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Sep 13, 2004
 |  BioCentury  |  Product Development

Exanta strikes out

AstraZeneca plc conducted a clinical development program in over 30,000 patients and persuaded European regulators to allow Exanta ximelagatran on the market. But last week, the company only managed to persuade one voting participant in an FDA advisory committee meeting to support the use of Exanta for any indication.

On Friday, the Cardiovascular and Renal Drugs Advisory Committee and its consultants voted 11-1 and 10-1 with one abstention, respectively, that AstraZeneca failed to demonstrate a favorable risk-benefit ratio for two long-term indications for Exanta: prevention of stroke and other thromboembolic complications associated with atrial fibrillation, and long-term secondary prevention of venous thromboembolism (VTE) after standard treatment of an episode of acute VTE.

The panel also unanimously rejected one short-term indication: prevention of VTE in patients undergoing knee replacement surgery.

The European indication is prevention of VTE following major elective orthopedic surgery (hip or knee replacement). Acting as the reference member state for the Mutual Recognition Procedure, France approved Exanta in December 2003. The product was launched in Germany on June 21.

AstraZeneca (LSE:AZN; AZN, London, U.K.) characterized the indication as a "proof of principle" in press releases announcing the approval, and emphasized that applications for blockbuster markets in chronic indications are pending in Europe and the U.S. It also noted that "the worldwide market for anticoagulants is around $4 billion and growing at 13 percent annually, while the worldwide anti-thrombotic market is around $12 billion, growing at 15 percent annually."

Although last week's votes were unambiguously negative, the accompanying commentary provided some glimmers of optimism. Several members said they could support approval of Exanta for short-term use following surgery if the company successfully completed a new trial.

The committee also strongly concurred with AZN's arguments about the need for a drug like Exanta to replace warfarin.

Warfarin is one of the top 10 most-prescribed drugs - 3 million patients receive 32 million prescriptions annually in the U.S. - and one of the most problematic. Because of its unpredictable kinetics, as well as interactions with numerous foods and drugs, safe and effective use requires close monitoring of the patient's blood coagulation levels. Even with frequent dose titration, it is often impossible to avoid either a sub-therapeutic dose, which poses dangers such as the fatal pulmonary embolism it is intended to prevent, or serious bleeding and stroke from over-dosing.

Indeed, an entire industry has developed to monitor coagulation levels in warfarin patients, and failure to adequately manage the drug is a leading cause of malpractice litigation.

Exanta is an oral small molecule direct thrombin inhibitor. The compound is a prodrug of melagatran, a non-marketed compound.

AZN has touted Exanta as a major breakthrough: a direct thrombin inhibitor that can be safely administered in a fixed oral dose without coagulation monitoring. But doubts about safety, as well as the ability to manage safe use of the drug,...

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