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New Anticoagulant: Ximelagatran / Exanta

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http://news.bbc.co.uk/1/hi/health/2913089.stm

Clot drug 'safer than warfarin'

A drug which thins the blood and can be taken as a pill is being hailed as a major breakthrough in the prevention of stroke. It could have fewer side effects and be easier to take than warfarin, which is used by thousands of patients in the UK. The drug is the first in a new class of anticoagulants that can be swallowed instead of injected. Called ximelagatran, research shows it is at least as safe and effective as warfarin, a drug more commonly known for its use as rat poison. Doctors have relied on warfarin for the past 50 years to reduce the risk of stroke in patients with a condition called atrial fibrillation abnormal heart rhythms. Around one in 20 people aged 65 or over have atrial fibrillation. Sufferers face a very high risk of clots forming within the heart and making their way to the brain, where they cut off the blood supply. Although warfarin is extremely effective, it is difficult to use and can be dangerous. It can cause serious internal bleeding in the brain and patients need regular blood tests to make sure the drug is not exceeding safety levels. As a result, it's believed a high proportion of patients with atrial fibrillation do not get the treatment they need to prevent life-threatening strokes. The new drug can be taken easily, needs no safety monitoring and does not increase the risk of bleeding. Experts believe it could dramatically improve the treatment of the condition. "These are remarkable results and this is a major breakthrough," said Dr Jean-Pierre Bassand, from the department of cardiology at the University of Besancon, France, who was not involved in studies on the drug. "The advantages are clearly evident." Researchers presented the results of a major trial comparing ximelagatran with warfarin in nearly 3,500 patients in 23 countries around the world. Patients were given regular warfarin or a daily dose of ximelagatran and monitored to see how many how many developed strokes as well as the number of adverse events. The results showed that after 17 months of treatment, 56 patients in the warfarin group had suffered strokes compared to only 40 in the ximelagatran group. When researchers looked at bleeding complications, they found "significantly fewer" cases of haemorrhaging among those on the new drug. "We found ximelagatran was at least as effective as warfarin and there were fewer bleeding complications," said lead researcher Dr Jonathan Halperin from the Mount Sinai School of Medicine in New York. "This study is the culmination of more than decade of drug development research. "We have found something safer and easier to tolerate than warfarin. "It means we could extend treatment more widely across the population and brings us closer to our goal of preventing thousands of strokes."

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http://www.loftusmd.com/Articles/stroke/exanta.html

Exanta? or Ximelagatran is an oral anticoagulant that is currently being studied the world over. It is a small compound that is absorbed and converted to the active substance Melagatran. Melagatran can also be given by injection (as can a number of other anticoagulants). Exanta? interferes with thrombin which is the final step in the activation of the clotting pathway.

Oral anticoagulation has been hampered by the difficulties in using Coumadin? or Warfarin. Coumadin? interacts with many other medications. In addition, Coumadin? is a drug with a narrow therapeutic index (which means the dose has to be adjusted very exactly and individually for each patient in order to avoid adverse effects). Because of this, many patients who would benefit from this medication cannot receive it because they are unwilling to have sufficiently close monitoring (monthly) or because the patient is judged incapable of handling a medication with potentially devastating consequences.

Exanta? does not have the same difficulties with dose adjustment or drug interaction as Coumadin? does. The presence of an injectable form will also be very useful when patients still need to be anticoagulated but are temporarily unable to take oral medication. Early studies have been promising but large studies to prove the medication is at least as good as coumadin for the prevention of stroke in atrial fibrillation are currently in progress. The results of these two studies, one in North America where the subjects and physicians are both blinded to treatment, and the other in the rest of the world are expected during 2003.

All anticoagulants increase the risk of bleeding and this risk must be weighed carefully against the potential benefits before prescribing this type of therapy.

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http://www.warfarinfo.com/ximelagatran.htm

Ximelagatran: a new drug to replace warfarin?

