Two experimental pills that weren't on anybody's radar screen six months ago delivered impressive clinical trial results at the annual meeting of the European Society for Cardiology in Barcelona.
These medicines are blood thinners, drugs that prevent the clots that cause heart attacks and strokes and one of the few big cardiology markets left. Brilinta, from London-based drug giant AstraZeneca, was shown in the study to prevent heart attacks and deaths better than Plavix, the second-best-selling drug in the world. Dabigatran, manufactured by privately held German company Boehringer Ingelheim, outperformed warfarin, a 60-year-old drug used to prevent strokes.
"Both these agents appear to be significant advances," says Deepak Bhatt, chief of cardiology at the Boston VA Healthcare System, who was not associated with either study. "The major challenge now will be picking the ideal agent for individual patients."
And both medicines, despite some real drawbacks, represent sneak attacks on more hyped drugs on which companies including Eli Lilly, Bayer and Johnson & Johnson are pinning high hopes. The New England Journal of Medicine is publishing articles on both agents, along with favorable editorials.
Brilinta is similar to Plavix, the $8.6 billion-per-year drug from Bristol-Myers Squibb and Sanofi-Aventis, in that it prevents blood cells called platelets from clumping together to form clots. But in a study of 18,600 patients who presented to the hospital with chest pain, 10% of those who got Brilinta had heart attacks, strokes, or died compared with 12% who received Plavix, a statistically significant 16% decrease.
"The efficacy is superb," says Steven Nissen, head of cardiology at the Cleveland Clinic, "and the bleeding [risk] seems pretty reasonable."
Plavix keeps working even after the drug is stopped. Brilinta stops working fairly quickly, potentially making it an appealing option in patients who show up in emergency rooms, in those at risk for bleeding, and in those who might need surgery.
Brilinta has a few marks against it. One problem with drugs in this class is that patients often stop taking them. Particularly for patients whose arteries are propped open with metal mesh stents, this can be dangerous, increasing the risk of heart attack. Brilinta must be taken twice a day; Plavix has once-daily dosing. About one-sixth of the patients in the study experienced shortness of breath, 50% more than on Plavix. That's a side effect that could make patients stop taking their drug.
Then there's the matter of price: Plavix is going to get very cheap when its patent expires in 2012, so health insurers will push its use.
Still, Brilinta could put a crimp on the prospects of another Plavix replacement, the recently launched Effient from Eli Lilly. Kirk Garratt, clinical director of interventional cardiovascular research at Lenox Hill Hospital in New York, notes that Brilinta significantly decreased the risk of death compared with Plavix, and that bleeding appears to have been less of a problem than with Effient. He expects both Brilinta and Effient will be prescribed often by doctors.
An even bigger surprise comes from Boehringer Ingelheim, off the map for most U.S. investors because it is based in Germany and is privately held--a new blood thinner for atrial fibrillation.
So-called a-fib is a troublesome heart rhythm afflicting 2.4 million Americans in which the top chambers of the heart, responsible for bringing blood back from the rest of the body, start to flutter. This produces blood clots that can lodge in an artery and cause a stroke.
The main treatment now is warfarin, a blood thinner derived more than a half-century ago from rat poison. It's annoying to use; doctors and patients must work to get blood levels exactly right to prevent clots without causing dangerous bleeding. Then they have to watch out for drugs and foods that interact with it, including broccoli and spinach.
Efforts to find a replacement for warfarin have ended up on the shoals. The last one was Exanta, an AstraZeneca drug that was nixed because it caused liver problems.
Along comes Boehringer's dabigatran, which works similarly to Exanta but doesn't cause liver problems. The top dose did a better job preventing strokes than warfarin, cutting the risk of strokes by one-third to 1.1% per year, without increasing bleeding. A lower dose caused less bleeding than warfarin and was equally effective. The study included 18,000 patients.
"It looks like we finally may have a safe, effective alternative for warfarin," says Robert Harrington, a professor of medicine at Duke. Adds Bhatt: "Doctors and patients want an alternative to warfarin, and I think dabigatran delivers."
Here, too, there are drawbacks. The rate of heart attacks was higher with dabigatran. That "will need further study," Harrington says. Doctors and patients knew who was getting which drug, which could raise questions with U.S. regulators. The study enrolled lots of patients who hadn't gotten warfarin before, which could make the warfarin group look comparatively worse. Study investigator Michael Ezkowitz of the Lankenau Institute for Medical Research in Wynwood, Pa., will present an analysis Wednesday that will try to get to the bottom of that issue.
