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Ximelagatran / Exanta


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AstraZeneca today announced results from the first phase III stroke prevention data for Exanta? (ximelagatran), the first of a new class of oral direct thrombin inhibitor (Oral DTI), presented at the 52nd Scientific Session of the American College of Cardiology (ACC), Chicago. The results show that fixed dose twice daily 36mg oral Exanta compares favourably with dose-adjusted warfarin in preventing stroke and systemic embolic events (SEE) in patients with atrial fibrillation (AF), meeting the study?s primary efficacy endpoint.

SPORTIF III*, a multi-national, randomised, open-label, parallel-group study with blinded event assessment, was designed as a non-inferiority** study to compare oral Exanta with the current standard treatment, dose-adjusted warfarin. While the study was not aimed at demonstrating superiority, the incidence of stroke and SEE seen for Exanta compared with a well-controlled warfarin treatment (average study INR 2.5) was numerically lower (40 Exanta vs 56 warfarin) in the whole population (ITT - including those who stopped treatment). Furthermore, a statistically significant relative risk reduction (RRR) of 41% (p=0.018) was demonstrated for Exanta compared with well-controlled warfarin in patients who remained on treatment for the duration of the study (OT population).

These promising efficacy results need to be considered alongside the safety profile for Exanta emerging from this study and from other ongoing clinical trials, which will define its overall benefit-risk profile. In SPORTIF III, the incidence of liver enzyme (ALT) elevations was 6.5% for Exanta and mostly occurred within the first six months of treatment. These elevations were associated with no specific clinical symptoms and decreased with treatment continuation or discontinuation. With regard to bleeding and recognising that Exanta was used in a fixed dose regimen without coagulation monitoring, the combined rate of major and minor bleeding events was found to be significantly lower for Exanta than warfarin (475 vs 554 events; p=0.007) and there was no significant difference in all cause mortality between the Exanta and warfarin groups.

?Today?s results confirm the potential of Exanta in stroke prevention for AF patients and highlight the important practical advantages that this unique first-in-class treatment holds over the traditional, standard treatment,? says Dr. Hamish Cameron, Vice President, Head of Exanta, AstraZeneca. ?These data, together with the results of SPORTIF V and other important studies, will form the basis for the FDA and EU submissions for Exanta in this indication, which are on track for the fourth quarter this year.?

SPORTIF is the largest clinical study programme ever undertaken in the prevention of stroke in atrial fibrillation. The SPORTIF III study will be complemented later this year by the North American SPORTIF V study, which only differs to SPORTIF III in that it is a double-blind study.

Exanta is currently under review in Europe for the prevention of venous thromboembolism (VTE) following elective hip or knee replacement surgery and will be submitted for regulatory approval in the US for the same indication in Q4 2003. A regulatory submission for the treatment of VTE is also scheduled to be submitted in Europe in the fourth quarter of this year, following the outcome of studies in this indication.

Stroke is the third leading cause of death in adults worldwide, with five million fatal events per year. Atrial fibrillation has been found to increase the risk of stroke fivefold, yet less than half of eligible patients receive effective treatment4. This unmet need may be attributed to the limitations of the current standard treatment, warfarin, which requires regular coagulation monitoring, dose titration and has several food and drug interactions. The current worldwide market for antithrombotics is $9.6 billion.

Exanta is the first of a new class of oral anticoagulants called oral DTIs. The drug is currently under phase III investigation and is the first oral anticoagulant to reach late clinical development in more than 50 years ? since the development of warfarin.

AstraZeneca is a major international healthcare business engaged in the research, development, manufacture and marketing of prescription pharmaceuticals and the supply of healthcare services. It is one of the top five pharmaceutical companies in the world with healthcare sales of over $17.8 billion and leading positions in sales of gastrointestinal, oncology, anaesthesia (including pain management), cardiovascular, central nervous system (CNS) and respiratory products. AstraZeneca is listed in the Dow Jones Sustainability Index (Global and European) as well as the FTSE4Good Index.

