FDA questions vedolizumab PML risk

FDA reviewers said Entyvio vedolizumab from the Millennium Pharmaceuticals Inc. subsidiary of Takeda Pharmaceutical Co. Ltd. (Tokyo:4502) is effective for moderately to severely active ulcerative colitis (UC) and Crohn's disease but said if approved the product may require postmarket risk management beyond labeling due to a potential risk of progressive multifocal leukoencephalopathy (PML). The reviewers highlighted the PML risk with Tysabri natalizumab from Biogen Idec Inc. (NASDAQ:BIIB), which is also an integrin antagonist with a similar mechanism of action to vedolizumab. In its briefing documents, Takeda noted that vedolizumab and Tysabri bind to integrin alpha(4)beta(7) differently. There were no reported cases of PML in the clinical development program for vedolizumab, but FDA reviewers questioned whether vedolizumab's safety database provides an "acceptable pre-marketing assessment" of the PML risk.

Vedolizumab met the primary endpoint in four of five Phase III trials evaluating the compound for induction and maintenance of UC and Crohn's disease. The reviewers said the "key" efficacy question is whether there is "substantial evidence of efficacy" that vedolizumab induces clinical remission in Crohn's disease patients, as one of the two induction trials in the indication missed the primary endpoint. The comments came in tumor necrosis factor (TNF) alpha therapy. Given the potential PML risk, FDA is asking the committee to discuss limiting the population further. ...