FDA tells Aveo no, again, for tivozanib as biotech tries to find yet another path forward

In a "Groundhog Day" scenario, the FDA has once more slapped down Aveo Oncology’s attempt to get its ill-fated cancer drug on the U.S. market.

The U.S. regulator outright refused to approve the drug, known as tivozanib, all the way back in 2013, but Aveo has kept plugging away, with no success.

Back in February, Aveo scrapped plans to file for approval of tivozanib when the agency advised the biotech against filing an NDA after data failed to address the concerns that led it to reject the drug in renal cell carcinoma (RCC) in 2013.

Nine months down the line, and it’s the same story. The history runs like this: The FDA hit Aveo with a complete response letter in 2013 after an advisory panel criticized the design of the pivotal trial and questioned the benefits of the VEGF inhibitor in light of its failure to beat the overall survival (OS) achieved by Bayer’s Nexavar.

And it was more than just an embarrassing setback for the company: It reached another level of seriousness when the Securities and Exchange Commission investigated claims it had been aware of the FDA's concerns but failed to disclose them to investors ahead of the verdict.

Aveo paid $4 million to settle those allegations without admitting any wrongdoing.

In 2013, another trial—comparing tivozanib to Roche's antibody-based VEGF blocker Avastin (bevacizumab) on top of standard chemotherapy in colorectal cancer patients—found Aveo's drug was comparable but no better than its comparator, and the study was discontinued.

A setback in a breast cancer trial followed the ensuing year, and a run of bad form could have made partners anxious. Aveo has lost Biogen and former tivozanib partner Astellas since the FDA rejection.

Aveo then responded to this catalogue of woes by initiating another clinical trial designed to alleviate the concerns of the FDA and its advisers.

Aveo posted top-line data from the trial a year ago, and the readout included a preliminary look at the critical OS endpoint. Aveo thought the data may enable it to file for approval around May, but the FDA thought differently.

The FDA’s position meant Aveo needed to wait until it had mature data to file for approval, which it had in August. Now, armed with those data, the FDA still doesn’t see a case for its approval.

That trial, known as TIVO-3, was an open-label phase 3 study designed to compare tivozanib to Nexavar (sorafenib) in 350 patients with highly refractory metastatic RCC.

The biotech notes in its release today that the TIVO-3 trial “was designed to address the FDA’s concerns regarding the OS trend in the TIVO-1 trial,” in which it found that “the inconsistent progression free survival (PFS) and OS results and imbalance in post study treatments made the trial results uninterpretable and inconclusive when making a risk-benefit assessment necessary for drug approval.”

The company says that TIVO-3 trial met its primary endpoint “of demonstrating a significant improvement in PFS [and] also demonstrated a significant improvement in the secondary endpoint of overall response rate.”

The FDA combed over these data and the other results but once again denied the application. “The FDA recommended that the company not submit an NDA at this time,” Aveo reports.

“The FDA stated that it remained concerned about the results of TIVO-3 in the context of the overall development of tivozanib. The FDA noted that the Company’s 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, Aveo is changing tack slightly. Now, the plan is to narrow its proposed indication to relapsed/refractory RCC.

This still didn’t sit well at the meeting, as the FDA “acknowledged Aveo’s responses and reiterated its concerns about the survival information and the totality of data” but added it could submit the data and that it would need to talk with the Oncologic Drug Advisory Committee.

“The FDA said that if Aveo wishes to proceed with a revised OS analysis in June 2020, Aveo should submit an updated statistical analysis plan (SAP) with a planned OS update based on the projected number of events at that time.”

What happens now? Well, the biotech will try again using the FDA feedback and hope for an NDA early next year. But, if the final analysis of the trial hits an OS HR above 1.00, “the company will withdraw its NDA application.”

Remarkably, given the FDA ordeal, the drug was actually approved in Europe based on TIVO-1 back in 2017 under the name Fotivda, though this hinged on the outcome of TIVO-3. With the data in hand, Aveo has already said the drug is at risk of being withdrawn if the regulator doesn’t like what it sees.

Shares were down 40% Monday morning after the news broke.