Exanta, the Blood Thinner is Withdrawn from the Market
(2/21/06)- AstraZeneca PLC announced that it would terminate all development of its new anticoagulant drug Exanta. The announcement followed a serious case of liver damage, and would result in the termination of the clinical trial involving some 600 individual. The company also announced that it was no longer approving the usage of the drug in some 400 patients who were taking the drug for the short-term prevention of venous thromboembolism after surgery.
Sales in 2005 totaled $575,000 according to the company. At one point the company had hoped that the drug would eventually result in sales of $3 billion.
(8/07/05)- The following is the reply that we got to an email that we sent to AstraZeneca to see if we could find out what the latest developments were in regards to their anti-clotting drug Exanta-
"Thank you for contacting AstraZeneca LP regarding EXANTAŽ (ximelagatran).AstraZeneca announced on October 8, 2004 that the US Food and Drug Administration (FDA) did not grant approval for the investigational oral anticoagulant EXANTA. The company had submitted a New Drug Application (NDA) for EXANTA for the prevention of strokes in patients with atrial fibrillation, for the prevention of blood clots in patients undergoing knee-replacement surgery, and for the long-term secondary prevention of blood clots following standard treatment of a clot.Following receipt of this letter, the company is considering how to proceed further with the FDA.EXANTA has been approved by European regulatory authorities for the prevention of blood clots in patients undergoing hip- and knee-replacement surgery, and has been launched in seven European markets. AstraZeneca continues to believe in the benefit/risk profile of EXANTA and will work with European and other regulatory authorities towards further approvals.If we can further assist you or your health care professional, please contact the Information Center at AstraZeneca at 1-800-236-9933, Monday through Friday, 8 a.m. to 7 p.m. ET, excluding holidays."
Sincerely,Linda DiMartinoBrand SpecialistInformation Center at AstraZeneca
(9/18/04)- Approval in the US was widely anticipated but is in doubt after a key FDA panel of experts recommended rejection of Exanta over concerns about hepatotoxicity. Submissions to the FDA included use of Exanta in stroke prevention in patients with atrial fibrillation, long-term secondary prevention of VTE and prevention of VTE in total knee replacement. Analysts believe AstraZeneca may now withdraw its application to avoid a 'non approvable' letter from the FDA, and re-submit with new data in one to two years time.
Following the review by the French Regulatory Authority
(AFSSAPS) of the ExantaŽ regulatory submission made in December
2003 AstraZeneca today announced receipt of a request for more
information before the drug can be considered for approval of
long-term use in Europe.
The French authority has been acting as the Reference Member
State for the European Mutual Recognition Procedure (MRP) and has
been reviewing data on Exanta in the prevention of stroke and other
thromboembolic complications associated with atrial fibrillation
(AF, an irregular heartbeat) and the treatment of venous
thromboembolism (VTE).
AFSSAPS has requested further clinical information confirming the
efficacy and demonstrating safety of Exanta in AF to allow a
definitive benefit/ risk assessment to be made while, for VTE
treatment, the authority does not believe the data presented in
the single THRIVE Treatment study provides adequate support for
this use of Exanta and is proposing a rejection of this
indication. AstraZeneca will now have discussions with AFSSAPS to
examine what additional data needs to be generated for the AF
file to be progressed further.
"Given the limitations of current therapy in the prevention
of thrombosis in patients with atrial fibrillation and its
potentially life threatening complications, this remains an area
of great unmet need," commented Dr Hamish Cameron, Vice
President, Head of Exanta, AstraZeneca. "AstraZeneca remains
committed to research in this area of medicine."
In May 2004, Exanta was approved by the European regulatory
authorities for the short-term indication, the prevention of
blood clots in patients undergoing hip- or knee-replacement
surgery. This included a commitment to perform an additional
study post-approval and the protocol is currently under
discussion within the EU. Exanta has since been made available in
nine European countries and Argentina.
Further enquiries to:
Media Enquiries:
Edel McCaffrey, Tel: +44 (0) 207 304 5034
Steve Brown, Tel: +44 (0) 207 304 5033
Investor Enquiries:
Mina Blair, Tel: +44 (0) 207 304 5084
Jonathan Hunt, Tel: +44 (0) 207 304 5087
(10/18/04)-The FDA will vote on October 22 2004 at its formal hearing whether or not it will accept the committee's recommendation in connection with Exanta. It can approve the drug even if the advisory committee voted to deny its approval of the application.
