AstraZeneca knocked back by FDA on Exanta
Administration (FDA) not to approve its oral anticoagulant Exanta
(ximelegatran), despite the fact that it is already on the market
in Europe.
Exanta is the first new oral anticoagulant to reach the market in around 50 years, and is also the front runner in the new class of direct thrombin inhibitors, aimed as replacements to warfarin.
The latter is the most widely used anticoagulant, despite being introduced on to the market decades ago. It is very effective when well managed, but is also associated with a number of drawbacks, including the need for costly and time-consuming coagulation monitoring, dose adjustments and extensive food and drug interactions
The US Food and Drug Administration's Cardiovascular and Renal DrugsAdvisory Committee voted against approving the drug for the prevention of venous thromboembolic events in patients undergoing knee replacement surgery, as well as for the prevention of stroke and other thromboembolic complications associated with atrial fibrillation and long-term secondary prevention of VTE after standard therapy for an episode of acute VTE.
The decision by the panel could be a substantial blow to the Anglo-Swedish drugmaker as Exanta had been tipped as a potential new blockbuster at a time when the firm's other major new product, Crestor (rosuvastatin) for cholesterol lowering, is plagued claims that it is unsafe from the likes of US pressure group Public Citizen. And AstraZeneca's other recent launch - the anticancer drug Iressa (gefitinib) - is not likely to be the blockbuster once expected as it has proved less effective than hoped.
Analysts at Lehman Brothers said they expect a non-approvable/approvable letter to be issued by the FDA by October 23 or December 23 at the latest, with a request for more data.
And this delay in clearance could result in Exanta losing its head-startagainst other competitor drugs in development for this category, according to the analysts. Of particular interest are other oral thromin inhibitors entering trials, although oral versions of another anticoagulant class - the Factor Xa inhibitors, are also being developed.
AstraZeneca has said it thinks it has a two-year headstart over the competition, but this could erode if it has to conduct additional clinical trials looking at Exanta's safety.
Concerns were raised over both the safety and efficacy of Exanta. Interms of the efficacy, the Exanta SPORTIF trials were powered to shownon-inferiority to warfarin, but the 2% margin chosen was too liberaland "a margin of this magnitude could leave open the possibility thatExanta was only half as effective as warfarin and still be considerednon-inferior to warfarin," noted the panel.
A range of safety issues were also highlighted by the committee,including that: - liver enzyme monitoring on the label (as proposed by AstraZeneca) may not be sufficient to control safety, as the intense monitoring in Phase III studies failed to prevent two deaths owing to liver failure;
In addition, the firm's proposed label had no provisions for dose adjustment in patients with varying degrees of renal impairement and this may compromise safety; blood levels of Exanta are five times higher inrenally-impaired patients, said the panel.
Finally, a clinical safety review suggested a risk of myocardial infarction and the absence of clear methods to control excessive bleeding with Exanta, should it occur.
In June, Exanta was launched in Germany, its first marketworldwide, for the prevention of venous thromboembolic events inorthopaedic surgery. This followed the successful completion of theEuropean Union's Mutual Recognition Procedure.
