By Bill Berkrot and Ransdell Pierson
DALLAS Nov 19 A new blood clot and stroke preventer from Daiichi Sankyo proved as effective and safer than widely used warfarin in a large, late stage trial of patients with atrial fibrillation, paving the way for it to compete with other new warfarin alternatives on the market.
The drug, edoxaban, met the main efficacy and safety goals of the study by demonstrating "non-inferiority" to warfarin in preventing strokes and blood clots and led to significantly less major bleeding - the greatest danger of blood thinning medicines.
The trial, dubbed Engage AF, tested two doses of edoxaban against warfarin in 21,105 patients with atrial fibrillation - a dangerously irregular heartbeat - at moderate to high risk of stroke. It followed patients on average for nearly three years, making it the largest and longest study to date of any of the new generation of blood thinners.
Results of the trial were presented on Tuesday at the American Heart Association scientific meeting in Dallas.
Atrial fibrillation, which affects nearly three million Americans and makes them five times more likely to suffer a stroke, is seen as the most important use for these drugs.
Edoxaban is already sold in Japan under the brand name Lixiana and Daiichi said it plans to file its application seeking U.S approval in the first quarter of 2014. The company will seek approval to market the medicine for venous thromboembolism, blood clots that form in the veins.
"Personally, I think it will be used. We know this drug is safer than warfarin," said the study's lead investigator, Dr. Robert Giugliano, a cardiologist at Brigham and Women's Hospital in Boston.
But it will enter a market that already has three other new medicines 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-Myers Squibb Co and Pfizer Inc, which belong to the same class of drugs as edoxaban, as well as a similar medicine from Boehringer Ingelheim called Pradaxa.
Industry analysts believe the new blood thinners could eventually generate sales of more than $10 billion a year.
But without any head-to-head trials that can definitively show one of the novel anticoagulants is better than another, this will likely come down to a marketing war among pharmaceutical heavyweights.
"We see an uphill battle for edoxaban and do not expect the product to meaningfully change market dynamics in the atrial fibrillation space," JP Morgan analyst Chris Schott said in a research note.
Dr. Mark Link, a professor at Tufts University Medical Center in Boston, who was not involved in the trial, said: "If you look at the four new drugs, they're more similar than different. All these drugs are safer than warfarin."
TAKEN ONCE A DAY
One potential differentiator is that edoxaban and Xarelto are once a day pills, while Eliquis and Pradaxa are taken twice a day.
Sixty-year-old warfarin works well in preventing strokes, but is notoriously difficult to use. It requires careful monitoring of patients' blood levels, dose adjustments and dietary changes.
The new drugs, while more expensive for patients, have several advantages.
"They're safer, more convenient to use and there's no need for monitoring," said Giugliano, who presented the data at the meeting. "These drugs dramatically reduce bleeding in the brain. They are saving lives," he added.
The edoxaban trial tested two doses of the drug - 60 milligrams and 30 mg - against warfarin.
In an effort to more mirror likely real world use, the study allowed for dose reductions for factors such as kidney function impairment or patients of particularly low weight. About a quarter of edoxaban patients had the dose cut in half after starting the trial, researchers said.
Overall, the higher dose of edoxaban reduced stroke and blood clots by 21 percent compared with warfarin, which was deemed to be non-inferior - the study's intended goal - but fell just shy of superiority. The lower dose was not as effective due to much higher incidence of ischemic strokes, caused by blockages of blood vessels.
But for the more troubling hemorrhagic strokes, which often involves fatal brain bleeding, edoxaban was far better than warfarin. Those were reduced by 46 percent in the higher dose group and by 67 percent for the low dose versus warfarin.
Overall, major bleeding was reduced by 20 percent versus the older medicine with the higher edoxaban dose and by 53 percent for the lower dose, which was considered highly statistically significant, researchers said.
Significantly fewer edoxaban patients died from heart related causes. Death for any reason was significantly lower for low dose edoxaban and numerically lower for the high dose of the Daiichi drug, but that was not statistically significant, researchers said.
"I think it's good news for the patients and good news for health care providers. You can feel very secure when you have over 21,000 patients in a trial and followed for almost three years," said Giugliano.
"This trial was extraordinarily well done," said Dr. Nathaniel Reichek, director of research at St. Francis Hospital in Roslyn, New York, who was not involved in the study. "Edoxaban seems clearly like it's going to be a competitor."