A new study suggests that factor Xa inhibitors, such Eliquis™ apixaban from BMS and partner Pfizer, can be superior to warfarin.  On a composite efficacy end-point in atrial fibrillation patients apixaban was significantly better than warfarin (1.3% versus 1.6%; p<0.01), while bleeding side-effects and death from any cause were both significantly improved, according top data from the vast 18,000 patient ARISTOTLE trial announced at the European Society for Cardiology meeting in Paris.

This is in marked contrast to the results published in the New England Journal of Medicine (365:699-708), also in August 2011, showing that apixaban increased bleeding episodes without reducing cardiovascular events in patients with acute coronary syndromes.

Factor Xa inhibitors can, therefore, be better than decades-old generic medicines like aspirin and warfarin, but only in some circumstances – and then only to a small degree.  In a trial as large as ARISTOTLE, there is statistical power to detect even a small improvement in event rates (in this case, from 1.6% to 1.3%).

All this has powerful echoes of the launch of Effient™ prasugrel by Ely Lilly.  Prasugrel is another cardiovascular drug potentially serving vast markets that shows marginal improvements over an earlier soon-to-be-generic medicine: in this case, clopidogrel.

In both cases, the drugs owners have assembled convincing datasets to demonstrate the effectiveness of their drug, and have rightly won regulatory approvals for their launch.  In both cases, they have published data from very large clinical studies to demonstrate (statistically) a degree of superiority.  But in both cases the standard of care is a low cost generic medicine with decades of clinical experience.  The (literally) billion-dollar question is whether the very small differences in clinical profile can justify the cost of a proprietary medication over a generic one.

As we noted a year ago, demonstrating efficacy (or even a small degree of superiority) is no longer sufficient to convince either doctors or payors to adopt a new product.  Winning market acceptance for these products will be at least as challenging as winning regulatory approval.

Two factors will likely influence the outcome: the pricing differential over the generic competitor; and the balance between improvements in efficacy and improvements in safety.

Both prasugrel and apixaban are likely to be sold at premium price points relative to the competition (prasugrel is already 20-25% dearer than branded clopidogrel, and this gap will only widen from May 2012 when generic clopidogrel floods the market; apixaban is being positioned at a premium to the earlier direct Faxtor Xa inhibitor dabigatran, which has already largely failed to displace use of the much cheaper warfarin).  It seems certain, therefore, that the big pharmaceutical companies continue to believe that, with a big enough marketing budget, you can move mountains.  By contrast, all the evidence on the ground suggests that current clinical practice will prove harder to shift.

While current pricing policy counts against the eventual success of both these drugs, the savior at least for apixaban, might come from the safety profile.  While its hard to justify paying a premium price for a marginal improvement in efficacy, the threat of litigation always provides an extra incentive to prescribe the safest option between two similarly effective drugs, irrespective of price.  The secondary end-point data from ARISTOTLE suggests that, at least in the atrial fibrillation population, the safety profile may be quite significantly superior to warfarin (major bleed rates were a third lower at 2.1% compared to 3.1% for warfarin; p<0.001).

“If you cant be substantially more effective, be cheap.  And if you cant be cheap, you better be safe.”

The jury is still out on whether prasugrel and apixaban will prove to be blockbusters.  If they are, it will be a close shave – and detailed scrutiny of the safety profiles may ultimately be the factor that tips the balance one way or the other: market acceptance and mega-riches or market rejection and another nail in the coffin of incremental innovation.

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