The finishing post

Venous thromboembolism (VTE) is a life-threatening condition which is the result of low blood flow most commonly in deep veins in the leg. VTE is most commonly referred to as deep vein thrombosis (DVT).

A detachment of a DVT can lead to a pulmonary embolism, where a clot detaches and goes on to block blood flow to the lungs.

The American Heart Association (AHA)
estimates that 200,000 new cases of VTE occur annually, and of those patients 30 per cent die within three days, mainly due to pulmonary embolism.

There are two major markets for a new oral pharmaceuticals developed for the treatment of VTE.

The first market is for patients under-going major orthopaedic surgeries, such as knee replacement and hip replacement surgery, who are usually prophylactically dosed with anticoagulants post-surgery in an attempt to prevent thromboses.

Post-orthopaedic surgery VTE is also classed as a relatively high-risk event and a relatively high degree of antithrombotic activity is required.

The second market is patients with an underlying risk of thromboses (eg, acute coronary syndromes), who can be given an antithrombotic as a preventative measure.

In 2003, guidelines provided by the US DVT Prophylaxis Consensus Panel stated that doctors should consider the use of antithrombotic therapy in all patients with reduced mobility and at least one VTE
risk factor.

These risk factors include malignant cancer, obesity, inflammatory diseases including, inflammatory bowel disease, heart failure and varicose veins.

The oral anticoagulant market is currently dominated by the generic vitamin K antagonist warfarin, which is indicated for the prevention and treatment of VTE, thrombosis prevention in orthopaedic surgery, post-stroke or myocardial infarction and in the prevention of stroke in patients with atrial fibrillation.

However, warfarin has a narrow therapeutic index and is associated with a serious adverse event profile which includes an increased risk of haemorrhage. As such it is vital that the industry develops anticoagulants with improved safety profiles.

During the activation of the blood coagulation cascade, various serine proteases are activated that facilitate the formation of coagulation Factor Xa, which is a key player in coagulation and platelet activation. Factor Xa is an essential component of the prothrombinase complex, which leads to the formation of thrombin. Hence, inhibition of Factor Xa represents a promising strategy for the development of antithrombotic drugs.

The race to get oral Factor Xa anticoagulants onto the market has heated up recently with positive phase III and II results for Bayer and Johnson & Johnson's rivaroxaban (Xarelto) and Bristol-Myers Squibb and Pfizer's apixaban, respectively - both of which were presented in July 2007 at the 21st International Society of Thrombosis and Haemostasis.

Rivaroxaban is in phase III development in the US, Canada and Europe for the prevention VTE following orthopaedic surgery, chronic VTE prevention and treatment and the prevention of stroke in atrial fibrillation. It is also in phase II development for acute coronary syndromes.

Positive phase III data presented from the RECORD 3 trial demonstrated a reduction in deep vein thrombosis and pulmonary embolism in patients undergoing orthopaedic surgery compared with enoxaparin, with similarly low bleeding rates. The firms expect to make regulatory submissions for rivaroxaban in Europe in late 2007 and in the US in 2008.

Bristol-Myers Squibb and Pfizer's apixaban is currently in US and European phase III trials for the same indications as rivaroxaban. Apixaban, like rivaroxaban, is also in phase II development for acute coronary syndromes.

Phase II results demonstrated apixaban had similar efficacy and bleeding results when compared with an open-label vitamin K antagonist. Apixaban does not need regular monitoring or dose adjustments, and there have been no reports of adverse events, including signs of liver toxicity. The companies are planning to apply for registration of apixaban in the second half of 2009 and subsequently launch in 2010.

Boehringer Ingelheim's dabigatran etexilate (Rendix) is the product most likely to be launched first in the market for deep vein thrombosis and pulmonary embolism prevention. Dabigatran etexilate is an oral direct-acting thrombin inhibitor currently in phase III development in US, and in pre-registration in Europe for venous thromboembolism prevention in total knee replacement surgery.

Dabigatran etexilate has the same mechanism of action as AstraZeneca's Exanta that was withdrawn from pre-registration due to liver toxicity, which has raised some concerns regarding dabigatran etexilate's safety in chronic settings.

Other oral Factor Xa inhibitors in clinical development include Portola Pharmaceutical's PRT054021, which is in phase II trials in the US and Canada; Daiichi Sankyo's DU-176b, which is in phase II trials in the US, Europe and Japan; Pfizer's PD-348292, which is in phase II trials in the US and Astellas Pharma's YM150, which is in phase II trials in the US, Europe and Japan.

It is estimated that the global market for oral anticoagulants could exceed USD 6bn by 2012 with the addition of a new branded product to the market. A new oral antithrombotic agent brought to market with a better bleeding profile than warfarin, can be assured a large share of these estimated profits in the coming years. Oral anticoagulants could be a very lucrative target for pharmaceutical companies to develop.