This week was supposed to reveal the FDA's decision on Dai-Ichii Sankyo and Eli Lilly's anticlotting drug prasugrel. That one's in the same chemical class as Plavix (clopidogrel), and works by the same mechanism. Since Plavix did about eight billion dollars of business last year, and the anticlotting area seems to be a limitlessly huge market in general, you can understand why another drug is entering the space.
Both clopidogrel and pasugrel are prodrugs - their structures, as they come out of the bottle, are inactive. But they're converted by cytochrome P450 enzymes in the liver to their active forms, which bind irreversibly to the P2Y12 purinergic receptor on platelets. The clopidogrel link above shows the active form - that thiophene ring gets broken open, and a reactive SH is exposed. The P2Y12 receptor mediates platelet aggregation, so shutting it down extends clotting time.
A few points: for one, you'll note that the structures of the two drugs are very similar indeed. Is pasugrel just a "me-too", then? Well, it certainly is trying to do the same thing by the same mechanism, but as I've said here many times, it's hard to sell a drug unless you can point to some difference. The advantage that prasugrel has is that its metabolic activation takes place through a broader number of liver enzymes, so more of the active metabolite is produced across a wider patient population. And it is indeed about ten times more potent in humans - which may, though, prove to be its downfall.
In the clinic, the large TRITON-TIMI trial ran the two drugs head to head in over 13,000 patients, which is certainly the expensive (and definitive) way to go. The end result was that the prasugrel-treated group had fewer cardiovascular problems of all kinds (good!), but more episodes of severe bleeding (bad!). Overall mortality was the same between the two groups, and that's where the arguing has started. There's a lot of room to break down the numbers more thoroughly to see if there's some real benefit to the drug (or alternatively, to show that it really isn't any more useful than Plavix).
Of course, this is the job of the FDA. And now it seems that they've chosen to punt, delaying their decision by three months. Since the companies don't seem to have been asked to submit any more data, this seems to be an internal wrangle at the agency. I'm not sure what they're going to accomplish by holding their heads and moaning for another quarter, unless the hope is that the numbers can be crunched in some direction which will offer enough of a fingerhold to justify a decision. This is a very, very close call.
If I had to predict - and hey, I write this blog, so I've got a license to do that sort of thing - I'd say that the agency will ultimately approve the drug, but with label restrictions. In the end, they'll turf the problem over to the cardiologists, but with enough warning language on it that no one should be surprised if patients bleed out on occasion. The best outcome would be for some sort of clinical sign to indicate which patients should avoid the drug. The FDA will probably head in that direction, since it appears that the majority of bleeding problems occurred in the oldest and/or lowest-body-weight groups in the trial.
Update: but is that the case? Looking at the NEJM paper, it appears that patients not in these groups did have better efficacy with prasugrel, which improves the numbers. But the hazard ratio for major bleeding was 1.42 in the risky patients (>75 years old, or body weight < 60 kilos, or history of stroke/TIA), but still 1.24 in the ones outside these groups. So it's not at all fair to say that most of the bleeding events were in the risky patients - frankly, it looks like everyone bled, but the healthier cohort just responded better to the drug at the same time. That complicates my guess in the above paragraph, and raises the worst-case chance that the FDA might want to wait until the current trial comes in. What a mess. . .
There's another 10,000 patient study underway which might clarify the situation, or might just emphasize what a tied-up tangle it all is. In the end, I think that the FDA will let the drug be sold until that one finishes up, with the option to revise its opinion when the data come in. The three-month delay will serve to show how seriously they're taking all the safety issues - a big political consideration these days - and to work up the most bulletproof labeling they can come up with.