AstraZeneca is to pull its clotbuster Exanta (ximelagatran) from the global market after new patient safety data threw up a single case of serious liver injury, and 18 months after the compound failed to garner approval in the crucial US market.
However, the news failed to make much of a dent in the firm’s share price, despite Exanta once being touted as a $3-$4 billion product, and AstraZeneca calling it the first major development since conventional warfarin treatment was introduced 60 years ago. Trials showed it to be as effective as the decades-old treatment, and to offer significant safety advantages, as well as being administered orally.
However, it soon came clear that it would fail to meet expectations. Although Exanta was first approved in Germany, it was already under a grey cloud after the UK and Ireland withdrew from the mutual recognition process. And the grey soon turned to black after a US Food and Drug Administration advisory panel knocked back Exanta in all three sought after indications - to prevent blood clots in knee surgery, the long-term secondary prevention of blood clots, and as a stroke prophylactic in patients with atrial fibrillation. As well as questioning the trial designs, the panel also placed a question-mark over Exanta's long-term safety, particularly with regard to raised liver enzymes, adding: "In the clinical development programme, severe liver injury - including fatal liver injury - occurred even though compliance with liver testing and discontinuation met or exceeded 83%." The agency's Office of Drug Safety warned that its use be limited to less than 12 days.
And now the firm’s EXTEND trial, which looked at Exanta therapy in orthopaedic surgery up to 35-days post-operatively, showed a risk of severe liver injury “with rapid onset of signs and symptoms” in the weeks following treatment end. This, says the firm, indicates that regular liver function monitoring may not mitigate the possible risk. While there is no evidence of a risk of liver injury with approved use of up to 11 days, any unapproved use beyond 11 days is a concern.”
For this reason, AstraZeneca has decided to cut its losses and not only pull the drug from the global market, but to terminate two ongoing clinical trials of Exanta. Only 400 patients currently receive Exanta for the short-term prevention of venous thromboembolism, and sales just tipped over the $500,000 mark for 2005.
David Brennan, Chief Executive of AstraZeneca, said the company had decided to take the “precautionary measure in the interests of patient safety,” but added it is committed to pursuing new medicines in this area. The UK giant has a follow-up agent – code-named AZD0837 – which AstraZeneca hopes will not be accompanied with the same liver problems as Exanta, but this is not expected to be filed for approval until some time beyond 2008.