Shares in Aveo Pharmaceutical Inc. (NASDAQ:AVEO), commonly called Aveo Oncology, fell 36.7% Monday to 57 cents after the FDA dashed hopes that positive interim data from a late-stage study of tivozanib would overcome agency concerns about the drug's efficacy in relapsed/refractory renal cell carcinoma (RCC). Advised by the regulator not to submit an NDA at this time, Aveo now plans to collect more mature data ahead of filing its NDA in the first quarter of 2020. A discussion with the FDA's Oncologic Drug Advisory Committee will likely be required too, the agency said.

Tivozanib, often shorthanded as "tivo," is already approved for the treatment of adults with advanced RCC in the EU and several other countries. But Aveo has had a harder time getting it approved in the U.S. following inconsistent progression-free survival (PFS) and overall survival (OS) results in the company's initial RCC pivotal trial, Tivo-1. A subsequent NDA including those data led to a complete response from the FDA in 2013. (See BioWorld, May 1, 2013, and June 11, 2013.)

Undaunted, Aveo's team has pressed ahead with Tivo-3, a randomized, controlled, open-label trial comparing tivozanib to Nexavar (sorafenib, Bayer AG) in patients who have failed at least two prior regimens. Designed to convince the agency of tivo's benefit, it has supported two interim readouts so far, the latest suggesting "durable improvements" for study participants. (See BioWorld, Sept. 11, 2019.)

In all, the trial enrolled 350 participants who were randomized evenly between the two treatment groups. As of an Aug. 15 prespecified analysis, 114 patients on tivo have died and 113 on sorafenib, a hazard ratio of 0.99. Of the rest, 20 patients remain progression-free on tivo vs. only two on sorafenib, while roughly 60 patients on each arm are still alive. Median PFS at the August cut-off hit 5.6 months for tivozanib vs. 3.9 months for sorafenib. "With another OS update, we hope to maintain or even improve the OS hazard ratio we've seen," Bailey said.

But that FDA is not yet convinced, noting, in the company's words, that "current interim OS results do not abrogate the FDA's concerns over detriment and that those results may worsen with final analysis at 263 events, and that the median OS for tivozanib is worse than that of sorafenib." So everyone will wait.

In March, when Aveo's team has a strong enough sense of the more mature OS data, they plan to file a tivo NDA in relapsed/refractory RCC. In June, when even more data become available, the company will update the application, either pressing ahead or withdrawing the filing if the data favor sorafenib.

The FDA is "concerned that the next overall survival update is going to go in the wrong direction," Aveo CEO and President Michael Bailey told BioWorld. But "we're still optimistic based on all the forward-looking indicators that we have," he said, including the PFS data from the most recent interim update. "So, if you believe that progression-free survival is a reasonable surrogate for overall survival, we hope to see that kind of improvement continuing," he added.

An impatient market

Hope aside, the delay from an earlier anticipated NDA filing in RCC this quarter left some Aveo investors registering impatience with tivo's slow-unfolding story. Trading volumes spiked to 16.6 million shares vs. the more typical average 3 million shares changing hands, pushing the company's stock near its 52-week low of 49 cents.

"With more patients still alive on tivo, we believe there is real opportunity for TIVO-3 OS HR to remain below 1.0, but will have to wait and see next year," said Piper Jaffray analyst Edward Tenthoff, maintaining his "overweight" rating on the company. But the setback put the company close to a tipping point, he seemed to suggest, while lowering his price target to $2 from an earlier $4. "If OS HR stays below 1.0, AVEO intends to file an NDA for tivozanib in 3rd/4th-line RCC. If the OS HR returns above 1.0, we do not believe FDA would accept a tivo NDA resubmission," he said.

Meanwhile, other studies with tivo are underway. A phase Ib/II study called Deductive is looking at the combination of tivo with Imfinzi (durvalumab, Astrazeneca plc) for the treatment of advanced, unresectable HCC. The company also recently reported final results of a phase II trial of tivo in combination with Opdivo (nivolumab, Bristol-Myers Squibb Co.) in first-line and second-line treatment of RCC, suggesting potential for further follow-up.

The Cambridge, Mass.-based company is also advancing ficlatuzumab, a hepatocyte growth factor inhibitor antibody now under study in an ongoing randomized phase II in head and neck cancer, with another randomized phase II test planned in acute myeloid leukemia. "Ideally, we're in a situation at the end of next year where we've got data coming out of those studies that could warrant a phase III study to move forward," Bailey said.

Working with Canbridge Life Sciences Ltd., Aveo is also developing AV-203, an anti-ErbB3 monoclonal antibody.

As the company moves ahead, Bailey said that despite the tivo delay, Aveo is in "a good financial situation," with recent cash guidance pointing to an ability to carry operations ahead into the third quarter of 2021, "well beyond when we flip over these cards with the updated overall survival data."

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