



The company has revamped its manufacturing process and expects that AndexXa will become widely available in the second half of 2018, Lis said.



Antidote For Lawsuits?

The real-world need for an antidote has always been said to be low and the new anticoagulants have much faster clearance rates than the standby generic warfarin, which minimizes the need for a reversal agent, but nevertheless the lack of an antidote has always been a source of psychological insecurity for doctors and has posed a risk for lawsuits.



In its annual report for 2016, Bayer noted that as of Jan. 23, 2017, US lawsuits have been served from about 16,400 patients treated with Xarelto.



"Plaintiffs allege personal injuries from the use of Xarelto, including cerebral, gastrointestinal or other bleeding and death, and seek compensatory and punitive damages. They claim, amongst other things, that Xarelto is defective and that Bayer knew or should have known of these risks associated with the use of Xarelto and failed to adequately warn its users. Additional lawsuits are anticipated. Cases pending in US federal courts have been consolidated in a multidistrict litigation for common pre-trial management," the report states.



State Of The NOAC Market

Nevertheless, the commercial impact is still a bit unclear. Boehringer gained accelerated approval in the US in October 2015 for Praxbind (idarucizumab), an antidote for Pradaxa for use in emergency situations, which was expected to give the drug an advantage over other novel oral anticoagulants. (Also see "BI's Praxbind US Approval May Boost Pradaxa Sales" - Scrip, 16 Oct, 2015.)



But Datamonitor's Allen notes there was little effect on sales, because physicians prefer the safety profiles of the Factor Xa inhibitors.



"As a result, the approval of AndexXa is likely to continue to drive the strong uptake of Eliquis and Xarelto by physicians, some of whom were tentative to use these medications due to the lack of antidote. However, it is unlikely the approval of AndexXa will result in the loss of share by Pradaxa patients as conversations with physicians suggest Eliquis and Xarelto are heavily preferred regardless of the antidote situation, as compared to Pradaxa," Allen said.



Privately-held Boehringer reported global sales for Pradaxa of €1.4bn ($1.6bn) in 2016, up by 8% from the prior year. (See table for NOAC sales.)



Sales For Leading Novel Oral Anticoagulants


2016 Global

2016 US

Global 2Q2017

US 2Q2017

Bristol/Pfizer's Eliquis

$3.3bn (+80%)

$1.9bn (+92%)

$1.2bn (+51%)

$703m (+58%)

J&J/Bayer's Xarelto

€2.9bn ($3.45bn, +30%) reported by Bayer

$2.3bn reported by J&J (+22.5%), €489m ($575m, +24.4%) by Bayer

€834m ($981m, +18.6%) reported by Bayer.

$642m (+8%) reported by J&J, €117m ($138m, +13.6%) by Bayer

Boehringer's Pradaxa

€1.4bn (+8%)






J&J executives said during the company's July 18 earnings call that Xarelto's total market share in scripts was up by more than two points compared to a year ago, as "warfarin continues to decline in favor of branded products."



But the company also reported that it needed to offer higher discounting in managed care and government channels in order to gain better positions on formularies in the US.



"If you look at Xarelto, however, we continue to be encouraged by the ongoing stream of really positive data, our very strong managed care account management capabilities, and so we feel optimistic about the future with Xarelto. And while there will undoubtedly be pricing pressure, we think that by continuing to differentiate the brand with strong clinical information, strong value information, as well as, frankly, execution in the field, that we'll be well positioned going forward," CEO Alex Gorsky said during the call.



New datasets are also expected and could boost sales, in particular a readout of the full data from the COMPASS study is set to be presented at the European Society of Cardiology meeting on Aug. 27. COMPASS tests Xarelto for prevention of major cardiovascular events in patients with arterial disease, a new indication for novel anticoagulants. J&J and Bayer stopped the trial in February because the study met the primary endpoint early. (Also see "COMPASS Success Reinforces J&J/Bayer's Broad Labeling Strategy For Xarelto" - Scrip, 10 Feb, 2017.)



Bayer CEO Werner Baumann said during a July 27 earnings call that he had not seen the COMPASS data in order to maintain data integrity of the study. Once the data are available, the company will be able to gauge the market opportunity.



The partners are planning to submit a supplemental filing for the new indication by the end of the year.



J&J/Bayer have had an aggressive development strategy for Xarelto with the EXPLORER development program, including indications in coronary artery disease (CAD) and peripheral arterial disease (PAD), which J&J's Gorsky said could expand the market by 10 million or 12 million patients in the US.



Xarelto's current indications cover 7 million to 8 million patients. Overall, the EXPLORER development program for Xarelto has the potential to add 30 million to 35 million additional patients in the US, J&J execs said during the company's second-quarter call.



"So it's a matter of market expansion. We don't believe that our competition has anywhere near as robust a clinical development program as we do for all of those indications that we're seeking. And so we seem to be in pretty good position," Joseph Wolk, vice president of investor relations , commented.



Bristol Chief Financial Officer Charles Bancroft said during the company's second-quarter earnings call on July 27 that Eliquis delivered strong growth and is leading new-to-brand share for novel anticoagulants.



"Given the strength of our data, including the real-world outcomes data presented over the last two years, we believe we have significant opportunity for continued growth," he said.



Internationally, growth outpaced that of the NOAC class in key markets around the world, Bancroft noted. "Eliquis is the number one NOAC in new-to-brand share in countries such as Germany, France and the UK," the exec added.



Chief Commercial Officer Murdo Gordon noted that there is still a lot of warfarin used in the US. Warfarin has a 47% share of the US market in terms of total prescriptions and about 26% of new-to-brand scripts, according to the company.



"So we still see a lot of headroom for growth on Eliquis, but very, very good share trends there and leading in our categories in VTE [venous thromboembolism] and atrial fibrillation," Gordon said.

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