ESC – Daiichi joins the US-EU blood-thinning race with positive Lixiana data

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Daiichi Sankyo walks away from the European Society of Cardiology meeting this week with a clear win following release of positive data for its factor Xa inhibitor Lixiana. Proving the equal of warfarin in preventing recurrence of venous thromboembolism (VTE), while causing significantly fewer bleeding incidents, gives it a good chance of earning approval from authorities in the US and Europe.

Earning market share will be Lixiana’s clear challenge, as, if approved, it would be the third factor Xa and fourth oral anticoagulant to hit Western market in recent years, and it has yet to prove itself in the far bigger stroke prevention indication. However, it is a challenge Daiichi will need to accept as its big seller Benicar goes off patent in three years, blowing a $1.8bn hole in its revenue stream. Investors took heart in the news, pushing shares up 3% to ¥1,746 in trading today.

To the rest of the world

Lixiana, known generically as edoxaban tosylate, has been on the market in Japan since July 2011 and is awaiting the results of two global pivotal trials before applying to regulators in the other two major markets. As with the oral anticoagulants that have come before it, smaller studies in venous thromboembolism prevention have reported data earlier than the huge studies necessary to support approval in stroke prevention in patients with atrial fibrillation, which number in the tens of thousands – in the case of Lixiana, the Engage AF-Timi 48 trial has enrolled more than 20,000 patients.

But as an indicator of success in stroke prevention, positive data in the venous thromboembolism indication is a strong one. The 8,300-patient Hokusai-VTE study was in patients with symptomatic deep vein thrombosis or pulmonary embolism, with a goal of preventing VTE recurrences. Patients were put on low-molecular weight heparin for at least five days, and were randomised to take either warfarin or placebo; warfarin patients continued on that treatment, whilst the patients initially given placebo progressed to Lixiana when heparin treatment was discontinued.

The patients took the oral drugs for at least three months and up to one year, based on clinicians’ opinion. All patients were followed up to a year.

The primary endpoint combining deep-vein thrombosis or pulmonary embolism events showed no statistical difference between the two groups, 3.2% for Lixiana patients vs 3.5% for warfarin patients. Significantly fewer Lixiana patients experienced clinically significant bleeding at 8.5%, compared with 10.3% for warfarin patients.

Getting superiority on both counts would have been even better, but showing that Lixiana reduces the major risk of taking a potent blood-thinner should be sufficient to win eventual approval, assuming other safety issues do not arise. However, approval of the other drugs in this class, was not routine by any stretch – in stroke prevention Xarelto faced an FDA staff sceptical of its efficacy and the Eliquis took two cycles to get a yes – so it seems probable that there will be a couple of twists yet in Lixiana’s story.

And the next chapter is approaching rapidly. Daiichi says the Engage AF-Timi trial will read out at the American Heart Association meeting in November, whilst regulatory submission will happen early next year. Success in that trial is no guarantee that Lixiana will live up to current expectations – Eliquis proved superiority to warfarin and still has seen its early sales come up short.

Missteps

If any company was in need of a growth driver, it is Daiichi Sankyo. As was the case with many pharma companies, Daiichi sales grew rapidly in the previous decade, but now are facing stagnation in coming years. Its one blockbuster, hypertension pill Benicar, loses patent protection in 2016 and revenue is forecast to decline rapidly from a peak of $2.6bn in 2011 to $654m in 2018, according to EvaluatePharma’s consensus forecast.

Addition of generics revenue from its controlling stake in Ranbaxy Laboratories will be the only thing keeping the ship steady in the disorder it is facing in coming five years, and even that has been beset by some turmoil (Daiichi board takes responsibility for corporate disappointment, December 22, 2011).

Even if Lixiana lives up to current forecasts of $853m in 2018, comes nowhere near making up for the loss of Benicar – indeed, even growth from Daiichi’s five biggest growth drivers including Nexium, Mamary and Effient will not make up for Benicar. But Lixiana revenues will be nice to have to keep sales from going into a decline.

And given that the stroke prevention indication makes up three-quarters of that forecast, it will be imperative that data at the AHA meeting is at least as good as the VTE data released yesterday.

Trial ID
Hokusai-VTE  NCT00986154
Engage AF-Timi  NCT00781391

To contact the writer of this story email Jonathan Gardner in London at jonathang@epvantage.com or follow @JonEPVantage on Twitter

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