The Pink Sheet
November 6, 2012
By Paul Bonanos
Although one day it may compete with Bristol-Myers Squibb and Pfizer in the market for anticoagulant Factor Xa inhibitors, Portola has partnered with the two pharmas to fund a study on its class-wide antidote compound that prevents serious bleeding events.
Privately held anticoagulant drug developer Portola Pharmaceuticals Inc. one day may face competition from Pfizer Inc. and Bristol-Myers Squibb Co. if their Factor Xa inhibitor compounds are approved. But for now, Portola has partnered with the two pharmas on an antidote compound designed to stanch serious bleeding in patients who take anticoagulants in that class.
Portola said Nov. 1 that Pfizer and Bristol will fund a proof-of-concept study of PRT4445, Portola’s antidote that reverses the activity of Factor Xa inhibitors, in conjunction with Eliquis (apixaban), the drug in that class that Pfizer and Bristol market jointly in Europe. Eliquis has yet to receive approval in the U.S., while Portola’s own Factor Xa inhibitor, betrixaban, remains in Phase III clinical trials.
Portola won’t surrender any rights to the compound, but will receive an upfront payment of undisclosed size in the deal. CEO Bill Lis said the payment gives Portola enough cash “to help advance the molecule well beyond the proof-of-concept study,” but declined to provide more details.
A Phase I study already has been completed on PRT4445. Healthy, anticoagulated patients will be dosed for the proof-of-concept study by the end of 2012, with data appearing by mid-2013. If the results are positive, Lis said Portola could ask regulators for an accelerated approval path for the antidote, so that it could be brought to market in tandem with betrixaban.
PRT4445 is designed to counteract all Factor Xa inhibitors, which block the function of a key enzyme in the blood-clotting process. As a new class of Factor Xa drugs emerges to compete with the commonly used generic warfarin, along with other coumarin derivatives and additional anticoagulants, several candidates are aiming for approval in key indications (“Momentum Grows For Novel Oral Anticoagulants Out To Replace Warfarin” – “The Pink Sheet,” Mar. 29, 2010). Among them are Eliquis, betrixaban and Xarelto (rivaroxaban), jointly owned by Bayer AG and Johnson & Johnson.
And while Factor Xa inhibitors generally have performed well thus far, some believe the presence of an approved antidote to combat serious bleeding events could be a strong boon to the drug class. Lis said the lack of an antidote is “the only known, major liability of Factor Xa inhibitors,” a class which he believes has surpassed expectations for safety, efficacy and superiority to standard-of-care drug warfarin. Recent reports of excessive and serious bleeding events associated with new users of Boehringer Ingelheim Corp.’s direct thrombin inhibitor Pradaxa (dabigatran) have put a spotlight on the need for antidotes for the new oral anticoagulants (“Mini Sentinel Alleviates FDA Concern Over Pradaxa Bleeding Issue” – “The Pink Sheet” DAILY, Nov. 2, 2012).
A Class-Wide Antidote, A Substantial Market
If PRT4445 is approved, Portola will aim to make it available to patients taking all the Factor Xa inhibitors, for bleeding events that are the result of either the drugs themselves or a trauma event. “As all of the drugs are expected to do well,” Lis said, “we expect this drug will be developed in a universal fashion to be used with all the agents.”
Lis said Portola plans to position the antidote as its own franchise rather than a companion drug delivered in bundles with others, although it would be sold by the same commercialization team that sells betrixaban. The company is attempting to position betrixaban as a drug to prevent venous thromboembolism (VTE) in acute medically ill patients, giving it a niche among other anticoagulants. Lis says it will be “first to market for the acute medically ill, which is the second-largest indication for the Xa inhibitors.”
Lis said that by 2020, as many as 300,000 hospital visits annually will be the result of major bleeding events, based on extrapolations of analyst estimates of adoption. Between 1% and 4% of patients taking next-generation anticoagulants suffer from major bleeding events, he said, representing an improvement on the one out of eight warfarin patients who experience major bleeding.
According to Lis, the figure of 300,000 hospital visits is derived from Factor Xa Phase III outcomes trials which, he suggests, underestimate the “real-world” incidence. Further, Lis says that the 300,000 estimate only includes spontaneous bleeds due to the drug and bleeds that are the result of traumatic events. It does not include anticoagulated patients undergoing emergency surgery.
“Anywhere from 12% to 13% of patients on an antiplatelet or antithromobotic agent will have a surgical procedure during the course of a year. And if you take a smaller percentage of that,” says Lis, “it will be emergency surgery. Those patients also will require an antidote. So, the 1% to 4% of patients quoted in our press release does not include patients undergoing emergency surgery” while on an anticoagulant.
Both Portola and other developers of Factor Xa inhibitors stand to benefit from collaborations demonstrating that the antidote works and is safe. For Pfizer and Bristol, the profile of Eliquis is improved by the presence of an available antidote, while Portola can demonstrate that PRT4445 works universally against Factor Xa inhibitors and not just against betrixaban, its own drug.
Going It Alone In A Complex Market
Portola previously partnered betrixaban with Merck & Co. Inc. in a 2009 deal worth $50 million upfront, but the big pharma returned rights to the drug in 2011 following a pipeline review (“Back To The Drawing Board For Portola After Merck Returns Betrixaban” – “The Pink Sheet” DAILY, Mar. 24, 2011). While the drug’s clinical performance has been strong, some view it as late-to-market behind Eliquis and Xarelto, as well as Boehringer’s Pradaxa.
Xarelto has been approved for stroke prevention in atrial fibrillation patients, deep vein thrombosis prevention in hip and knee surgery patients, and on Nov. 2, for treatment and reduction of the risk of recurrent deep vein thrombosis and pulmonary embolism. Pfizer and Bristol have secured European approval of Eliquis for venous thromboembolic events in hip and knee surgery patients, and are seeking U.S. approval to reduce risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation.
Portola raised $89 million in a Series D round of funding announced in November 2011 about eight months after Merck returned rights to betrixaban, with first-time investors Eastern Capital Ltd. and Temasek Holdings a long roster of existing investors (“Freed From Merck Deal, Portola Set To Move Betrixaban Forward With $89M Funding” – “The Pink Sheet” DAILY, Nov. 22, 2011). The company has raised more than $300 million since 2003, and received $75 million in a non-dilutive upfront payment as part of its 2009 partnership with Novartis AG around cardiovascular drug elinogrel (“Coulda, Shoulda? Sanofi’s Skip On Portola Proves Clot-Buster Gain For Novartis” – “The Pink Sheet” DAILY, Feb. 12, 2009).