Tammy Kolacny, PharmD candidate

Frequently Asked Questions:

**Disclaimer: Provided information is based on limited, unpublished data from the drug manufacturer and may carry with it bias that would be expected from a party with such vested interests. This product is not approved for use in the U.S. yet and long-term data is limited.

What is ximelagatran?

Ximelagatran is an oral anticoagulant being developed by AstraZeneca as Exanta?.

How does it work?

Ximelagatran is termed a "direct thrombin inhibitor" because it slows the coagulation cascade by directly binding to thrombin, a clotting factor essential in the clotting process. If thrombin is blocked, clot formation is delayed (as with warfarin).

Does ximelagatran work differently than warfarin and what does this mean clinically?

Warfarin and ximelagatran both delay clot formation, but they do so in different ways. Warfarin binds to different clotting factors (II, VII, IX, X) within the coagulation cascade to delay the formation of a clot. A major difference between the two medications is the following: warfarin is dependent on vitamin K to work and ximelagatran is not. Therefore, ximelagatran is not affected by changes in vitamin K intake from diet or medications. For patients that are currently on warfarin, they can quickly recognize the affect that this small difference may have on their lifestyle. A person may no longer have to be concerned about bleeding or clotting based on changes in their diet or vitamin consumption.

What type of monitoring is involved?

According to current studies and manufacturer data, ximelagatran will not involve coagulation monitoring (INR/PT). Unlike with warfarin, dosing and patient response may be more predictable with ximelagatran. Dose proportionality studies have shown that changes in drug dose produce predictable and consistent changes of drug levels in the blood. Therefore, it is expected that ximelagatran may have one dose that is effective for most patients without the variability in dosing that is seen with warfarin.

What drugs interact with ximelagatran?

Manufacturers state that there are "no known pharmacokinetic drug interactions with ximelagatran." Pharmacokinetics is the study of "what the body does to the drug." This process often involves absorption, distribution to tissues, metabolism, and elimination of drugs. The majority of the drug interactions seen with warfarin are due to changes in distribution and/or metabolism as a result of concurrent and often times conflicting drug therapy. Ximelagatran has different drug properties than warfarin that make it less likely to interfere with other medications in this way. Potential drug interactions could include those seen between anticoagulants and other medications that may cause or worsen bleeding effects (such as aspirin or ibuprofen). At this point, drug interaction data is still limited but ximelagatran may be better than warfarin in this regard.

How effective is ximelagatran?

Clinical trials are still ongoing, but finalized studies indicate that ximelagatran is at least as effective as warfarin and enoxaparin (Lovenox?) when studied for short-term use following total knee and total hip arthroplasty (replacement), respectively. These two orthopedic studies demonstrated ximelagatran efficacy for the prevention of venous thromboembolism such as deep vein thrombosis (DVT) or pulmonary embolism (PE) that was comparable to that seen with traditional agents such as warfarin and enoxaparin.

Long term studies to evaluate the use of ximelagatran in DVT treatment, atrial fibrillation, and arterial conditions (following a heart attack) are ongoing as well. Limited information is known about the results of these trials, but preliminary data indicates that ximelagatran was found to be comparable in efficacy to warfarin and enoxaparin when evaluated in various conditions. Ximelagatran was shown to be at least as effective as current therapies.

How safe is ximelagatran and what side effects are possible?

The most common and expected side effect from ximelagatran (and any other anticoagulant) is bleeding. Clinical trials indicate that the bleeding risk associated with ximelagatran is comparable to that of traditional anticoagulants (warfarin and enoxaparin) and is not statistically better or worse than either tested medication. However, bleeding and safety issues will always be a concern for patients on anticoagulant medications.

When will ximelagatran be available in the United States?

An expected date of arrival on the U.S. drug market is unknown, but the earliest possible release date is probably autumn of 2003.

Why would a person want to switch from warfarin to ximelagatran when it becomes available?

A patient may want to switch to ximelagatran from warfarin for the following reasons (based on current data):

1. No coagulation monitoring (INR measurements)

2. Fewer drug/food interactions

3. Similar efficacy and safety to warfarin (so far)

4. Better overall quality of life for many patients (due to less monitoring and interactions)

5. Reduced costs from lab tests and visits related to coagulation monitoring

Why might a person NOT want to switch from warfarin to ximelagatran?

