First oral warfarin alternative approved in the US

For more than 50 years, warfarin has been the standard of care for long-term anticoagulation therapy in the United States, but now the FDA has approved the first oral anticoagulant that could replace it.

Developing an alternative oral anticoagulant to warfarin has been a holy grail for pharmaceutical companies for many decades. “The first attempts to develop oral thrombin inhibitors started in the mid-1960s,” says David Gustafsson, Chief Scientist at AstraZeneca, who was responsible for the development of the pioneering direct thrombin inhibitor Ximelagatran (Exanta) from the discovery phase to the start of Phase III trials. Ximelagatran had been approved in several European countries for the prevention of venous thromboembolic events following orthopaedic surgery, but was withdrawn from these markets in February 2006 owing to an association with an increased risk of severe hepatotoxicity.

Designing compounds that could be administered orally has been a major challenge in developing inhibitors of the proteases thrombin and factor Xa. “Some compounds were useful intravenously, but there were problems with bioavailability with the oral compounds,” says Lars Wallentin, Professor of Cardiology at the Uppsala Clinical Research Centre in Sweden. “How we solved this problem with Ximelagatran,” explains Gustafsson, “is that we had a structure, melagatran, that was too hydrophilic for absorption but then we added two protecting groups that gave the new drug, ximelagatran, decent permeability through the gastrointestinal barrier and so it could be absorbed. After ximelagatran is absorbed, the two protecting groups are cleaved off and melagatran is formed. Dabigatran etexilate also has two protecting groups that are cleaved off after absorption and dabigatran is formed.”

On 19 October 2010, the US Food and Drug Administration approved the oral anticoagulant dabigatran (Pradaxa; Boehringer Ingelheim), a direct thrombin inhibitor, for stroke prevention in atrial fibrillation (SPAF). “Clinicians in the United States are excited to have the first new oral anticoagulant in over half a century,” says Richard Becker, Director of the Cardiovascular Thrombosis Center at Duke School of Medicine in North Carolina, USA. “This approval gives clinicians an opportunity to select therapies based on patient need,” he adds.

More than 2 million people have been diagnosed with atrial fibrillation (AF) in the United States alone, and its prevalence is expected to increase for three main reasons. “One is that we have an ageing population in which AF is particularly common. The second reason is an increased incidence of hypertension, which contributes to the occurrence of AF. The third is related to advancing therapies for the treatment of acute myocardial infarction, with an increasing number of individuals who survive the event who may later have heart failure — another common cause of AF,” explains Becker. He also stresses that these are the issues worldwide, not just in the United States.

The approval of a new oral anticoagulant for SPAF is not only important because the prevalence of AF is increasing however, as between 30% and 50% of patients with AF currently do not receive the vitamin K antagonist warfarin — the current gold standard therapy — for stroke prevention. “One of the major reasons that they do not get warfarin is because of a perception by the patient, physician, or both, that it is too complicated to use,” says Jeffrey Weitz, Executive Director of the Thrombosis and Atherosclerosis Research Institute, McMaster University in Ontario, Canada.

This perception is not unfounded as warfarin treatment requires regular monitoring using a test called the international normalized ratio (INR), which provides a measure of how rapidly blood clots. “Unless a lot of resources are put in to anticoagulation clinics to achieve optimal warfarin management, patients tend to have high or low levels of anticoagulation that put them at risk of bleeding or clotting, respectively,” says Weitz, adding that drug and food interactions with warfarin also cause problems. It is also known that patients with certain variants of two genes, CYP2C9 and VKORC1, require lower or higher doses of warfarin than average to obtain the same therapeutic effect, and are more likely to suffer from bleeding complications

Despite the excitement about dabigatran, not all patients are likely to be prescribed the new drug. “It will probably be used primarily in patients who haven't previously received anticoagulation therapy and in patients who have problems with INR management. It might not be used in patients who have good INR control,” says Lars Wallentin, Professor of Cardiology at the Uppsala Clinical Research Centre in Sweden and Co-Chairman of the 18,113-patient RE-LY trial — the pivotal Phase III trial; the results of which were submitted as part of Boehringer Ingelheim's new drug application for dabigatran use in SPAF.