With release of complete data on andexanet alfa’s ability to undo factor Xa anticoagulation, the pieces are now in place for Portola Pharmaceuticals to submit its lead project to regulators. The company could also have partners or buyers redoubling efforts to strike a deal.
Boehringer Ingelheim, meanwhile, has played an effective game of catch-up by publishing pivotal results of its Pradaxa-reversal agent idarucizumab, which should help ensure that its blood-thinner is not disadvantaged by lack of a specific antidote. The availability of a quick remedy perhaps as soon as the year's end could help the newer anticoagulants overcome the main clinical advantage of the older drug warfarin, and for Pradaxa perhaps provide a new stimulus to overcome lagging sales.
Both groups released phase III results at the International Society on Thrombosis and Haemostasis meeting, with Boehringer’s also being published in The New England Journal of Medicine. While Portola’s positive data were largely known, investors were encouraged by what they saw at the meeting and drove shares up 8% to a record high $48.27. Shares have now doubled since Portola’s float two years ago.
Block the blocker
The two-part Annexa-A study was designed to demonstrate that andexanet alfa could block the anticoagulant action of Bristol-Myers Squibb and Pfizer’s Eliquis, used primarily to prevent stroke in patients with atrial fibrillation, in the event of dangerous bleeding or if a patient has a need for invasive procedures. This has been warfarin’s main advantage over the factor Xa inhibitor drugs, as a dose of vitamin K can reduce its blood-thinning action within four to six hours.
At the thrombosis meeting Portola unveiled data from the second part of the Annexa-A trial showing that andexanet alfa could not only reverse Eliquis’s action but also sustain it through a continuous two-hour infusion following an initial bolus. At the end of the two-hour treatment, factor Xa inhibition had been suppressed by 92.7%, mostly unchanged from the 93.5% seen following the bolus. The study was in 33 patients who took Eliquis for four days and were randomised to take andexanet alfa or a placebo.
Andexanet alfa also has proven itself to block the action of the biggest-selling factor Xa inhibitor, Bayer and Johnson & Johnson’s Xarelto (Vantage Point – As Eliquis limps on Xarelto dominates oral blood thinners, October 9, 2013). As a sign that Bristol-Myers and Pfizer are anxious to use any means necessary to get their twice-a-day pill on even footing with once-a-day Xarelto, the two companies have helped fund Portola’s phase III on Eliquis in a non-exclusive collaboration (Portola chalks up two big pharma names in factor Xa antidote tie-up, November 5, 2012).
Given that Xarelto has seen its 2020 forecast skyrocket by more than $1bn worldwide in the last 12 months, according to EvaluatePharma’s consensus, while Eliquis has not changed much, Bristol-Myers and Pfizer could use some help. Having an antidote may prove little help in offsetting Xarelto’s first-mover advantage, however – Eliquis proved better than warfarin on both safety and efficacy while Xarelto only had an efficacy benefit.
Portola plans to submit andexanet alfa to regulators by the end of 2015, which puts it further from the market than Boehringer’s antidote, which is due a decision by the year’s end.
The private German group did not say much about its antidote until last year, so phase III was largely its public unveiling. Idarucizumab’s Re-Verse AD trial was perhaps a little more rigorous in that it enrolled a bigger population and recruited patients already taking Pradaxa who were either undergoing a procedure or were experiencing a clinical bleeding episode.
Re-Verse found that idarucizumab reversed thrombin inhibition in all patients, and normal coagulation patients in 90% of patients at four and 12 hours after treatment; normal blood clotting was achieved in 92% of the patients undergoing invasive procedures.
Pradaxa is probably even more in need than the factor Xa inhibitors in terms of good safety news, since it has been under the spotlight and its outlook has suffered more than the other agents. Its 2020 outlook is off by $400m in the last 12 months.
But as all of these drugs have struggled to establish themselves against generic warfarin as physician familiarity, safety, and perhaps most of all cost have proved to be obstacles. The new drugs are gaining on the first two counts – but at more than $3,000 per patient per year in the US, the last will continue to be a big barrier.