Bayer is putting its weight behind its new clotbuster rivaroxaban (BAY 59-7939), a once-daily oral therapy it hopes will prove to be a safer, more convenient way to treat and cut the risk of deep vein thrombosis in the acute and chronic care setting.

In two Phase II studies unveiled at the World Congress of Cardiology this week, the Factor Xa inhibitor was shown to have similar levels of efficacy to standard therapy – in terms of reducing clot size - with low bleeding rates and low levels of venous thromboembolism.

Bayer says this is the largest dose-finding clinical programme ever conducted in this indication, and comprised two trials - ODIXa-DVT and EINSTEIN-DVT – which together enrolled 1,150 patients with acute DVT. Various treatment regimens of rivaroxaban were compared to a heparin-based therapy, such as Sanofi-Aventis’ Lovenox (enoxaparin), followed by warfarin for up to three months.

In ODIXa-DVT, recurrent DVT rates ranged from 0.9% to 1.0% for rivaroxaban versus 0.9% with the comparator, while major bleeding ranged from 1.7% to 3.3% in the highest 60mg dose of rivaroxaban versus 0% with the comparator.

Similar results were shown in EINSTEIN-DVT. Recurrent DVT rates ranged from 0.8% to 1.7% versus 6.9% with the comparator, while major bleeding ranged from 0.0% to 1.5% with rivaroxaban and 1.5% with the comparator.

The rush is on

Factor Xa (the target enzyme) is a protease that acts at the pivotal point in the coagulation cascade and has been the subject of intense research to find a safer, more predictable way to reduce blood clot risk. The current standard of therapy – oral warfarin – has been around for 50 years but its use must be closely monitored and it is associated with a significant bleeding risk, as well as being notorious for interacting with other drugs and food.

The other alternatives are anticoagulants such as the low-molecular weight heparins, but these must be given by injection, which makes them unsuitable for long-term use in stroke prevention.

Importantly, the trials also showed rivaroxaban significantly cut the combined risk of VTE-related death, pulmonary embolism or recurrent DVT versus the comparator therapy at 1.7%-3.6% versus 6.9%. And, importantly, Bayer says the three-month studies showed no sign of liver abnormalities: the problem that hampered AstraZeneca’s oral clotbuster Exanta (ximelagatran), which was touted as a potential blockbuster but failed to get past regulators because of concerns over its liver safety.

Rivaroxaban is already in a Phase III clinical trial – dubbed RECORD - for the primary prevention of VTE after major elective orthopaedic surgery but now Bayer plans to push the drug into further development to prevent stroke in atrial fibrillation patients, as well as in the treatment and secondary prevention of VTE.

A first filing for market authorisation in the primary prevention indication is planned in late 2007. Bayer has hooked up with Johnson & Johnson’s subsidiary Ortho-McNeil Pharmaceutical to market the drug; the latter has exclusive marketing rights for the cardiology, primary care and hospital specialty markets in the USA, with Bayer retaining co-promotion rights there, as well as sole marketing rights for the compound outside the USA.

_ Agnelli et al. Eur Heart J 2006; 27(suppl):abstract 87447, Büller. Eur Heart J 2006; 27 (suppl):abstract 89702