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AVEO: The FDA Giveth and the FDA Taketh Away

Investors in shares of AVEO found out last week that the FDA is not waving through every oncology drug that comes down the road. The vote by the Oncologic Drugs Advisory Committee (ODAC), which we recently previewed in this column, was a resounding 13-1 against a recommendation for approval for AVEO’s multi-VEGF kinase inhibitor, tivozanib. As you can read, we expected the panel discussion to be a difficult one that would result in a narrow victory for tivozanib. Our discussion with Dr. Brian Rini of the Cleveland Clinic, the principal investigator of the AXIS study for axitinib, the most recent VEGF kinase inhibitor to gain a positive ODAC vote and FDA approval, felt that AVEO would overcome the trial’s obvious flaws (discussed below), was even more positive than even our measured assessment. As we wrote, Dr. Rini felt that, while concerning, the inverted OS curve could be explained by the trial’s one-way crossover, and that the company would prevail.

Obviously, FDA and all the panel members save one didn’t see it that way. In fact, it appears that the meeting was over before it even started. While we have seen drug sponsors overcome negative briefing documents and even hostile assessments from medical reviewers, it was clear from the opening comments by Amna Ibrahim of the Division of Oncology Products that there was no way AVEO was coming away from the meeting with a positive recommendation. Comments from cancer czar, Dr. Richard Pazdur, Director of the Office of Hematology and Oncology Products, sealed the company’s fate late in the afternoon with his dubious perspective on the drug’s risk/benefit relationship.

A number of issues doomed tivozanib’s prospects but clearly the inverted OS curve was something the drug could not surmount. Our concerns were raise when the briefing documents were made available and the FDA review narrative indicated that the FDA requested in May of 2012 that AVEO conduct another study of tivozanib in a patient population “comparable to that in the US” (recall that the vast majority of patients in the TIVO-1 trial were from Eastern Europe). Whether AVEO refused or declined to follow the FDA’s recommendation, investors still don’t know. One thing is certain, however; the regulatory track record of sponsors who decline to follow what the FDA recommends and instead throw themselves on the mercy of an advisory committee is poor. Additionally, the multitude of therapeutic options clearly has raised the bar, formally or informally, for follow-on compounds with mechanisms similar to those already on the market. Surprisingly, the lengthy absolute level of OS in the tivozanib arm and the drug’s favorable safety profile counted for very little in the panel discussion. A hard lesson to be learned for others in the business.

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