A patient needs to keep the following issues in mind when considering a switch from warfarin to ximelagatran?

1. Limited long-term data to support ximelagatran use

2. Expensive cost of the medication compared to generic warfarin

3. Compliance issues

-Less monitoring and fewer clinic visits may translate (for some patients) into thoughts that the drug is very safe and that missed doses are not harmful (when this can actually be very dangerous).

4. Potential loss of relations with anti-coagulation provider

-From my experience as a pharmacy student in Al Lodwick?s clinic, I have found that patients come into the clinic for the following reasons: to have their INR measured for warfarin management and to see Al.

-Many patients have developed great relationships with their anti-coagulation providers and the loss of monthly visits is certainly a consideration for many patients that may want to switch medications.

5. Overall patient care may suffer from fewer clinic visits

-More frequent provider visits (of any kind) have been shown to play a critical role in preventive healthcare by detecting problems early for better treatment outcomes. Anti-coagulation providers not only give advise about warfarin, but about all types of health conditions and medications.

6. Safety data (bleeding risk) is not fully established

-Hesitation and caution need to accompany any anticoagulant therapy changes because of the risk of bleeding or clotting that can result.

References:

Erikson, BI et al. A dose-ranging study of the oral direct thrombin inhibitor, ximelagatran, and its subcutaneous form, melagatran, compared with dalteparin in the prophylaxis of thromboembolism after hip or knee replacement: METHRO I. Thromb Haemost 2002 Feb;87(2):231-7.

Francis, CW et al. Ximelagatran vs. Warfarin for the Prevention of Venous Thromboembolism after Total Knee Arthroplasty. Ann Intern Med. 2002;137:648-655.

Heit, JA et al. Comparison of the Oral Direct Thrombin Inhibitor Ximelagatran with Enoxaparin as Prophylaxis Against Venous Thromboembolism After Total Knee Replacement. Arch Intern Med. 2001;161:2215-2221.

Hirsh, J et al. Current and Future Concepts in the Management of Venous Thrombosis and Pulmonary Embolism. 2002.

Katona, B, Sarich, TC. Ximelagatran Preclinical and Clinical Pharmacology Data: A Pharmacokinetic and Pharmacodynamic Overview. 2002 presentation.

? 2002 Tamara Kolacny?? Used by Permission

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http://www.ananova.com/business/story/sm_7...4580.html?menu=

AstraZeneca says Exanta cuts blood clot risk by 26% compared to warfarin

WILMINGTON, Del (AFX) - AstraZeneca said its oral anticoagulant drug Exanta (ximelagatran) was shown to reduce the risk of blood clots after total knee replacement surgery by 26% compared with warfarin, according to results of a Phase III clinical trial.

There were "no statistically significant differences" between the Exanta treatment and warfarin with respect to incidence of pulmonary embolism or death, it said.

In addition, results of a second Phase III clinical trial in patients who had completed a conventional six-month course of treatment for blood clots showed that treatment with Exanta for an additional 18 months resulted in about 84% relative risk reduction of developing recurrent events compared with a placebo, it said.

The estimated cumulative risk of a recurring deep vein thrombosis or pulmonary embolism during 18 months of treatment was 12.6% for the placebo compared with 2.8% for Exanta.

? AFX News

Story filed: 17:08 Monday 9th December 2002

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http://www.astrazeneca.com/mainnav1/mediao...elease-240.html

2?April?2003

NEW STUDY DEMONSTRATES THE POTENTIAL OF EXANTA? (ximelagatran) FOR PREVENTION OF STROKE IN ATRIAL FIBRILLATION

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:

Media Enquiries

Steve ?Brown

+44 (0)20 7304 5033

Emily ?Denney

+44 (0)20 7304 5034

Investor Relations

Mina?Blair-Robinson

+44 (0)20 7304 5084

Jonathan?Hunt

+44 (0)20 7304 5087

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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