A doomsday scenario played out for Aveo Oncology (NASDAQ: AVEO) today. The Cambridge, MA-based company saw 13 of 14 members of an FDA advisory panel vote against its kidney cancer drug, tivozanib, saying it shouldn’t be cleared for sale in the U.S. because of questions about clinical trial design and the drug’s overall benefits to patients. Shares immediately fell close to 50 percent, to $2.80 from $5.26, when its stock resumed trading.
The disastrous vote, combined with some particularly harsh words from FDA oncology chief Richard Pazdur, likely squash tivozanib’s chance to win approval from regulators without Aveo conducting another clinical trial. The FDA considers the input of its advisory committees when it makes final decisions on whether a drug should be allowed on the U.S. market. The agency’s deadline to complete its review is July 28.
One of Pazdur’s concerns, for example, was the fact that Aveo’s 517-patient study—which compared patients taking tivozanib to a group taking Onyx (NASDAQ: ONXX) and Bayer’s sorafenib (Nexavar)—showed a higher risk of death among patients who were randomly assigned to get the Aveo drug. By comparison, each of the studies used to approve the seven other tyrosine kinase inhibitors for renal cell carcinoma, or kidney cancer showed, at minimum, a trend favoring the applicant’s drug, FDA staffers argued.
“We’re well aware that people want new options for the treatment of cancer,” Pazdur said just prior for the vote. “But that enthusiasm should not be just a wild enthusiasm without looking at the data. This would really set a precedent for an oncology approval. To accept that risk is very tenuous for us to do.”
Aveo was also harshly questioned for the design of its study for two key reasons. Firstly, the FDA argued—and the panel agreed—that it is difficult to apply the result of a study with a majority of its patients at testing sites in Central and Eastern Europe to patients in the U.S., where there is a different standard of care.
Second, several panel members critiqued Aveo’s unbalanced crossover study design. Once a patient’s disease worsened, they were allowed to “cross over” to get another drug that might help them—even if that “cross over” injected some uncertainty into the study about which drug might be the one that’s most helpful.
In this case, the “cross over” design created a lot of uncertainty that ended up hurting Aveo. Patients who were randomly assigned to get Aveo’s tivozanib first generally didn’t get a second therapy, researchers said. Yet those who got sorafenib first mostly ended up taking Aveo’s tivozaib thereafter. Aveo cited the crossover design as the reason that the data showed that 81 percent of those in the sorafenib group were alive after one year, compared to 77 percent of the people who were in the tivozanib group. The median overall length of survival for patients taking sorafenib was 29.3 months, compared to 28.8 months for those taking tivozanib.
The FDA used that uncertainty to prove its point—that currently the risks outweigh the benefits, and further tests are needed.
“What would be the compelling evidence that would warrant a vote of approval?” Pazdur asked.
Aveo had been leaning on two things. For one, it had data showing that tivozanib met the primary goal of its study by keeping tumors from spreading longer than sorafenib. Specifically, tivozanib kept tumors in check for a median time of 11.9 months, compared with 9.1 months for those randomly assigned the drug from Onyx/Bayer.
Secondly, it strongly touted tivozanib’s tolerability, noting that fewer patients were reporting side effects such as skin rash and diarrhea. Robert Motzer, a kidney cancer expert at Memorial Sloan-Kettering Cancer Center in New York, vouched for that tolerability profile, calling it “second to none” in the field of approved drugs for this particular set of patients.
That didn’t sway the panel, however, and Aveo executives at the hearing admitted they made a mistake designing their study.
“We did think it would have some impact on overall survival, but we did not anticipate that would be a bad thing,” said Bill Slichenmyer, Aveo’s chief medical officer, said of the crossover design. “It had a bigger impact than we had anticipated.”
Aveo executives also explained that at the time it began its study, there were several other trials with the same patient population going on in the U.S., so Aveo needed to look to other parts of the world where it could enroll patients for the study.
That decision, however, came back to haunt Aveo on Thursday.
The vote is a big setback for a company that has been driving 11 years of R&D towards this one moment and has yet to put a drug on the market.
Tivozanib is a once-daily pill that works by cutting the blood flow to tumors. It does so by blocking the three types of VEGF receptors, which are markers on the surface of cancer cells. Aveo has been hoping to bring tivozanib into crowded field that includes sorafenib, Pfizer’s sunitinib (Sutent) and axitinib (Inlyta), GlaxoSmithKline’s pazopanib (Votrient), and Roche/Genentech’s bevacizumab (Avastin).