The kinase inhibitor tivozanib (for renal cell carcinoma) was shot down this morning at an FDA committee hearing. There are going to be a lot of arguments about this decision, because feelings have been running high on both sides of the issue.
And this has been an issue for over a year now. As that FierceBiotech story puts it:
Tivozanib hit its primary endpoint, demonstrating a slim but statistically significant improvement in progression-free-survival of patients with advanced renal cell carcinoma when compared to Nexavar (sorafenib). But the sorafenib arm experienced a slightly better overall survival rate, and Aveo has been trying to explain it away ever since.
The developer had to start in the spring of 2012 at a pre-NDA meeting. According to the review document, "the FDA expressed concern about the adverse trend in overall survival in the single Phase III trial and recommended that the sponsor conduct a second adequately powered randomized trial in a population comparable to that in the US."
The Phase III in question was performed in Eastern Europe, and one of the outcomes of today's decision may be a reluctance to rely on that part of the world for pivotal trials. I'm honestly not sure how much of tivozanib's problems were due to that (if the data had been stronger, no one would be wondering). But if the patient population in the trial was far enough off the intended US market to concern the FDA, then there was trouble coming from a long way away.
Aveo, though, may not have had many options by this time. This is one of those situations where a smaller company has enough resources to barely get something through Phase III, so they try to do it as inexpensively as they can (thus Eastern Europe). By the time things looked dicey, there wasn't enough cash to do anything over, so they took what they had to the FDA and hoped for the best. The agency's suggestion to do a US trial must have induced some despair, since (1) they apparently didn't have the money to do it, and (2) this meant that the chances of approval on the existing data were lower than they'd hoped.
One of the other big issues that this decision highlights is in trial design. This was a "crossover" trial, where patients started out on one medication and then could be switched to another as their condition progressed. So many crossed over to the comparison drug (Nexavar, sorafenib) that it seems to have impaired the statistics of the trial. Were the overall survival numbers slightly better in the eventual Nexavar group because they'd been switched to that drug, or because they'd gotten tivozanib first? That's something you'd hope that a more expensive/well-run Phase III would have addressed, but in the same way that this result casts some doubt on the Eastern European clinical data, it casts some doubt on crossover trial design in this area.
Update: a big problem here was that there were many more patients who crossed over to tivozanib from Nexavar than the other way around. That's a design problem for you. . .
What a mess - and what a mess for Aveo, and their investors. I'm not sure if they've got anything else; it looks like they'd pretty much bet the company on this. Which must have been like coming to the showdown at the poker table with a low three-of-a-kind, knowing that someone else probably has it beat. . .