Further enquiries to:

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Note to News Editors:


*SPORTIF: Stroke Prevention by ORal Thrombin Inhibitor in atrial Fibrillation.

* SPORTIF III involves 3407 patients from 259 centres in 23 countries across Europe, Australia and Asia. 36mg fixed dose oral Exanta twice daily was compared with dose-adjusted warfarin (INR 2.0-3.0) once daily. Patients in the study had Non-valvular atrial fibrillation (AF) and at least one additional risk factor for stroke, which included: previous cerebral ischaemic attack; previous systemic embolism; hypertension; left ventricular dysfunction; age >= 75 years; age >= 65 years and coronary artery disease; age >= 65 years and diabetes mellitus. Patients were treated for an average of 17 months in SPORTIF III.

* ** The rationale for ?non-inferiority? studies:

* As many highly effective treatments are now available in various therapeutic areas, placebo-controlled trials are often now considered unethical. Therefore, the concept of non-inferiority testing is now increasingly common where objective of these studies is to demonstrate that a treatment is ?not inferior to? or 'as effective as' a gold standard treatment. This can then enable treatments to be differentiated in terms of their respective additional advantages to the patient and physician, such as predictability and convenience.

* Abstracts will be available online at www.acc.org and once these data have been presented media materials will be available on www.AstraZenecaPressOffice.com

* For further information please see www.AstraZenecaPressOffice.com

EXANTA?is a trademark, property of the AstraZeneca group of companies.

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Secondary Prevention of Venous Thromboembolism with the Oral Direct Thrombin Inhibitor Ximelagatran

Sam Schulman, M.D., Karin W?hlander, M.D., Torbj?rn Lundstr?m, M.D., Solveig Billing Clason, M.Sc., Henry Eriksson, M.D., for the THRIVE III Investigators


For many patients with venous thromboembolism, secondary prevention with vitamin K antagonists is not extended beyond six months, since the risk of recurrence may be outweighed by the risk of major bleeding.


In a double-blind, multicenter trial, we randomly assigned 1233 patients with venous thromboembolism who had undergone six months of anticoagulant therapy to extended secondary prevention with the oral direct thrombin inhibitor ximelagatran (24 mg) or placebo, taken twice daily, for 18 months without monitoring of coagulation. At base line, bilateral ultrasonography of the legs and perfusion lung scanning were performed.


Data from 612 patients in the ximelagatran group and 611 in the placebo group were analyzed. The occurrence of the primary end point, symptomatic recurrent venous thromboembolism, was confirmed in 12 patients assigned to ximelagatran and 71 patients assigned to placebo (hazard ratio, 0.16; 95 percent confidence interval, 0.09 to 0.30; P<0.001). Death from any cause occurred in 6 patients in the ximelagatran group and 7 patients in the placebo group, and bleeding occurred in 134 patients and 111 patients, respectively (hazard ratio, 1.19; 95 percent confidence interval, 0.93 to 1.53; P=0.17). The incidence of major hemorrhage was low (six events in the ximelagatran group and five in the placebo group), and none of these hemorrhages were fatal. The cumulative risk of a transient elevation of the alanine aminotransferase level to more than three times the upper limit of normal was 6.4 percent in the ximelagatran group, as compared with 1.2 percent in the placebo group (P<0.001).


Oral ximelagatran was superior to placebo for the extended prevention of venous thromboembolism. There was no significant increase in the frequency of bleeding complications, but there was an increase in the number of patients with a transient elevation in the alanine aminotransferase level.

Source Information

From the Coagulation Unit, Department of Medicine, Karolinska Hospital, Stockholm (S.S.); AstraZeneca Research and Development M?lndal, M?lndal (K.W., T.L., S.B.C.); the Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, Gothenburg (K.W.); and the Department of Medicine, Sahlgrenska University Hospital??stra, Gothenburg (H.E.) ? all in Sweden.

Address reprint requests to Dr. Schulman at the Coagulation Unit, Karolinska Hospital, S-171 76 Stockholm, Sweden, or at sam.schulman@ks.se.

