FDA to Aveo: That's still a 'no' on tivo. Aveo: We'll be back.
In the never-ending but hardly-changing saga of the FDA and Aveo Oncology, the US regulator has once again spurned the company for failing to prove that their drug helped renal cell carcinoma patients live longer.
Aveo announced this morning that the FDA recommended they not submit an NDA application because the latest Phase III trial data don’t allay the agency’s concern that their drug, tivozanib, is hurting patients, as compared with the baseline treatment, Bayer’s sorafenib. Once again, the concern is about the overall survival rate.
“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,” Aveo wrote.
In response, Aveo said it will narrow its proposed indication to relapsed/refractory renal cell carcinoma, with plans to submit an NDA in the first quarter of 2020. But they agreed with the agency that if in the final analysis, the overall survival hazard ratio is over 1.00 – if people are more likely to die in the tivozanib arm– they will withdraw their NDA. In Aveo’s telling, the regulators don’t sound optimistic about Aveo’s recommendation.
“At the meeting, the FDA acknowledged AVEO’s responses and reiterated its concerns about the survival information and the totality of data,” Aveo wrote. “The FDA noted that the choice to submit the data is the Company’s, and that a discussion with the Oncologic Drug Advisory Committee will likely be required.”
The news sent Aveo’s stock plummeting deeper into penny stock territory, down 30% to $0.62 per share.
The FDA first rebuffed Aveo in 2013 at the end of their first Phase III trial, after the agency raised concerns about the survival rate and experts on the review panel expressed outrage at the trial design and disappointment over the proposed label. Most notably, the agency said the drug improved disease-free progression by 20%, but also increased the risk of death by 25%.
“If we approve this drug based on this study how would we communicate to patients the potential 25 percent increase in the risk of death?” Jonathan Jarow, then-medical officer at the FDA, asked the panel, per Reuters. The panel voted 13-1 against the drug, and the FDA rejected it.
The FDA had, in fact, already recommended a new trial, an SEC investigation would later allege, and Aveo failed to notify investors of that fact – eventually leading to executive resignations and a $4 million settlement.
Aveo is now nearing the end of its second trial, titled TIVO-3, and still has not allayed FDA concerns. They did manage to convince the EMA in 2017 to approve tivozanib for renal cell carcinoma but with the caveat that the European agency would review the TIVO-3 results as part of its post-marketing requirements.
That approval is also at risk. After Aveo’s first released preliminary data for Tivo-3 last November, revealing an OS HR of 1.12, the EMA warned “regulatory action” was possible if an August interim analysis didn’t yield a better overall survival rate. The August number, HR 0.99, wasn’t enough for the FDA. It remains to be seen what the EMA thinks — and what the final results will be.