Portola Seeks Narrower Label For AndexXa Antidote After FDA Rebuff

Portola Pharmaceuticals Inc. will be pursuing a narrower label for its reversal agent AndexXa in treating patients exposed to Eliquis and Xarelto – the novel anticoagulants with the largest market shares – following a complete response letter from FDA.

AndexXa (andexanet) had breakthrough therapy status with FDA for reversing effects of anticoagulants in emergency situations. The company indicated it had excellent access to and communication with FDA officials, but the program wasn't enough to ensure regulatory success.

Portola had aimed for accelerated approval for the product in reversing anticoagulant effects of all approved direct Factor Xa inhibitors – Bristol-Myers Squibb Co./Pfizer Inc.'s Eliquis(apixaban), Johnson & Johnson/Bayer AG's Xarelto (rivaroxaban), Daiichi Sankyo Co. Ltd.'s Savaysa (edoxaban) – as well as Sanofi's now generic Lovenox (enoxaparin), an indirect Factor Xa inhibitor.

However, late on Aug. 17, the company announced it received a complete response letter from FDA citing a range of problems with the filing, including manufacturing issues, the need for time to review amendments to the ANNEXA-4 confirmatory study, and insufficient data supporting approval for use in patients who had taken edoxaban or enoxaparin (only Phase II data is available for those two drugs).

The company said during an investor call Aug. 18 that it will be talking to FDA as soon as possible regarding next steps to get the filing back on track.

CEO Bill Lis noted that the company "turns things around pretty quickly" but that it will be putting together a "daunting amount of data." If things go well in discussions with FDA, "there's a possibility" of resubmission by the end of the year, he said.

One strategy is to initially secure a label limited to use with Xarelto and Eliquis, the leading Factor Xa anticoagulants in the market, and expand labeling later on to include edoxaban and enoxaparin. Although Boehringer Ingelheim GMBH's direct thrombin inhibitor Pradaxa (dabigatran) was first novel oral anticoagulant (NOAC) on the market in 2010, Xarelto has emerged on top, with about $4.4bn in global sales for 2015. Savaysa has been disappointing (see table).

The label could "easily be written" for apixaban and rivaroxaban, CEO Lis said during the investor call. "That's where the overwhelming predominance of the market and the need is, as we all know," he said.

The company does have Phase III data in healthy volunteers for Xarelto and Eliquis, but not the two other products. Lis said that the data and activity for the class was consistent and there were questions about not putting healthy volunteers at risk unnecessarily.

"I think it is clear now that the FDA, after many discussions with them on this, would still like some additional data," Lis said.

It would be possible to add something in the clinical section of labeling with regards to the limitations of the data – that's an option FDA could have taken on its own and the company was surprised that the issue would rise to the level that it has, Lis said.

FDA's request is not that unexpected, since the company only had Phase II data in these patients, and it will take time to collect additional data, Datamonitor Healthcare analyst Jack Allen told Scrip.

While FDA "should be amenable," the company will need to see if there is some reason the agency will require that these studies be done prior to approval, Allen said.

Portola's Loss, Boehringer's Gain?

Currently, there is no FDA-approved antidote for Factor Xa inhibitors and the CRL could represent a commercial setback for the class, especially relative to Boehringer Ingelheim's Pradaxa. Boehringer's antidote Praxbind (idarucizumab) was approved in October 2015 in the US, and November of that year in Europe. (Also see "BI's Praxbind US Approval May Boost Pradaxa Sales" - Scrip, 16 Oct, 2015.)

"The delay in the launch of AndexXa will extend the duration of Pradaxa’s market advantage, as the drug will remain the only NOAC with an approved antidote," Datamonitor's Allen noted.

Of the new anticoagulants, Pradaxa had been particularly damaged by bad publicity about severe bleeding events. (Also see "Can Praxbind Push Pradaxa Ahead?" - Pink Sheet, 16 Oct, 2015.) The drug's sales dropped by 1% to €1.2bn in 2014 (about $1.36bn), but started to rise again in 2015, up 7.4% to about €1.29bn.

Boehringer's filing for Praxbind included Phase I data in 283 healthy volunteers and an interim analysis from the Phase III RE-VERSE AD study.

Boehringer notes that Praxbind is now available in more than 2,760 local hospitals across all 50 states in the US. Each dose has a list price of $3,500.

During Boehringer's annual investor event in April, execs said that they were bullish about prospects for Pradaxa following the approval of Praxbind, and in light of the still low penetration of anticoagulants in patients with atrial fibrillation. (Also see "Barner Goes Out On A High As Boehringer Ingelheim Returns To Growth" - Scrip, 19 Apr, 2016.)

Datamonitor expects a boost in Pradaxa sales in the short term.

Surprised And Disappointed

CEO Lis said that Portola had been "confident in the clinical data that we provided and certainly confident that we met the requirements for accelerated approval."

Execs said that the CRL left them feeling surprised and disappointed.

John Curnutte, executive vice president of R&D, said that a "well-known problem" with breakthrough therapy is that the review goes so quickly that "all of the i's are not always dotted and t's crossed, with regard to much of the analytic bookkeeping and validation that is required for a usual approval pathway."

It's clear now that contrary to the company's expectations, the agency wanted to see many more issues resolved prior to approval, the company said.

Manufacturing was a big issue cited in the CRL. This was probably the biggest surprise, because the company had a pre-approval inspection in April and felt that the inspection went well, Lis said.

"This was highlighted by the very few, if any, non-critical observations," the CEO said. "And following our responses to what were really non-critical observations, we had very little communication, if any at all, on this topic. And therefore, we were led to believe that we were in pretty good shape or very good shape on this front."

FDA also cited issues related to amendments to the confirmatory ANNEXA-4 study in the action letter. The agency had asked the company to separate a surgical cohort from a bleeding cohort.

Portola acknowledged that the data is difficult to interpret, since there is no control. "As a result, there is some uncertainty on what the FDA is looking for specifically, but we should note that Praxbind’s data was also difficult to interpret, yet did not hold up approval," Datamonitor's Allen said.

"There were also questions about amendments to the post-approval usual care cohort, who do not receive the drug, which is for final approval (the current submission is for accelerated approval). More clarity is needed on what the FDA will be looking at when comparing this to the drug treated patients," Allen noted.

Portola submitted some final amendments for the usual cohort study and changes to ANNEXA-4.

Portola's ability to resubmit by the end of the year is hard to gauge without knowing more about the manufacturing issues, Datamonitor analysts concluded.

The news of the CRL is just the latest blow for the company. In March, Portola announced that its Factor Xa inhibitor betrixaban missed a major endpoint in the Phase III APEX study of high-risk, acute medically ill patients. At the time the company said it did not think it would have to do a new Phase III study and that the totality of the data would support approval. (Also see "Will Portola’s Betrixaban Data Pass Muster With FDA?" - Pink Sheet, 24 Mar, 2016.)

Portola says that it is on track to submit an NDA for betrixaban in early fall.

The company's stock traded down from $27.09 to $23.69 on Aug. 17. On August 18, it opened at $19.11 and closed at $20.12. At the end of the second quarter, the company had $354 million in cash.