Demonstrating once again an impressive ability to generate income, Portola Pharmaceuticals has raised $89m to fund phase III trials of anti-coagulant betrixaban and development of a companion antidote. Rejected by Merck & Co only eight months ago and coming way behind other oral agents that are already changing clinical practice, the company has somehow managed to convince investors the project is worth backing (Competitive outlook takes its toll on Merck and Portola's factor Xa inhibitor, March 25, 2011).
The antidote could be the key here as none of the new agents – Pradaxa, Xarelto and Eliquis - have one and Portola’s product should work with at least the latter two. The company has also picked a very challenging patient population for betrixaban’s first pivotal study. All of which points to an interesting if high risk strategy to clear a path in an increasingly crowded field of medicine.
A factor Xa inhibitor like Bayer’s Xarelto and Bristol-Myers Squibb’s Eliquis, betrixaban is certainly lagging behind in a field that also includes Boehringer Ingelheim’s thrombin inhibitor Pradaxa. Another candidate from Astellas Pharma, darexaban, was recently scrapped due to the competitive environment, while Daiichi Sankyo's edoxaban is also waiting in the wings with a huge 21,000 patient trial due to report next year, in stroke prevention.
Despite this and perhaps because of this Portola is planning its first phase III study in a setting in which its two direct rivals, Xarelto and Eliquis, have failed – preventing clots in acute medically ill patients. An incredibly frail and often elderly group, these patients have been hospitalised for heart problems, respiratory failure and other illnesses such as pneumonia; many are often too ill to walk across a room unassisted and are at a high risk of thrombotic events.
The results from Eliquis’ Adopt trial in this setting was presented at the American Heart Association meeting last week (AHA 2011 - Eliquis' value in medically ill debated, November 14, 2011).
The drug failed to prevent any more clots than Lovenox and patients were more than twice as likely to suffer major bleeding episode. The Magellan study with Xarelto produced similarly uninspiring results (Xarelto misses on Magellan, April 6, 2011).
Commentary from physicians at AHA made it clear that there is a significant need for better treatments for these patients and indeed the design of the Adopt trial came in for much criticism; none ruled out that these agents might find a role in treating these patients.
Assuming betrixaban is a similarly safe and effective compound, Portola should be able to learn from these experiences and focus on selecting patients more carefully. Finding the right dose will also be extremely important, so theoretically betrixaban could well succeed where others have failed.
Nice to have antidote
The antidote product, PRT064445, is destined for phase I studies next year; only pre-clinical data has been released on the compound so far.
These early studies have demonstrated the compound’s potential to act as a universal antidote to all current Factor Xa inhibitors, including the new oral agents such as Xarelto and older therapies including Lovenox. For all its drawbacks the blood thinning effects of warfarin can be reversed with vitamin K, and the lack of an option to quickly counter the effects of the newer agents, if needed, has caused some concern.
Still, this has not been a big enough concern to prevent widespread regulatory approvals and predictions of huge commercial potential. Eliquis and Xarelto alone are forecast to generate sales of more than $6bn by 2016.
As such, the antidote is likely to be viewed as a nice-to-have product. How betrixaban stacks up remains to be seen – medically ill patients represent a big challenge to treat and the trials will be long and costly. Being so far behind, Portola has no choice but to take this risky path.
Luckily Portoloa appears to have no problem finding backers of its strategy. The new cash has been raised from existing investors and two new shareholders from overseas – Singapore-based asset Temasek and Eastern Capital Limited. It previously tapped investors in 2008, which netted $60m; only the year before $70m was raised in what the company described as a Series C round.
Together with the Biogen deal last month, which included a $45m upfront, the $50m from Merck for betrixaban in 2009 and $75m from Novartis for blood thinner elinogrel, Portola has raised almost $500m since 2003 (Portola strikes again with bumper Biogen deal, October 28, 2011).
It is a wonder Portolo's management team finds time to oversee any clinical work, with that sort of deal flow.