ESC 2016 – Portola strengthens FDA re-submission


Had everything gone to plan for Portola Pharmaceuticals, the European Society of Cardiology meeting would have been an ideally timed chance to roll out its anticoagulant reversal agent Andexxa to a major prescriber audience.

As it stands, the California-based group only had the opportunity to outline interim data in patients experiencing bleeding after taking a factor Xa inhibitor, providing the first sign that Andexxa might improve outcomes. The FDA will no doubt be interested in reviewing results from this study once Portola re-submits its application, a move necessitated by the agency’s complete response letter earlier this month (No antidote to Portola’s bleeding as FDA rejects Andexxa, August 18, 2016).

Stopping the bleeding

The data were taken as good news by Portola’s investors, who sent shares up 2% to $20.85 in pre-market trading today. Before the FDA’s rejection, shares had been trading above $25.

It has been a year of double setbacks for Portola, as its own factor Xa, betrixaban, stumbled in a phase III trial, though company executives still plan to submit it to US and European regulators by the end of 2016.

Thus it came as some relief that Annexa-4 returned positive interim results. The data in 47 patients enrolled showed that 37 achieved good or excellent haemostasis 24 hours after beginning treatment with Andexxa, as judged by independent analysts.

Confirming the results of previous Andexxa studies in healthy patients, factor Xa inhibition was reduced by 89% in patients who took Xarelto and 93% in those patients who took Eliquis, who later took a bolus of Andexxa.

Patients were enrolled if they had taken a factor Xa inhibitor like Xarelto or Eliquis in the 18 hours preceding a diagnosis of major bleeding. All but two in this population were suffering from gastrointestinal or intracranial bleeding.

In 30 days of follow-up, 12 of 67 patients in a safety analysis had a thrombotic event, and there were 10 deaths, of which six were cardiovascular. Only 18 patients had re-started anticoagulation after their bleeding incident, only one of whom had a thrombotic event. The safety analysis included 20 patients given Andexxa who had low levels of anti-factor Xa activity or who were later not considered to be experiencing a major bleed.

Chief investigator Stuart Connolly, a professor at McMaster University in Canada, said that this event rate was to be expected in this sick and elderly population, which had an average age of 77. Meanwhile, a placebo arm was not included in this trial because its steering committee decided that it would not be ethical to do so.

In an accompanying article in the New England Journal of Medicine Dr Connolly acknowledged that a placebo-controlled study would be necessary to determine whether treatment with Andexxa put patients at increased risk of thrombotic events.

Asked about whether the thrombotic events were raised by the FDA in its complete response letter, Dr Connolly said, “That was not an issue raised at all.”

Missed opportunity

The decision to release interim data at ESC was built around the assumption that the FDA would approve Andexxa on its decision date of August 17. Portola had wanted to provide clinicians with results from use in patients in addition to the biomarker data in healthy subjects that have been released so far.

Annexa-4 now will proceed until data from 162 patients are available for an efficacy analysis, which is expected to yield a safety population of 230. There will not be a statistical penalty for multiplicity because investigators decided to continue the trial regardless of the findings of the interim analysis, Dr Connolly said.

These data do nothing to hurt Portola’s case, but the company is still reeling from the setback at the regulator. More news about regulatory activity, both for Andexxa and betrixaban, would help even more.

Study Trial ID
Annexa-4 NCT02329327

To contact the writer of this story email Jonathan Gardner in Rome at or follow @ByJonGardner on Twitter

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