New approaches to anticoagulant therapy

New approaches to anticoagulant therapy

Until recently, warfarin has been the medication of choice for patients at risk of thrombosis and requiring long-term oral anticoagulation treatment, in particular for the reduction in risk of stroke in patients with non-valvular atrial fibrillation (NVAF). People with AF are five times more likely to have a stroke compared to those in correct sinus rhythm, and these strokes are more severe and carry a higher mortality. Rates of AF are increasing and more common as we grow older, affecting around 10% of those over 80 years. In 2009, more than 2 million patients in the USA started on warfarin therapy. Despite its success, this drug has a number of problems, not least the need for frequent lab monitoring of blood coagulability, measured as the international normaiized ratio (INR). It is important to maintain the correct dosage of warfarin due partly to its interactions with Vitamin K, alcohol, and common pain killers such as paracetamol.

Warfarin can also produce a wide range of side effects. The drug’s mechanism of action means the most significant danger is the risk of uncontrolled bleeding: in the US alone, an estimated 65,000 people are treated annually in emergency departments for warfarin-related haemorrhage. Addressing these issues, the pharma industry has developed a new generation of potentially more effective anticoagulants, including other vitamin K antagonists, and also direct thrombin inhibitors and factor Xa inhibitors, known collectivel;y as non-Vitamin K oral anticoagulants or NOACs. Indeed, the market for alternative anticoagulants is expected to expand by 11.5% annually, reaching $15.3 billion by 2018.

Pioneering successes and failures

Warfarin is clearly a difficult act to follow. Ximelagatran, marketed as Exanta by AstraZeneca, was the first of the new generation of oral direct thrombin inhibitors. In trials it showed comparable efficacy to warfarin, but it was withdrawn in 2006 after liver toxicity problems emerged. Sanofi also had problems with its drug idraparinux, investigated in sodium and biotinylated forms, which were discontinued after signs of intracranial bleeding emerged in phase III trials. More recently, Sanofi also abandoned otamixaban, an injectable factor Xa inhibitor, due to poor performance in trials. Tecarfarin, a selective inhibitor of the vitamin K epoxide reductase enzyme from ARYx Therapeutics failed in Phase II trials, and the company subsequently folded. But there have been successes too: this includes Orgaran (danaparoid), a factor Xa inhibitor from Merck. This was approved in the EU as an alternative to heparin (the common IV anti-coagulant) in the 1990s, but later withdrawn in the US due to chemical shortages. Another success has been Arixtra (fondaparinux sodium), a factor Xa inhibitor, from Mylan/Aspen/GSK, for prevention of venous thromboembolic events in surgery. First approved in 2001, it reduced the risk for heparin-induced thrombocytopenia but lower rates of renal excretion prevents its use in patients with kidney dysfunction. It is now generic, as is Sanofi’s factor Xa inhibitor Lovenox/Clexane (enoxaparin sodium), first approved in the 1990s, and which brought market success in deep vein thrombosis (DVT), earning £1.7 billion in 2014.

Rise of the blockbusters

One of the first major successes in second generation anticoagulation treatment came with Pradaxa/Rendix (dabigatran etexilate), from Boehringer Ingelheim. This oral direct thrombin inhibitor was approved in both the US and EU for venous thromboembolism (VTE), stroke-prevention in AF, and DVT, beginning in 2008. Benefits seem clear cut: for example, a recent Phase III trial shows that relative to warfarin, patients with NVAF treated with dabigatran had fewer strokes and fewer major bleeding events. Meanwhile pooled Phase III data in acute DVT and pulmonary embolism consistently favour treatment with dabigatran over warfarin. As a result, Pradaxa earns Boehringer Ingelheim about $1.2 billion annually.

These earnings are dwarfed by dabigatran’s main competitor, Xarelto (rivaroxaban), from Bayer HealthCare/Janssen. This was the first oral once-a-day factor Xa inhibitor. Initially approved in 2008, it is indicated for VTE, DVT, stroke prevention (in AF), acute coronary syndrome and cardioversion. Rivaroxaban is expected to achieve peak annual sales of $6.4 billion, though patent expiry starts around 2020–21.

BMS/Pfizer have their own factor Xa inhibitor, Eliquis (apixaban) which is approved for stroke prevention in AF, DVT, and VTE in the EU and US. Clinical trials have demonstrated that apixaban-treated patients have greater reduction in stroke risk and less major bleeding compared to warfarin, but in practice many patients are continued on warfarin due to lower cost. Indeed cost is likely to be the biggest single barrier to use of any of the novel new anticoagulants. Peak annual sales for Eliquis are predicted at $2.8 billion by 2021 before patents start to expire in 2022.

More recently approved is Daiichi Sankyo’s once daily oral tablet, Lixiana/Savaysa (edoxaban tosylate), a factor Xa inhibitor approved in the US and EU for stroke prevention in AF, and VTE. Analysts predict that global sales of edoxaban will reach $1.6 billion in 2020. An assessment by the German IQWiG points to clear benefits of the drug, particularly in female patients, however the FDA has expressed concerns of side effects, in particular on renal function.

These four drugs are now battling for market dominance. Though dabigatran and rivaroxaban’s head start in the market has disadvantaged apixaban, the most obvious difference between the treatments is that while rivaroxaban and edoxaban are once-daily pills, dabigatran and apixaban are taken twice daily.

