No bleeding for Portola as factor Xa antidote comes good

Portola Pharmaceuticals’ antidote to the factor Xa blood thinners had a good deal going for it as it entered pivotal trials – clear medical need, FDA breakthrough therapy designation, and a requirement for studies of limited size and duration.

So news that the agent reversed Eliquis-induced anticoagulation with “high statistical significance” has made investors more comfortable that the project, andexanet alfa, will succeed with other factor Xa inhibitors and gain regulators’ blessing; shares rose 16% yesterday to $29.32. This was immediately followed with a $160m share offering to top up an already healthy war chest, which should put Portola in a strong position should it be engaged in M&A talks.

Necessary

The new factor Xa class that includes Eliquis and Xarelto target prevention of stroke in patients with atrial fibrillation and venous thromboembolism after hip or knee replacement surgery. Both carry an increased risk of bleeding, and in particular must be discontinued before elective surgery – up to 48 hours before in the case of Bristol-Myers Squbb and Pfizer’s Eliquis.

To treat emergency bleeding, haemostatic agents like NovoSeven or prothrombin complexes have been suggested as an off-label alternative, but a more specific product would be welcome. Warfarin, the product the factor Xa drugs are trying to replace, is a vitamin K antagonist that had an obvious natural antidote in vitamin K, and physicians’ familiarity and comfort both with warfarin and reversal protocols is thought to be a limiting factor on the factor Xa uptake.

Compared with the size of trials for the factor Xa agents, Portola’s phase III Annexa-A trial is tiny: just 33 patients. the subjects were all older, healthy vounteers, given 5mg of Eliquis twice daily for four days and then randomised in a 3:1 ratio to receive a 400mg bolus of andexanet alfa intravenously or placebo.

Portola said the trial showed that andexanet alfa “immediately and significantly reversed the anticoagulation activity of Eliquis”. Detailed data are set to be unveiled November 17 at the AHA scientific sessions in Chicago.

A second phase III trial has a similar design, with 32 healthy volunteers taking 5mg of Eliquis and then randomised 3:1 to a 400mg IV bolus of andexanet alfa followed by 4mg a minute for 120 minutes, or placebo. Data from that trial are due in early 2015.

Trials with additional factor Xa agents also are under way or planned – Annexa-R with Bayer and Johnson & Johnson’s Xarelto and Annexa-E with Daiichi Sankyo’s Lixiana. Andexanet alfa has shown in a phase II trial that it can block the blood-thinning action of Lovenox, which is from a different drug class, so it is hoped that it can show wide applicability in this space.

Portola says it plans to submit the results to the FDA by the end of 2015. Should it receive approval under accelerated review with the data it currently has planned for its phase III programme, a phase IV study of outcomes will be necessary to confirm andexanet alfa’s clinical value.

Who is offering?

The $160m share offering will be added to the $286m in cash Portola had on hand at June 30, leaving it in a healthy condition, by biotech standards, to complete the registration programme and cover its regulatory costs. This year the group is on a run rate to spend about $68m total.

Portola executives have signalled their intention to launch solo. Andexanet would be a drug most often administered in hospitals, so it could be marketed with a small sales force – executives have estimated that no more than 150 people would be necessary.

Valued at $1.2bn, with a huge cash pot and with an attractive late-stage development project looking increasingly less risky, Portola looks to be an enticing M&A target. It would be surprising if it were not already entertaining offers. Companies active in the factor Xa space or with hospital-administered blood products, like The Medicines Company or Baxter Laboratories, must be taking a long look.

To contact the writer of this story email Jonathan Gardner in London at jonathang@epvantage.com or follow @JonEPVantage on Twitter

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