Related Letters:

Ximelagatran for Secondary Prevention of Venous Thromboembolism

Vaknansky A., Kupfer Y., Tessler S., B?ger C., Schroll S., Holmer S., Schulman S., Eriksson H.

Extract | Full Text | PDF ?

N Engl J Med 2004; 350:618-619, Feb 5, 2004. Correspondence

This article has been cited by other articles:

* (2004). Preventing VTE with Ximelagatran. Journal Watch Cardiology 2004: 4-4 [Full Text] ?

* Vaknansky, A., Kupfer, Y., Tessler, S., Boger, C., Schroll, S., Holmer, S., Schulman, S., Eriksson, H. (2004). Ximelagatran for Secondary Prevention of Venous Thromboembolism. N Engl J Med 350: 618-619 [Full Text] ?

* Malik, I. (2004). JournalScan. Heart 90: 117-118 [Full Text] ?

* Goldhaber, S. Z., Elliott, C. G. (2003). Acute Pulmonary Embolism: Part II: Risk Stratification, Treatment, and Prevention. Circulation 108: 2834-2838 [Full Text] ?

* (2003). Ximelagatran to Prevent Venous Thromboembolism. Journal Watch (General) 2003: 2-2 [Full Text] ?

* Shapiro, S. S. (2003). Treating Thrombosis in the 21st Century. N Engl J Med 349: 1762-1764 [Full Text] ?

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UK watchdog NICE to assess AstraZeneca drug Exanta

Reuters, 10.14.03, 7:18 AM ET

LONDON, Oct 14 (Reuters) - Britain's medical cost effectiveness watchdog, NICE, is to assess AstraZeneca Plc's <AZN.L> new anti-coagulant Exanta as part of its latest work programme, the government said on Tuesday.

The evaluation is one of the first to be launched by the National Institute of Clinical Excellence (NICE) before a potential new blockbuster drug has reached the market. A positive assessment could help boost sales.

Exanta, which industry analysts tip as an eventual $3 billion-a-year seller, is expected to be approved in its first use for preventing blood clots after orthopaedic surgery in France before the end of the year. That would pave the way for its roll-out in other European Union countries.

Announcing the NICE assessment, the Department of Health said in a statement there was "strong evidence that this treatment could offer significant patient benefit" both in orthopaedic surgery and for prevention of stroke in patients with atrial fibrillation, a common heart arrhythmia.

Other products that will be examined by NICE include the heart failure drug Natrecor which was developed by Scios Inc, now part of Johnson & Johnson (nyse: JNJ - news - people), and which GlaxoSmithKline Plc <GSK.L> hopes to start marketing in Europe in 2004.

NICE was set up to tackle the problem of uneven access to medicines across the country. The National Health Service is now required to make drugs available throughout England if NICE decides they are cost effective.

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No FDA priority review for AstraZeneca's Exanta

Tuesday February 24, 10:40 AM

By Ben Hirschler

LONDON, Feb 24 (Reuters) - AstraZeneca Plc (LSE: AZN.L - news - msgs) , Europe's second-biggest drugmaker, said on Tuesday the U.S. Food and Drug Administration had accepted its filing for anticoagulant pill Exanta but decided not to award it a priority review.

"We can confirm that the FDA has accepted the Exanta filing and, as expected, we have been granted a standard review," company spokesman Steve Brown said.

Analysts estimate the new drug could eventually generate sales of $3 billion a year, mostly as a treatment to prevent strokes in patients with atrial fibrillation -- a common heart arrhythmia.

There had been some hopes the product would receive a priority review given the problems associated with using the existing drug, warfarin, in treating the condition.

But analysts at Goldman Sachs (NYSE: GS - news) said a standard review process was always more likely, given liver safety issues surrounding the drug. They continue to expect the product to generate sales of $800 million by 2007.

FDA approval targets require the U.S. watchdog to respond to 90 percent of new drug filings within 10 months of submission. Exanta was submitted at the end of 2003.

