With its once-daily oral anticoagulant AZD0837 ready to move into Phase III, AstraZeneca is talking up the lessons it learned from its experience with the failed anticoagulant Exanta (ximelagatran).

A selective and reversible direct thrombin inhibitor, '0837 is being investigated for the prevention of stroke and systemic embolic events in patients with atrial fibrillation. In part because '0837 was the back-up compound to Exanta, the anti-thrombotic attracted much investor attention during the firm's July 31 second quarter sales and earnings call.

Exanta's development was discontinued after being deemed "not approvable" due to liver toxicity.

Phase III recruitment for '0837 will begin this year. "You can bet your life we have had discussions with the regulators, particularly with the FDA, ... about the size and powering of the Phase III and what the endpoints should be, and of course sharing with them the Phase II data. So we are going into Phase III with our eyes widely open," Executive Director-Development John Patterson stated.

With the safety issues of Exanta in mind, the firm has "scrutinized the tolerability in general and the liver effects in particular," Patterson said.

So far '0837 has been dosed in more than 900 AF patients, with the longest exposure being 16 months. Phase IIb data will be presented next year. According to the firm, the studies so far have demonstrated a positive overall benefit-risk profile for '0837 compared with vitamin K antagonists, such as warfarin, in the prevention of stroke in patients with AF.

During the call, Morgan Stanley analyst Andrew Baum noted '0837 as "late to the party" in terms of Phase III development of small-molecule oral anti-thrombotics, and questioned the decision to start with AF, as opposed to the established route of first being evaluated in patients undergoing orthopedic surgery. He asked the firm to address the risks it is taking with development of the compound.

Patterson acknowledged that other oral anticoagulants, including Factor Xa and thrombin inhibitors, are ahead of '0837. "But we have looked at them very carefully and we think they are not perfect."

Johnson & Johnson and Bayer submitted their Factor Xa inhibitor Xarelto (rivaroxaban) to FDA on July 29 for prevention of deep vein thrombosis and pulmonary embolism in patients undergoing hip or knee replacement surgery. The firms also plan to study the agent for stroke prevention in AF and secondary prevention of acute coronary syndrome (¹ Also see "With European Approval Imminent, J&J/Bayer File Rivaroxaban In The U.S." - Pink Sheet, 30 July, 2008.).

Also in Phase III development ahead of '0837 is Pfizer and Bristol-Myers Squibb's oral Factor Xa inhibitor apixaban for prevention of VTE and prevention of stroke in AF patients. The firms have plans to submit the NDA to FDA in 2009. Astellas and Daiichi Sankyo also have oral Factor Xa inhibitors in development.

Additionally, enrollment of more than 18,000 patients in the Phase III trials of Boehringer Ingelheim's oral thrombin inhibitor dabigatran for stroke prevention in AF patients was completed in January (² Also see "Atrial Fibrillation Data For Boehringer Ingelheim’s Dabigatran Due In Early 2009" - Pink Sheet, 18 January, 2008.).

Regarding the competitors, Patterson told investors that "we think there are things we can do that actually are smarter, and [we] can learn from our Exanta experience ... [to] bring a very competitive molecule through to the marketplace."

AstraZeneca's experience with the immediate-release program for its failed Exanta informed its decision to develop '0837 as an extended-release formula (³ Also see "AstraZeneca Expects Exanta Experience To Benefit Future Anticoagulant R&D" - Pink Sheet, 19 June, 2006., p. 11).

"We actually went back and developed the extended release formulation [of '0837] because we wanted to get rid of the peak-trough variability and to be able to really control the level of anticoagulation," he explained. '0837 has a predictable relationship between dosage and blood levels, plus low pharmacokinetic variability, he said.

The Exanta experience also guided the decision to study '0837 directly in AF patients. Patterson said that evaluating the compound first as short-term treatment in orthopedic surgery did not shed enough light on its risk-benefit profile as chronic therapy in AF. Studying the drug in a short-term indication "in many ways got in the way because the way orthopedic surgery is treated is very different on different sides of the Atlantic," he added.

- Jamie Hammon (j.hammon@elsevier.com)

Learning From Exanta: AstraZeneca Ready For Phase III With ‘0837

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