New Daiichi drug succeeds in major study; set to face rivals


By Bill Berkrot and Ransdell Pierson

DALLAS, Nov 19 (Reuters) - A new blood clot and strokepreventer from Daiichi Sankyo proved as effective andsafer than widely used warfarin in a large, late stage trial ofpatients with atrial fibrillation, paving the way for it tocompete with other new warfarin alternatives on the market.

The drug, edoxaban, met the main efficacy and safety goalsof the study by demonstrating "non-inferiority" to warfarin inpreventing strokes and blood clots and led to significantly lessmajor bleeding - the greatest danger of blood thinningmedicines.

The trial, dubbed Engage AF, tested two doses of edoxabanagainst warfarin in 21,105 patients with atrial fibrillation - adangerously irregular heartbeat - at moderate to high risk ofstroke. It followed patients on average for nearly three years,making it the largest and longest study to date of any of thenew generation of blood thinners.

Results of the trial were presented on Tuesday at theAmerican Heart Association scientific meeting in Dallas.

Atrial fibrillation, which affects nearly three millionAmericans and makes them five times more likely to suffer astroke, is seen as the most important use for these drugs.

Edoxaban is already sold in Japan under the brand nameLixiana and Daiichi said it plans to file its applicationseeking U.S approval in the first quarter of 2014. The companywill seek approval to market the medicine for venousthromboembolism, blood clots that form in the veins.

"Personally, I think it will be used. We know this drug issafer than warfarin," said the study's lead investigator, Dr.Robert Giugliano, a cardiologist at Brigham and Women's Hospitalin Boston.

But it will enter a market that already has three other newmedicines vying to displace cheap, decades-old warfarin.

It aims to compete with Xarelto, sold by Bayer AG and Johnson & Johnson, and Eliquis sold by Bristol-MyersSquibb Co and Pfizer Inc, which belong to thesame class of drugs as edoxaban, as well as a similar medicinefrom Boehringer Ingelheim called Pradaxa.

Industry analysts believe the new blood thinners couldeventually generate sales of more than $10 billion a year.

But without any head-to-head trials that can definitivelyshow one of the novel anticoagulants is better than another, this will likely come down to a marketing war amongpharmaceutical heavyweights.

"We see an uphill battle for edoxaban and do not expect theproduct to meaningfully change market dynamics in the atrialfibrillation space," JP Morgan analyst Chris Schott said in aresearch note.

Dr. Mark Link, a professor at Tufts University MedicalCenter in Boston, who was not involved in the trial, said: "Ifyou look at the four new drugs, they're more similar thandifferent. All these drugs are safer than warfarin."


One potential differentiator is that edoxaban and Xareltoare once a day pills, while Eliquis and Pradaxa are taken twicea day.

Sixty-year-old warfarin works well in preventing strokes,but is notoriously difficult to use. It requires carefulmonitoring of patients' blood levels, dose adjustments anddietary changes.

The new drugs, while more expensive for patients, haveseveral advantages.

"They're safer, more convenient to use and there's no needfor monitoring," said Giugliano, who presented the data at themeeting. "These drugs dramatically reduce bleeding in the brain.They are saving lives," he added.

The edoxaban trial tested two doses of the drug - 60milligrams and 30 mg - against warfarin.

In an effort to more mirror likely real world use, the studyallowed for dose reductions for factors such as kidney functionimpairment or patients of particularly low weight. About aquarter of edoxaban patients had the dose cut in half afterstarting the trial, researchers said.

Overall, the higher dose of edoxaban reduced stroke andblood clots by 21 percent compared with warfarin, which wasdeemed to be non-inferior - the study's intended goal - but felljust shy of superiority. The lower dose was not as effective dueto much higher incidence of ischemic strokes, caused byblockages of blood vessels.

But for the more troubling hemorrhagic strokes, which ofteninvolves fatal brain bleeding, edoxaban was far better thanwarfarin. Those were reduced by 46 percent in the higher dosegroup and by 67 percent for the low dose versus warfarin.

Overall, major bleeding was reduced by 20 percent versus theolder medicine with the higher edoxaban dose and by 53 percentfor the lower dose, which was considered highly statisticallysignificant, researchers said.

Significantly fewer edoxaban patients died from heartrelated causes. Death for any reason was significantly lower forlow dose edoxaban and numerically lower for the high dose of theDaiichi drug, but that was not statistically significant,researchers said.

"I think it's good news for the patients and good news forhealth care providers. You can feel very secure when you haveover 21,000 patients in a trial and followed for almost threeyears," said Giugliano.

"This trial was extraordinarily well done," said Dr.Nathaniel Reichek, director of research at St. Francis Hospitalin Roslyn, New York, who was not involved in the study."Edoxaban seems clearly like it's going to be a competitor."

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