Déjà vu for Aveo and tivozanib

As the plot thickens around the trigger for Aveo’s equity raise, the EU regulator considers pulling the group's renal cancer drug from the market.

Many an Aveo investor decided to exit the stock when the group’s controversial renal cancer project tivozanib blew up back in 2013. Those who wrote off the company in the intervening six years would be amazed to learn that tivozanib is today alive and kicking.

Not only that, but the drug is just as divisive now as it was then. The latest polemic centres on its EU approval – amazingly, this had been granted in 2017 – which could now be revoked. This revelation was quietly slipped out alongside an Aveo equity raise that had been facilitated by a spurious Seekingalpha article.

The article appears now to have been removed from the site, having first appeared on March 27. It had claimed that US investment banks thought Aveo could be acquired by Astrazeneca, citing a price of $800m to $1.2bn, or 10 times its current valuation.

That prompted a 46% one-day stock surge, and by close of play yesterday Aveo was sitting on a 130% increase – enough for it to announce plans to raise an undisclosed amount in common stock and warrants.

Meanwhile, in a separate filing with the SEC, Aveo disclosed that EU regulator, the EMA, was not satisfied with the group’s explanation for a major red flag in tivozanib’s pivotal Tivo-1 study in first-line renal cancer. Here the drug beat control in terms of progression-free survival, but did numerically worse on the gold-standard overall survival (OS) measure.

The EU regulator also said "regulatory action should be considered" if a separate interim OS analysis, of a third-line study called Tivo-3 and due in August "confirms a negative trend in OS”, the filing concluded. Aveo opened down 30% this morning.

So what’s new?

Long-standing followers of Aveo will simply shrug their shoulders. After all, the controversy over tivozanib and the Tivo-1 trial goes back years.

It was the same study that in 2013 had resulted in the US FDA slapping Aveo with a complete response letter – citing the very same discrepancy between PFS and OS that dogs the drug today. For the record, final analysis of Tivo-1 showed tivozanib cutting risk of progression by 20% (p=0.042), but tivozanib subjects being numerically at 15% greater risk of death than those on control.

Aveo put the negative OS result down to an imbalance in patients’ subsequent therapies. But the trial’s biggest problem was the use of Nexavar as control; it is not Nexavar but Sutent that is the first-line standard of care, and Aveo was slammed for denying both Tivo-1 cohorts this treatment.

That part of the saga ended with Aveo putting tivozanib development for renal cancer on the back burner and cutting costs. The group’s chief executive, Tuan Ha-Ngoc, ultimately resigned, and later paid $80,000 to settle fraud charges.

Remarkably, however, a Tivo-1 extension study continued, and – even more remarkably – tivozanib secured EU approval in August 2017, under the trade name Fotivda.

The US impasse has continued, with the FDA saying in January that interim OS data from Tivo-3 are insufficient for a filing; Aveo now plans to wait for the a more mature OS readout from this third-line trial, due in August.

Summary of numerical data for tivozanib in renal cancer
Study Tivo-1 Tivo-3
Trial ID NCT01030783 NCT02627963
Design 1st line, vs Nexavar 3rd line, vs Nexavar
PFS for tivozanib 20% reduction in risk of progresion 26% reduction in risk of progression*
OS for tivozanib 15% increase in risk of death 12% increase in risk of death*
Source: SEC filings; *preliminary analysis.

Not only is the Tivo-3 OS analysis already pointing the wrong way, but the August timeline comes after the June action date for FDA decisions on two regimens set to transform first-line renal cancer treatment: Pfizer/Merck KGaA’s Bavencio and Merck & Co’s Keytruda, both in combination with Inlyta.

With the standard of care set to change there is even less reason for the FDA to approve tivozanib on the back of a highly debatable dataset. For the EMA, Bavencio and Keytruda should provide further impetus to reverse an approval that should probably not have been granted in the first place.

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