UPDATED: Aveo shares plunge after FDA review raises fears of tivozanib rejection

Regulators at the FDA have weighed the data for Aveo's tivozanib, raising a simple question that could prove vexing for the biotech: Should another clinical trial be required before the agency delivers its verdict on the cancer drug, given that alternative treatments are available? Aveo ($AVEO) will make its case for immediate approval to an outside panel of FDA experts on Thursday, but the slim review document released this morning clearly spooked hopeful investors, pushing down the biotech's stock more than 25%.

Why the jitters? 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."

Earlier in the development game, though, the FDA told Aveo that the right PFS data could be used for an approval. In their words "a substantial, robust improvement in PFS that is clinically meaningful and statistically persuasive may be considered for regulatory decision." FDA also stated that "... a statistically significant improvement in OS is not required for regulatory approval, but a pre-specified OS analysis plan is still helpful in the regulatory decision making process."

The FDA review also raises questions about the difference in dose interruption/reduction and response rates for sorafenib, noting inconsistencies with other studies. And there are likely to be a number of questions regarding the small number of Americans who were included in the final data readout. 

As for the OS data, Aveo has asserted that slightly more than half of the patients in the sorafenib arm went on to receive a subsequent treatment after their disease progressed, and in many cases the subsequent therapy was tivozanib. That could have skewed the survival data, according to Aveo.

The FDA review certainly didn't offer any definitive conclusions, but it cast a cloud over Aveo's shot this week. The biotech has circled its wagons around tivozanib, confidently setting the stage for a launch in the second half of this year. A negative vote this week, though, would raise serious doubts about a drug that had been getting mixed reviews from analysts. 

Aveo reorganized last fall, laying off staffers as it concentrated on the regulatory process. The downsizing occurred just weeks after Leerink Swann analyst Howard Liang downgraded the stock, unconvinced that the company's argument that positive progression-free survival data could win the day at the FDA. And with other kidney cancer drugs on the market, troubling safety signals could scuttle its chances with regulators.

"In our regulatory reviews, we could not find another case where the FDA approved an agent on progression-free survival benefit that has a clear unfavorable survival trend as in tivozanib's TIVO-1 trial or a similar pivotal trial design," Liang noted at the time.

Other analysts, though, have not had the same doubts. And today's FDA review changed nothing for them.

"After review of the documents, we continue to believe there is a good likelihood of a favorable vote," noted J.P. Morgan's Geoff Meacham, according to Reuters. The review raised no new concerns about the safety and efficacy of the drug, he added. "Net-net, we would be buyers ahead of the panel."

- here's the FDA review (PDF)

Special Report: Tivozanib – Top 10 Late-Stage Cancer Drugs – 2012

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