Incidents of raised liver enzymes in a small proportion of patients have led to concerns that approval for Exanta's long-term use in stroke prevention could be delayed. The drug's supporters, however, say the liver effect is minor, transient and easily manageable by labelling.

Exanta is the first new oral anti-clot drug since the introduction of warfarin almost 60 years ago. Unlike warfarin, once widely used in rat poison, it does not need the constant monitoring that people taking warfarin require.

That is because patients are given standard doses of Exanta, rather than the ever-shifting individualized dosing required for warfarin. Moreover, warfarin patients have many diet restrictions that would not be an issue with Exanta.

Exanta won its first approval in France in December for use on patients undergoing major knee and hip surgery, but such orthopaedic use represents a much smaller market opportunity than long-term use in stroke prevention.

Exanta is one of a number of new medicines that AstraZeneca is relying on to make up for falling sales of ulcer pill Losec, also known as Prilosec.

Warfarin, a generic medicine, is also sold by Bristol-Myers Squibb under the brand name Coumadin.

Shares in AstraZeneca were 0.9 percent lower at 25.22 pounds by 1030 GMT while the DJ Stoxx healthcare index was off 0.6 percent.

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As a patient who has Protein S Deficiency and has had a PE and DVT, if this drug were available in the rest of Europe and available over here would this benefit me.

As I do get a few side effects from the Warfarin, could this drug replace the Warfarin and do the same job?


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Direct thrombin inhibitors (DTIs): hirudin, bivalirudin, argatroban and ximelagatran

There's been an increased interest in DTIs because of thrombin's major role in clot formation. Thrombin converts fibrinogen to clottable fibrin; activates factors VI, VIII, XI, providing a positive feedback mechanism that enhances thrombin formation; activates factors XIII, which crosslinks fibrin, and activates platelets. DTIs bind thrombin at its active site, thereby interfering with its downstream effects, and can inactivate fluid-phase as well as fibrin-bound thrombin. To date, hirudin has been used for prophylaxis; bivalirudin and argatroban have been used in acute coronary syndromes (ACS); and lepirudin and argatroban have been used to treat heparin-induced thrombocytopenia.

These DTIs are more potent than the indirect thrombin inhibitors. Comparison of hirudin with a low molecular-weight heparin (Enoxaparin) for thromboprophylaxis after total hip replacement showed that hirudin-treated patients had a significantly lower incidence of deep-vein thrombosis than the enoxaparin group (New England Journal of Medicine, Nov. 6, 1997). Bivalirudin has been shown to be safe and effective compared to unfractionated heparins in ACS patients receiving thrombolytic therapy. Using bivalirudin may obviate the need to administer blood thinners that inhibit glycoprotein 2b/3a in low- and moderate-risk ACS patients. Trials using DTIs in patients undergoing percutaneous interventions are underway. Disadvantages: DTIs must be administered parenterally and require a less-than-ideal monitoring system that interferes with the INR. There are no antidotes for any of the agents. Hirudin is affected by renal excretion and thrombin-antithrombin antibody formation. Argatroban is affected by hepatic dysfunction.

Several novel antithrombotics are in the pipeline. Our challenge is to determine the optimal combination and settings for these new therapeutics.

A phase III trial of the new oral DTI ximelagatran was recently completed (Annals of Internal Medicine, October 2002). This trial concluded that postoperative ximelagatran was well tolerated and effective for preventing venous thromboembolism. It was at least as effective as adjusted-dose warfarin, and no differences were seen in bleeding or wound complications between the groups.

The new drug is an oral agent with fixed dosing. It triggers immediate anticoagulation, eliminating the need for bridge therapy with heparin. It has a short half-life so patients can receive anticoagulation therapy until the day before surgery. No coagulation monitoring is required, and there have been no documented food or drug interactions. Potential drawbacks include no antidote and no optimal monitoring assay. It is renally excreted and is associated with elevations in liver function tests (about 5 percent).

Solomon Tafari, M.D., M.P.H.

Hospital Internal Medicine

(904) 296-5741

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