Emergence of a new challenge

As the use of these new anticoagulants rises, the number of hospital admissions due to bleeding associated with the treatments is growing. Each year approximately 2% of patients treated with factor Xa inhibitors experience bleeding and another 1% may require emergency surgery. Dabigatran, for example, has been linked to serious side effects including gastrointestinal bleeding, brain bleeding, other internal bleeds, and to more than 500 US deaths over a two-year period. As a result, Boehringer Ingelheim has had to settle 4,000 lawsuits in the USA over claims that it sold the drug knowing the medicine could cause excessive bleeding among some patients. Meanwhile in the year up to April 2015, there were over 50,000 apixaban- or rivaroxaban-treated patients admitted to hospital in the US due to bleeding. Again, lawsuits allege that patients given NOACs like rivaroxaban should be monitored in order to avoid bleeding episodes.

Race for an antidote

Not surprisingly, development of agents specifically designed to reverse the activity of NOACs has become a priority for the pharma industry. Pradaxa has become the first next-generation anticoagulant to get an antidote approved in the EU and US. Praxbind (idarucizumab), from Boehringer Ingelheim, has received accelerated approval in US and is approved in the EU as an antidote to dabigatran. In trials, specific and immediate reversal of the anticoagulant effect of dabigatran has been demonstrated, and the ongoing phase III RE-VERSE AD trial has shown that reinitiation of alternative antithrombotic therapy was possible any time after idarucizumab use. This development may have come late, however, as the first patent for Pradaxa is currently set to expire in February 2018.

Eliquis and Xarelto may also soon have their own antidotes: a universal factor Xa antidote PRT 4445 (andexanet alfa), from Portola Pharma is currently in Phase III trials. In the ANNEXA-A study, andexanet was applied with apixaban and in the ANNEXA-R study with rivaroxaban. Through its mechanism of action, andexanet alfa has the potential to act as a universal antidote for Factor Xa inhibitors and address the direct cause of the patient's inhibited clotting activity – without being prothrombotic. Portola plans to submit data from the ANNEXA-A and -R studies, and initial data from a Phase IV study, as part of its filing with the FDA under an accelerated approval pathway by the end of 2015. Andexanet alfa is also being studied with enoxaparin and edoxaban. Another antidote on the horizon is PER 977 (ciraparantag), from Perosphere, which is currently in early trials of its anticoagulant effects to directly bind to heparins as well as circulating direct factor Xa- and IIa-inhibitors. Trials are taking place with edoxaban, and the drug is being co-developed with Daiichi Sankyo.

NOACs in Phase III trials

There are a number of new anticoagulants in early trials. Betrixaban, an oral once-daily factor Xa inhibitor, from Portola Pharma, is in Phase III trials in acute medically ill patients with VTE. Portola expects to file for marketing approval in 2016 at which point it would be the first anticoagulant for both hospital and post-discharge VTE prophylaxis. Betrixaban is being developed for use alongside factor antidote PRT 4445.

In addition, tecarfarin, the vitamin K epoxide inhibitor that failed with ARYx Therapeutics has now been picked up by Armetheon and is in Phase III trials. If approved, it could become the best-in-class vitamin K antagonist: Tecarfarin was specifically designed to avoid the problems of warfarin because it is metabolised differently and minimises interactions with other medications. It may also present advantages over oral anti-coagulants that contain direct thrombin inhibitors and factor Xa inhibitors, because as a Vitamin K antagonist, tecarfarin could potentially be easily counteracted in the event of an emergency using existing antidotes. The drug is currently being investigated in underserved populations such as patients who respond poorly to warfarin, those with renal dysfunction, or patients with prosthetic heart valves for whom novel oral anticoagulants such as the anti-thrombin or Factor Xa inhibitors are either contraindicated or not recommended. In addition, tecarfarin may require less frequent monitoring than warfarin since it is not subject to wide fluctuations due to genetic variability or interaction with other medications.

Conclusions

Stroke risk in patients with atrial fibrillation remains a major and growing public health challenge. Dose-adjusted warfarin reduces stroke risk in NVAF by 60% compared to antiplatelets which reduce it by about 20%. Warfarin tends to be underused and it is associated with a higher rate of haemorrhagic side-effects compared to NOACs. The convenience of these newer agents is undisputed, particularly the fact that INR monitoring is not required. NOACs are many times more expensive however, and they cannot be used in patients with mechanical heart valves. Earlier concerns that they cannot be ‘turned off’ during a bleeding crisis are somewhat allayed by the development of antidotes which can rapidly reverse their anticoagulant effects. There are now four NOACS available and many more new approaches to anticoagulation in the pipeline.

References

Anticoagulation drug therapy: a review. Harter K, Levine M, Henderson SO. West J Emerg Med. 2015;16:11-17.

Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis. Robertson L, Kesteven P, McCaslin JE. Cochrane Database Syst Rev. 2015;6:CD010956.

Atrial fibrillation: Management. NICE guidelines [CG180]. Published date: June 2014.

Focused update on ESC Guidelines for the Management of Atrial Fibrillation. Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, et al. Eur Heart J 2012;33:2719-2747.