The FDA has picked holes in Epizyme’s filing for approval of tazemetostat, pointing to limited efficacy and safety concerns in its advisory committee briefing document. One analyst said the conclusions “read a bit harsh,” leading them to put the chances of a positive vote at no more than 25%.
Epizyme is seeking FDA approval of tazemetostat, an EZH2 inhibitor, in adults with metastatic or locally advanced epithelioid sarcoma who are not eligible for curative surgery. The filing is based on data from a non-randomized, open-label clinical trial that gave tazemetostat to around 100 epithelioid sarcoma patients.
In briefing experts on its advisory committee ahead of a meeting Wednesday, the FDA raised doubts about whether the objective response rate (ORR) seen in the EZH-202 trial is good enough.
“With limited clinical experience and lack of comparative data, FDA is concerned that the ORR of 13% observed in Cohorts 5 and 6 of EZH-202 does not provide sufficient evidence of benefit to outweigh the risks of tazemetostat in patients with epithelioid sarcoma,” the agency wrote.
The FDA thinks the ORR of 13% may flatter Epizyme’s drug, noting that “the true response rate to tazemetostat may thus be as low as 4-7%” given the position of the 95% confidence interval. The agency compared that figure to the 24% ORR that won doxorubicin approval in soft tissue sarcoma in 1974, although that side by side comes with the caveat that response criteria have changed over the intervening years.
Drugs have received positive advisory committee recommendations on the basis of limited evidence of efficacy in the past, particularly in rare diseases such as epithelioid sarcoma, but tazemetostat is also hampered by a safety signal. While the FDA thinks tazemetostat is generally well tolerated and may have a better toxicity profile than standard therapies, it also pointed to “a clear risk of secondary malignancies” associated with use of the EZH2 inhibitor.
Michael Yee and his colleagues at Jefferies called the briefing document “pretty cautious” and “a bit harsh,” leading them to put the likelihood of a positive advisory committee recommendation at 20% to 25%. Yee’s peers at SVB Leerink struck a softer tone, calling the briefing document “relatively balanced,” but still came away from the FDA analyses thinking tazemetostat “does not appear to confer superior benefit to [existing] agents based on available data.”
If shared by the advisory committee and the FDA reviewers, that conclusion could sink Epizyme’s hopes of bringing tazemetostat to market in epithelioid sarcoma. That outcome would only be a small blow to Epizyme’s prospects, though.
Epithelioid sarcoma is a small indication—Yee puts the opportunity at less than $50 million—that is dwarfed by the size of the other market targeted by Epizyme. Yee and his colleagues think the case for tazemetostat in the second disease, follicular lymphoma, is much clearer, meaning Epizyme could file for approval in an indication worth an estimated $500 million even if the FDA rejects the drug in epithelioid sarcoma.