Competitive Outlook Takes Its Toll on Merck and Portola's Factor Xa Inhibitor

March 25, 2011 Competitive outlook takes its toll on Merck and Portola's factor Xa inhibitor

Merck & Co’s decision to scrap further development of Portola Pharmaceuticals’ oral factor Xa inhibitor, betrixaban, points to the ruthless realism pervading R&D decisions today. It also raises questions over Merck’s original decision to license the drug less than two years ago for $50m.

The prospect of being the fifth factor Xa inhibitor to market as an agent to prevent stroke in patients with atrial fibrillation, requiring a large and expensive pivotal trial, probably against an active comparator such as Pradaxa, was clearly not appealing. Merck’s decision could also have wider implications for other factor Xas in development, particularly Astellas Pharma’s desire to secure a global partner for darexaban (see table below).

Poor odds

While the competitive landscape for factor Xa inhibitors has moved on since Merck licensed betrixaban from Portola, it is unlikely to have developed much beyond what would have been expected two years ago.

Bayer’s Xarelto should finally gain FDA approval this year and Pradaxa, a slightly different oral anti-coagulant, has made an impressive splash since approval last year (Event – Bayer hoping for Xarelto win in important new use, March 25, 2011). The development of the other late stage candidates, Bristol-Myers Squibb’s apixaban and Daiichi Sankyo’s edoxaban, has largely been on track. The European advisory committee recently issued a positive opinion in favour of apixaban - in venous thromboembolic events in adult patients who have undergone elective hip or knee replacement surgery - to be branded Eliquis in Europe.

If the dynamics of the factor Xa market have not changed materially in the last two years, perhaps the decision reflects the recent big pharma trend towards a more ruthless approach to development decisions.

R&D budgets are under increasing pressure and investment decisions more closely scrutinised, an environment and culture which perhaps did not exist to quite the same level a few years ago.

Tough times

For Portola they may have seen the writing on the wall given that Merck had been stalling on plans for a phase III trial – exactly a year ago the companies presented positive phase II data at the American College of Cardiology meeting, but no word on a pivotal trial had been forthcoming.

While Portola’s chief executive, William Lis, talks about regaining rights to betrixaban as a “transformational opportunity”, the pressure is now on the company's other anticoagulant, elinogrel, to deliver. Licensed to Novartis two years ago for $75m upfront, the Swiss group has said phase III trials should start this year, so Portola will be relieved to hear when this starts.

The private Californian group has raised $217m since the company’s creation in 2003, its last financing round being a $60m series D in 2008. Adding the $125m it received from Novartis and Merck in 2009, the company should be well funded for a while yet but investors will be fretting about seeing some return for the $342m invested and raised so far.

Wider ramifications

Just last month Astellas Pharma withdrew its Japanese filing for darexaban (YM150), as a potential agent to prevent venous thromboembolism (VTE) in patients undergoing orthopaedic surgery. The Japanese authorities decided further clinical studies are required for approval.

As a result, Astellas is now seeking global partners to develop and commercialise darexaban and its plan for the Japanese market will depend on the outcome of these discussions.

As if to emphasise the clinical trial challenge facing these candidates, Daiichi Sankyo recently completed the enrolment of more than 21,000 patients in its Engage AF-Timi 48 trial, testing edoxaban against warfarin in the stroke prevention in atrial fibrillation setting; data is due next year. Meanwhile the Rocket-AF trial of Xarelto, which forms the basis of global applications in stroke prevention, was conducted in more than 14,000 patients. As the table below shows, the sales potential of these products points to a massive commercial opportunity. However, with the approval of Pradaxa last year, to be followed by Xarelto and apixaban over the next 18 months, the bar is being raised all the time while the cost and effort required to reach the market continues to rise; facts that Merck has finally woken up to.

Portfolio of Factor Xa inhibitors WW annual sales ($m)

Generic Status Product Company Originator Launch 2010 2012 2014 Name

Bayer + Marketed Xarelto rivaroxaban Johnson Bayer 2008 92 1,110 2,972 & Johnson

fondaparinux Arixtra GlaxoSmithKline Sanofi 2002 465 544 547 sodium

Eliquis Bristol-Myers DuPont Filed apixaban 2011 - 286 1,239 (apixaban) Squibb + Pfizer Pharmaceuticals

edoxaban Daiichi DU-176b Daiichi Sankyo 2012 - 31 138 tosylate Pharmaceutical

darexaban Phase III YM150 Astellas Pharma Yamanouchi 2013 - - 83 maleate

Otamixaban otamixaban Sanofi-Aventis Hoechst 2013 - - 74 (XRP0673)

Portola COR Phase II Betrixaban betrixaban 2015 - - - Pharmaceuticals Therapeutics

TAK-442 letaxaban Takeda Takeda - - - -

Daiichi Phase I DB-772d Daiichi Sankyo - - - - Pharmaceutical

EP217609 Endotis Pharma Akzo Nobel - - - -

Source: EvaluatePharma