Progress on Antidote for Next-Generation Anti-Clotting Drugs
By Anette Breindl
In the March 3, 2013, online edition of Nature Medicine, scientists from Portola Pharmaceuticals Inc. reported on its PRT064445, a recombinant and "ever so slightly engineered" version of Factor Xa that the company hopes will become a universal antidote to next-generation anti-clotting drugs.
Anti-clotting drugs, Portola's executive vice president of R&D, John Curnutte, told BioWorld Today, are "in transition." The current anti-coagulation drugs of choice are warfarin, which interferes with the recycling of vitamin K, and heparin.
Several companies – including Portola – are developing drugs that directly target enzymes of the clotting cascade. One of those factors is Factor Xa, which cleaves prothrombin to thrombin – another protein that is being targeted by newer anti-clotting drugs – in one of the final steps of the coagulation cascade. Portola's betrixaban, which targets Factor Xa, is currently in Phase III studies for the prevention of venous thromboembolism in acutely ill patients.
To date, though, warfarin and heparin have at least one advantage over the newer anti-clotting drugs: They come with antidotes. And those antidotes "do not work at all, or don't work very well, for these newer drugs, because the mechanism is so different," Curnutte explained.
Curnutte said there are several circumstances under which the effects of anti-thrombotic drugs might need to be reversed more quickly than can be done by just stopping the anti-coagulation drug, meaning that patients benefit from an antidote.
In some patients, medical conditions that can lead to bleeding – such as an ulcer – can spin out of control if they are on an anti-coagulant. Others may have, for example, an auto accident, or need unplanned surgery for appendicitis. In such cases, Curnutte said, it would be "very helpful to be able to take away that headwind," making it safer for surgeons to operate.
Portola's antidote, PRT064445, began Phase II studies late last year. Portola has separate collaborations with both Bristol-Myers Squibb Co. and Pfizer Inc., whose Factor Xa inhibitor Eliquis (apixaban) is currently under review by the FDA, and with Bayer HealthCare and Janssen Pharmaceuticals Inc., whose Xarelto (rivaroxaban) is already on the market for reducing the risk of blood clots after knee or hip replacement surgery, to reduce stroke risk for patients with atrial fibrillation that is not caused by a heart valve problem, and to treat pulmonary embolism and deep vein thrombosis and reduce their risk of recurrence.
In their paper, senior author Uma Sinha and her team showed that PRT064445 inhibits betrixaban, apixaban and rivaroxaban, and that it reduced injury-induced bleeding in rivaroxaban-treated rabbits.
The protein is a recombinant form of Factor Xa itself that binds to the Factor Xa inhibitors. The protein, however, is engineered so that it does not contribute to blood clotting.
All drugs have side effects, of course, and the list of drugs that don't have specific antidotes is nevertheless a good deal longer than those that do. Still, developing a drug right along with its antidote is not unique, either.
The heart drug digoxin has its own antibody, digibind. The cancer drug methotrexate, which blocks nucleic acid synthesis, can be subverted by giving leucovorin.
Curnutte said there are several reasons why it makes sense to develop antidotes for an anti-coagulation drug. First, the mechanism lends itself to predicting what is most likely to go wrong with one.
"By definition they are designed to decrease clotting, and that means there is an obligatory side effect in the form of bleeding," he noted.
And though the newer drugs actually have that side effect less often than the older generation, the numbers of patients taking those drugs, even an adverse even rate of a few percent "creates a need for the drug. . . . [Bleeding] won't happen very often. But with millions of people on these drugs, it will happen," Curnutte added.
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