Ximelagatran Sets the Stage for Noacs Basis for the Approval of Ximelagatran in Europe

MILESTONES

compounds. Using this model, they identified ximelagatran, a derivative of melagatran that could efficiently cross the intestinal barrier and be converted to melagatran after absorption. Ximelagatran was investigated in numerous clinical trials for indica- tions including the prevention of VTE after orthopaedic surgery, treatment of symptomatic VTE, stroke prevention in patients with atrial fibrillation, and secondary prevention of major cardiovascular events after myocar- dial infarction. In many of these trials, ximelagatran was efficacious. For example, in the double-blind, multi- centre THRIVE III trial, ximelagatran was superior to placebo for the extended prevention of VTE. In the randomized, double-blind EXULT A Brian Jackson / Alamy Stock Photo trial, ximelagatran was superior to warfarin for the prevention of VTE MILESTONE 9 in patients undergoing total knee replacement. These results formed the Ximelagatran sets the stage for NOACs basis for the approval of ximelagatran in Europe. For >50 years, vitamin K antagonists Although injected inogatran had Despite these improvements in (MILESTONE 2) were the mainstay anticoagulant activity and favourable primary end points, ~6% of patients of oral anticoagulant therapy. In pharmacokinetic properties in The develop in most of the trials developed 2003, ximelagatran, an oral direct humans, oral bioavailability was <5%. ment of transient, asymptomatic elevations in thrombin inhibitor (DTI), was At this time, computer model- ximelagatran levels of liver transaminases through approved in Europe for short-term ling was an emerging technology. unknown mechanisms. Owing to venous thromboembolism (VTE) Using thrombin structures from ... laid the this observation, ximelagatran was prophylaxis following orthopaedic nuclear magnetic resonance studies, groundwork withdrawn from the market, and did surgery. The drug was subsequently along with energy calculations for for other oral not receive approval in the USA. In withdrawn, and its application to interactions between thrombin and a case–control study, these hepatic the FDA was rejected, because of potential inhibitors, they ultimately anticoagulants events were associated with particu- elevated levels of liver enzymes produced melagatran. This molecule lar alleles of the major histocompati- observed in treated patients. was not only more potent than inoga- bility complex, suggesting they were However, the development of xime- tran, but was also <500 Da, which the part of an allergic response. lagatran provided the proof of prin- team thought crucial to oral bioavail- The development of ximelagatran, ciple that a specific oral thrombin ability (later confirmed by Lipinski’s however, laid the groundwork for the inhibitor could be effective in treat- famous ‘rule of five’). Unfortunately, development of the non-vitamin K ing thrombotic disorders without although the oral bioavailability of antagonist oral anticoagulants the need for coagulation monitoring, melagatran was >50% in dogs, it was (NOACs) (MILESTONE 10). The tools and elucidated important character- only about 3–7% in humans. used to generate ximelagatran — istics of oral anticoagulants. Melagatran has three charged most notably computer modelling Thrombin is the final mediator of groups, and so this compound would and the intestinal absorption model fibrin formation. Thrombin cleaves be unlikely to cross the mucosal — were important advances in drug fibrinogen to fibrin: crosslinking of barrier in the intestine. The research- development. fibrin establishes the framework for a ers, therefore, sought to generate a Megan Cully, Senior Editor, thrombus. Thrombin is, therefore, a lipophilic prodrug that would be Nature Reviews Drug Discovery logical candidate target for anticoag- converted to melagatran after absorp- ulant therapies. tion. To do so, they introduced a new ORIGINAL ARTICLES Eriksson, H. et al. A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for In the mid-1980s, a team at model for gastrointestinal permeabil- the treatment of acute deep vein thrombosis: THRIVE I. J. Thromb. Haemost. 1, 41–47 AstraZeneca initiated a project to ity — the flux of the compound across (2003) | Francis, C. W. et al. Comparison of ximelagatran with warfarin for the identify oral DTIs. Starting with small a monolayer of colon cancer cell line prevention of venous thromboembolism after total knee replacement. N. Engl. J. Med. 349, 1703–1712 (2003) | Schulman, S. et al. Secondary prevention of venous peptides of 2–5 amino acids based cultured on plates with polycarbonate thromboembolism with the oral direct thrombin inhibitor ximelagatran. N. Engl. J. Med. on known competitive inhibitors filters — that, unlike the rat intestinal 349, 1713–1721 (2003) of thrombin, they developed their membranes that had been used pre- FURTHER READING Gustafsson, D. et al. A new oral anticoagulant: the 50-year challenge. Nat. Rev. Drug Discov. 3, 649–659 (2004) first clinical candidate, inogatran. viously, did not metabolize the tested