Adcom double play erases Aveo and Delcath

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By far the more promising of the two prospective cancer treatments that came before a US FDA advisory committee yesterday was Aveo Oncology’s tyrosine kinase inhibitor tivozanib.

This is not to say that its chances were good, but the beating it took at the hands of panellists, and the strength of the negative vote against it, came as a surprise. The other contender, Delcath Systems’ Melblez drug/device, was dead in the water ever since briefing documents had called for an additional study. Both companies now face the near-impossible task of raising cash at rock-bottom share prices.

Aveo and Delcath had taken a pounding when the panel briefing documents were released on Tuesday, the former dipping by 31% and the latter off 40%. Yesterday’s negative votes halved their market caps to $138m and a mere $36m respectively.

If there was a positive message for Aveo it was that tivozanib might hold promise, but it was a badly designed phase III study that had made it impossible for panellists to back it. The pivotal 517-patient Tivo-1 trial in first-line kidney cancer had allowed patients to cross over to subsequent therapy, which likely contaminated the data (Event – Aveo faces make or break at FDA panel, April 29, 2013).

Death risk overwhelms

Still, crossover trial designs are far from uncommon in oncology – indeed, it is hard to see how first-line patients could be recruited without the option of switching. And, whether caused by this design or not, the apparent 25% increased risk of death with tivozanib compared with Nexavar proved an overwhelming factor in the panellists’ deliberations.

This was surprising, given that this signal was not statistically significant, meaning that it was entirely due to chance. Moreover, overall survival was a secondary endpoint, and on the primary efficacy measure, progression-free survival, tivozanib did demonstrate statistically significant improvement.

The use as comparator of Nexavar, a drug hardly ever given first line in kidney cancer, was also questioned, as was the study population, which did not mirror the US. Only the patient representative voted in favour, and the 13-1 verdict against tivozanib’s benefit outweighing its risk was only slightly less damning than the 16-0 whitewash against Delcath’s Melblez for unresectable ocular melanoma metastasised to the liver.

Melblez uses percutaneous perfusion to deliver high-dose melphalan to the liver in a complex procedure involving filtration of blood outside the body and its return to the patient. The panel cited worsened quality of life, and Tuesday’s briefing documents had already called for a new clinical study using a different filter.

Given Melblez’s history of delays and Delcath’s cash of just $24m at the end of 2012 the project, as well as company, is likely finished. Of course the FDA has been known to go against panel advice, but only positive votes, and the strength of the opposition to tivozanib and Melblez makes approval hopelessly unlikely.

Aveo’s situation is interesting, though. The company has $165m of net cash, and its first move should be to slash spending. Then it will have to decide whether – and how – to fund an additional trial, likely comparing tivozanib against Sutent in a US population.

Promisingly the FDA panel confirmed that progression-free survival was an acceptable endpoint in kidney cancer, but Sutent would prove a tougher opponent than Nexavar, and in any case the kidney cancer landscape is shifting fast.

Even if such a study should prove viable, where would the necessary cash come from? Perhaps a bargain-basement buyout by its tivozanib partner, Astellas, is the best that Aveo and its investors can now hope for.

To contact the writer of this story email Jacob Plieth in London atjacobp@epvantage.comor follow@JacobEPVantageon Twitter

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