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Aveo’s tivozanib is knocked back by FDA once again

Company says it will delay any regulatory filing until first quarter next year

Aveo Oncology

Try as it might, Aveo Oncology just can’t persuade the FDA to accept a new regulatory filing for its kidney cancer candidate tivozanib.

After another knock back, the company now says it will delay any regulatory filing until the first quarter of next year, and will also narrow the proposed use for the drug, to try to break the impasse.

Originally filed way back in 2012, the first application was rejected by the FDA on the advice of its Oncologic Drugs Advisory Committee (ODAC), which said it wasn’t happy with the TIVO-1 trial of VEGF inhibitor tivozanib – then partnered with Astellas – which compared the drug to Bayer’s VEGF drug Nexavar (sorafenib) in renal cell carcinoma (RCC).

After the FDA concluded that the data from the study were 'uninterpretable' and 'inconclusive', Aveo went back to the drawing board in the US, although it was able to persuade the EMA to approve the drug as Fotivda in Europe in 2017 based on the TIVO-1 data.

The company opted to carry out another phase 3 trial – called TIVO-3 – to address the FDA’s concerns about TIVO-1 and build the case for tivozanib versus Nexavar.

Fast forward a few years , and Fotivda’s license in Europe is at risk of being withdrawn, and the company’s attempt to file in the US based on TIVO-3 has just been turned down by the FDA having been withdrawn by the company earlier this year.

In a statement, Aveo says that at a meeting with the FDA the agency "remained concerned about the results of TIVO-3 in the context of the overall development of tivozani" and had advised it not to file.

In a case of déjà vu, the agency has said it isn’t convinced by Aveo’s interpretation of overall survival data for tivozanib in TIVO-3, which the company says shows a trend towards improvement on Nexavar. Similar concerns were raised for TIVO-1 for both OS and progression-free survival (PFS) data.

At the meeting, 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", notes Aveo.

Now, Aveo is planning to narrow its proposed indication for tivozanib to relapsed/refractory RCC "in view of the changing first-line treatment landscape", which has seen combinations of immune checkpoint inhibitors and VEGF inhibitors – in particular Pfizer’s VEGF inhibitor Inlyta (axitinib) – emerge as a strong therapeutic option.

The FDA says that if the company wishes to proceed with a revised OS analysis in the second quarter of 2020, it should submit an updated statistical analysis plan with a planned OS analysis based on the projected number of OS events (deaths) at that time.

In the meantime, Aveo has also agreed that if the hazard ratio (HR) of tivozanib is greater than one – in other words suggests patients on its drug are doing worse than in the Nexavar group – it won’t proceed with a filing.

Shares in Aveo closed down 37% after the news broke.

Article by
Phil Taylor

5th November 2019

From: Research

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