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Portola in the News

Scrip
March 25, 2011
By Donna Young

Portola Pharmaceuticals CEO William Lis said Merck's decision to return the rights to his firm for betrixaban, an investigational oral factor Xa inhibitor anticoagulant being evaluated for the prevention of stroke in patients with atrial fibrillation, came as no surprise, insisting that the companies had been in discussions for awhile about the smaller biotech independently taking the drug forward.

In a joint 24 March statement, the companies revealed that they were ending their less-than two-year-old deal on betrixaban, which is on the verge of entering Phase III development, owing that decision to Merck determining it had other compounds in its late-stage pipeline that took precedence.

"We are constantly evaluating our pipeline with respect to our business. It is nothing new," Merck spokesman Ian McConnell told Scrip. "This is business as usual."

He said Merck's 2009 merger with Schering-Plough also triggered an evaluation and prioritization of the combined pipeline.

Nonetheless, Mr McConnell insisted that Merck's investment in cardiovascular disease remains "significant," with no plans to shift away from developing drugs in that space – pointing to the Whitehouse Station, New Jersey pharma giant's ongoing programs for anacetrapib, tridactive and vorapaxar, although the latter compound recently had one major study halted and another curtailed.

In January, Merck said the data safety monitoring board (DSMB) for the company's TRACER study, which is testing vorapaxar, a selective protease activated receptor-1 thrombin receptor antagonist designed to diminish clot formation, or thrombosis, in acute coronary syndrome, advised the firm to discontinue the drug in patients and shut down the trial as soon as possible after an increase in intracranial hemorrhage in patients with a history of stroke was observed. On the advice of the DSMB, the company also discontinued the drug in patients who experienced a stroke before entering or during the course of its chronic care, secondary prevention TRA-2P study, which was examining vorapaxar in 26,500 patients who have experienced a heart attack, an ischemic stroke or have documented peripheral vascular disease (scripintelligence, 13 January 2011).

Vorapaxar is one of the drugs Merck acquired through its merger with Schering-Plough.

Merck and Portola emphasized that the end of their partnership on betrixaban had nothing to do with safety – generally the issue when a partner decides to end a collaboration.

Indeed, betrixaban has shown good safety results, demonstrating similar or lower rates of bleeding compared with warfarin in Portola's recently completed Phase II EXPLORE-Xa trial, in which the drug also showed dose-dependent clinical activity.

In July 2009, Merck paid $50 million up front for betrixaban, with Portola eligible to earn up to $420 million on the achievement of certain development, regulatory and commercialization milestones, plus the potential for double-digit royalties on worldwide sales of the drug (scripintelligence, 10 July 2009).

Under the agreement, Merck had assumed all development and commercialization costs, including the costs of Phase III clinical trials.

But going forward, Portola will now bear those costs alone, which Mr Lis said the firm was prepared to do.

"Right now we have a strong cash position," he told Scrip, revealing that the firm has about $100 million in cash on hand.

Portola's need for going back to the venture capital market to raise more cash will depend on the indications the company plans to pursue in its Phase III program, Mr Lis said, adding that the firm would have a better idea of that need once it has held face-to-face discussions with the US FDA in the coming months.

While Portola plans to go it alone for now, the firm has not ruled out future partnerships on betrixaban "somewhere down the line" to maximize the drug's potential in the marketplace, Mr Lis said. But, he said, another potential collaboration on the drug is "not our focus at this point".

"We believe there is an independent path for Portola to do something transformational," Mr Lis said, insisting that the 81-employee firm is a fully integrated research, discovery and clinical development company capable of handling the task of getting betrixaban through Phase III development.

Portola's core group of scientists has worked together for over 15 years, many of them in the area of thrombosis, Mr Lis noted.

Indeed, while at COR Therapeutics, which was later acquired by Millennium Pharmaceuticals, now part of Takeda, a "good portion" of Portola's scientists pioneered the discovery and development of glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors, a class of antiplatelet agents used during percutaneous coronary interventions, he said.

While at Millennium, Mr Lis directed the marketing activities for Integrilin (eptifibatide), a GP IIb/IIIa antiplatelet agent, which is now marketed in the US by Merck. He also was responsible for cardiovascular business licensing and commercial operations while at Johnson & Johnson unit Scios, where he led in-licensing activities and precommercialization development for Xarelto (rivaroxaban), which is approved in Europe for the prevention of venous thromboembolism (VTE) and has pending applications there and in the US for use in stroke prevention. J&J is partnered with Bayer on that Xarelto, which also is awaiting approval for VTE and pulmonary embolism in the US (scripintelligence, 6 January 2011).

Xarelto is just one of the many new drugs that betrixaban faces competition against, with Bristol-Myers Squibb's apixaban being another.

But Boehringer Ingelheim's Pradaxa (dabigatran) is ahead of them all, gaining approval in the US in October 2010 as a preventive therapy for stroke and blood clots in patients with non-valvular atrial fibrillation (scripintelligence, 25 October 2010).

But Mr Lis expressed confidence that the 100,000 million patients at risk for life-threatening clots is a vast market with a need for more therapies, like betrixaban.

He said there were as many as 10 indications Portola could pursue for the drug, with some of those areas not yet targeted by any of the biotech's competitors.

"We think we have a great opportunity because our molecule is different. It has different pharmacologic properties that are most important for specific patient populations, broadly and narrowly," Mr Lis said.

In conjunction with its factor Xa program, Portola also is developing an antiplatelet antidote, which Mr Lis called a "unique" strategy that provides another clinical advantage over the firm's competition.

While factor Xa inhibitors can prevent blood clots, they are known to cause clinically relevant bleeding and their anticoagulant activity may need to be reversed in some patients, he explained.

No antidotes for factor Xa inhibitors currently are available, so Portola's antidote, PRT064445, a recombinant protein, provides the company a step ahead of its competition.

The antidote, however, is in early development, not entering the clinic until next year.