The dabigatran results complicate things for two other would-be warfarin replacements that work by blocking an enzyme called Factor 10. One is being tested by Bayer and Johnson & Johnson, the other by Pfizer and AstraZeneca. On one hand, the dabigatran results increase the chance that these drugs will prove efficacious--on the other, a new competitor has been added to the mix
Nov. 23 (Bloomberg) -- Boehringer Ingelheim GmbH’s blood- thinning pill Pradaxa was as effective and safe as the standard therapy for potentially deadly clots, according to the results of a head-to-head study.
Just 2.4 percent of patients given Pradaxa for six months after their initial treatment developed clots in the legs and lungs, similar to the 2.2 percent rate for those given the generic drug warfarin, according to an abstract of the so-called Recover study posted on the American Society of Hematology Web site last week. There was no increased risk of major bleeding, a complication of blood-thinning treatments.
Unlike newer medicines like Pradaxa and Bayer AG’s Xarelto, warfarin requires regular checks to ensure patients are getting the right dose. Doctors are divided over whether to keep using warfarin for longer than six to 12 months because of the monitoring required and because it can increase the risk of fatal bleeding. Some 1.6 percent of patients who took Pradaxa in the Recover study experienced major bleeding, compared with 1.9 percent of those on the older drug.
The pill “is as effective and safe as warfarin,” researchers led by Sam Schulman, a professor in the department of medicine at McMaster University in Hamilton, Ontario, wrote in the abstract.
Researchers will present full results of the trial in which none of the 2,539 patients or their doctors knew which medicine was being given on Dec. 6 at the American Society of Hematology medical conference in New Orleans.
The Boehringer drug and Bayer’s Xarelto, co-developed by Johnson & Johnson, are approved in some European countries.
›Thu Sep 16, 2010 12:07pm EDT By Ben Hirschler and Ludwig Burger
LONDON/FRANKFURT, Sept 16 (Reuters) - Boehringer Ingelheim's anti-coagulant pill Pradaxa should be approved in just the higher of two suggested doses for preventing strokes in people with irregular heartbeats, U.S. drug reviewers said on Thursday.
The verdict suggests Pradaxa has a good chance of making it to market in the United States, but potentially without the dosing flexibility that would set it apart from rivals.
Pradaxa is vying with Bayer and Johnson & Johnson's Xarelto and Bristol-Myers Squibb and Pfizer's apixaban to displace the old, problematic heart drug warfarin.
U.S. Food and Drug Administration (FDA) staff also said the unlisted German company's drug Pradaxa -- the most advanced of a number of clot preventers in late-stage development – should not be awarded a superiority claim over warfarin.
Industry analysts said the willingness to approve Pradaxa was positive for the whole class of new oral anti-coagulants.
The warfarin replacement market is expected to be worth more than $10 billion a year and possibly as much as $20 billion. Bayer Chief Executive Werner Wenning this week put the market opportunity at $12 billion to $15 billion.
RACE TO MARKET
The reviewers presented an in-depth analysis of Pradaxa in documents published on the FDA's website ahead of an advisory committee that will review Pradaxa on Sept. 20. The FDA is not obliged to follow the advice of its panels but it usually does.
The staff analysis said Pradaxa, or dabigatran, should be approved for use in patients with atrial fibrillation at the 150 mg dose but not 110 mg.
They added that although the 150 mg dose had proved better than warfarin in a pivotal clinical trial known as RE-LY, this result needed to be considered in the light of the fact that doctors and patients knew which drug they were getting[i.e. the trial was open-label].
"A positive decision by the adcom (advisory committee) on Pradaxa would show that there is willingness in general to approve the new generation of anti-coagulants," WestLB analyst Cornelia Thomas said.
She expects the panel to recommend the medicine, despite some questions about the design of the RE-LY trial.
While the first new oral drug to make it to market as a stroke preventer will have a clear marketing advantage, this will not be the end of the story. In an era of austerity, pricing will also be a key, along with perceptions among doctors as to which drug has the best profile.
Jefferies analysts said the recommendation that Pradaxa should not be able to claim superiority over warfarin left the door open for both Xarelto and apixaban to get a better label, especially since their key studies were double-blinded.[Maybe.]
"We believe that both of these products could now potentially gain an in-market advantage over Pradaxa by coming to market with superiority claims versus warfarin," they said in a note.
Overall, Jefferies expects apixaban to emerge as the class leader, with eventual peak annual sales of $6.1 billion, as against $5.2 billion for Xarelto and $4.6 billion for Pradaxa.[I wouldn’t take these forecasts too seriously at this point; the main point is that the drugs in question are addressing a very large market.]
Other experimental oral anti-coagulants in development include Daiichi Sankyo's edoxaban and Merck & Co's betrixaban.‹
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