From Promise to Payoff - Pharmaceutical Executive

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From Promise to Payoff


Pharmaceutical Executive


STROKE/ACUTE CORONARY SYNDROME

Difficult field sees first advances in many years

Antithrombotic drugs balance patients on a tightrope between two risks: blood clots and coagulants. Fall off on one side and thrombosis and stroke threaten; slip in the other and surgery is dangerous because of uncontrollable bleeding. For decades, warfarin has been just about the only drug to keep patients in balance. Now, a few possible successors are moving toward pharmacy shelves.



The desire to supplant warfarin has little to do with its efficacy as a blood thinner. Problems usually center on excessive bleeding and interactions with common drugs and foods, including aspirin derivatives, certain vitamins, and alcohol. "Any drug that posed a lesser risk of excessive bleeding while preventing clotting equally well would take patients from warfarin," says Nikhil Mehta, who heads the Cardiovascular and Metabolic Division at Decision Resources.

In Phase III data presented in August, Boehringer Ingelheim showed that a higher and a lower dose of dabigatran (Pradaxa), which inhibits thrombin directly, were superior to warfarin for patients with atrial defibrillation, a heart arrhythmia frequently associated with strokes. The higher dose was more efficacious than the lower, but both doses were safer when it came to unwanted, uncontrolled bleeding. "People with a high risk of bleeding can get the lower dose. People at higher risk of stroke can receive the higher dose," Mehta says.

A novel class of factor Xa inhibitors is also in the race for better oral anti-thrombotic therapies. These compounds works by inhibiting the catalyst, factor Xa, for the cascade that converts prothrombin into thrombin and thereby stimulates blood clotting. Slowing the catalyst slows the clotting process. Apixaban is expected to be approved for atrial fibrillation. "A-fib will be the first indication, we think, for apixaban—straight prevention in a-fib patients," says Mehta.

Another member of the class, rivaroxaban (Xarelto), has been launched for the prevention of post-surgical thromboembolism in Canada and Britain, but as with apixaban, the high stakes are riding on Phase III trials in acute coronary syndrome. If that indication is approved, the drugs will compete for a huge market. "We're predicting there will be room for both compounds—and in fact follow-on agents—in the market," says Mehta, who pointed to edoxaban as the next promising factor Xa inhibitor up the pipeline. "Both Pradaxa and Xarelto will hit that magic $1 billion number and become blockbusters."

Edoxaban is being developed by Daiichi Sankyo. The company announced in July that it was reshaping its Phase III design in light of new data showing that a single dose of the compound caused fewer adverse bleeding events than two doses—trough levels of the drug, not high peak levels, govern bleeding.

Further back in the pipeline are two compounds from hot biotech Portola Pharmaceuticals, which scored two major deals with big pharmas this year for two Phase II compounds. Merck bought its factor Xa inhibitor, betrixaban, for nearly $500 million in milestone payments. Novartis nabbed Portola's elinogrel, an adenosine diphosphate (ADP) receptor antagonist that aims to prevent thrombosis and heart attack in patients with acute coronary syndrome. The Swiss firm paid $75 million upfront and an undisclosed amount in milestones.

One of the major launches of 2010 in terms of potential sales is likely to be AstraZeneca's ticagrelor (Brilinta). This new antiplatelet is aimed squarely at the market for acute coronary syndrome, one of the largest cardiology markets in the world.

Because the need for antiplatelet agents is less acute than the need for new anticoagulants, drugs like Brilinta may not take off as fast as a new drug that proves superiority to warfarin. But head-to-head data comparing Brilinta to market leader Plavix presented at the American Heart Association meeting last month showing that Brilinta has clear clinical superiorities to the BMS/Sanofi megablockbuster. In the 18,000-patient study, the Brilinta group had fewer heart attacks and a lower death rate than the Plavix arm. The study had one unexplained statistical anomaly: The 9 percent of patients enrolled in North America showed no benefit over Plavix. Brilinta also appears to work faster than Plavix, and its effects are easily reversible. "If the doctor decided within a short window of time that they wanted to perform some sort of interventional surgery, they wouldn't have to worry about the long duration of the drug," says Barbara Ryan.

Some cardiologists see the new drug replacing Plavix, which boasts more than $9 billion in annual sales. (But Plavix already faces generic competition in Europe and will face it in the US in 2012.) Still, Physicians might hesitate to use Brilinta, since it must be taken twice a day instead of once. "That doesn't sound like much of a difference," says Mehta. "But there's that potential for someone to have an MI [myocardial infarction] if they're not very compliant."


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