The FDA's Cardiology and Renal Advisory Committee failed to approve AstraZenaca's Exanta at its meeting on September 10th.. The big question mark in connection with Exanta is the drug's safety profile, since liver toxicity is a key matter. The advisory committee voted to tell the FDA that the potential risk to hearts and livers outweigh the benefits for patients who have had knee-replacement surgery, and for preventing new blood clots in people being treated for one.
Earlier this year, European regulators approved Exanta for use in knee-replacement operations and for patients who were suffering from blood clots in their legs. Patients using the drug for knee surgery would be on the drug for 12 days. The company is also proposing that the drug be used for longer-term use in patients with atrial fibrillation, or irregular heartbeat, since this problem can cause fatal blood clots. The company also claims that the drug can be used as a secondary treatment for patients with deep vein thrombosis, or blood clots in the legs.
Dr. Hamish Cameron, an AstraZeneca vice president overseeing Exanta, said the benefit of the drug is that a standard, single dose can be administered and that patients would not face any dietary restrictions. Patients using the drug on a short-term basis would not have to be monitored. Dr. Cameron went on to state that patients using the drug on a long term basis would have to be monitored on a monthly basis for possible damage to the liver. The advisory committee however said that monthly monitoring is not sufficient and that a patient registry should be established by the company which would "restrict distribution measures to limit population risk."
The committee also found that its review of the clinical data for patients using Exanta for 12 days, or short term use, suggested a higher risk of adverse coronary events such as heart attacks, and that bleeding events were higher in Exanta patients compared to Warfarin patients.
The results for SPORTIF V were announced in November of 2003. 3,922 patients were enrolled and followed from 1 to 2 years. This study was a double blind study, meaning neither patient nof treating physician knew which medication was given to the patient. Patients on the study drug still had their INR measured (the value to determine proper dosing of coumadin). A computer program generated faxed data that would force the physician to make adjustments from time to time as if the patient was on regular coumadin. ExantaŽ was associated with fewer strokes and systemic emboli (though not statistically significant) and less bleeding (statistically significant) than those patients who were on Coumadin.
If approved by the FDA and European regulators, AstraZeneca's new blood thinning medication Exanta (ximelagatran) will be the first new drug to hit the market to deal with anticoagulation in almost 60 years. AstraZeneca hopes for approval of the NDA by the end of 2004.
The results of a study of Exanata TM (ximelagatran) as an
effective and convenient replacement for warfarin for prevention
of stroke in atrial
fibrillation was announced at the 52nd Scientific Session of the
American College of Cardiology (ACC) in Chicago in April 2003.
Results of the SPORTIF III, a multi-national, randomized study
suggest that Exanta can offer great improvement in preventing
stroke in patients with atrial fibrillation. The study also
supported the emerging benefit-risk profile of Exanta.
The primary endpoint was met, showing that a fixed dose taken
twice a day of 36mg oral Exanta compared favorably with
dose-adjusted warfarin in
preventing stroke and systemic embolic events in atrial
fibrillation. In the SPORTIF III trial, the incidence of liver
enzyme (ALT) elevations was
6.5% for Exanta, and mostly occurred within the first 6-months of
treatment. Levels returned back to normal shortly after the six
month period of time. The combined rate of major and minor
bleeding events was found to be significantly lower for Exanta
than warfarin (475 vs 455 events; p=0.007) and there was no
significant difference in all cause mortality between the
Exanta..
Warfarin has been around for over 50 years but it requires constant monitoring and dosing adjustments to keep the blood from clotting or getting too thin. Another negative side effect that has plagued warfarin is that it reacts with many drugs and food. Atrial fibrillation effects some two million Americans a year, and is associated with a five-fold increase in the risk of stroke. It is estimated that atrial fibrillation accounts for about 15% of all strokes worldwide.
Exanta is the first of a new class of drugs called direct thrombin inhibitors. One of the negative side effects associated with the drug is that it was associated with elevated liver enzymes in about 6% of patients. While this effect was only transient, it will mean that patients will have to be closely monitored for about 6 months. The drug does however eliminate the need for constant dosing adjustment.
Astra plans to submit the drug for approval by the FDA and European authorities by year's end. We must however caution that Astra sponsored the study. In the study 7,329 patients were randomly assigned to either Exanta or warfarin, and were treated for an average of 20 months. Even though 51 of the Exanta patients suffered from a stroke or other serious clotting episode, as compared to 37 of the coumadin patients, the findings were not considered statistically significant.
Since warfarin is a generic drug it is inexpensive, but because of the added expense that could be eliminated if close monitoring of the patient is eliminated, the long run saving to the medical system could be substantial.
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Allan Rubin
updated February 21, 2006
To e-mail: hrubin12@nyc.rr.com or rubin@brainlink.com