Zeposia: what flexibility did regulators accept, and why?

“Overall, the nonclinical studies are adequate to support approval of ozanimod for the proposed indication, although systemic exposures to the two major (and active) human metabolites (CC112273 and CC1084037) were lower in several pivotal studies than in humans at the maximum recommended human dose (0.92 mg/day).”

“The Applicant was requested to address the clinical implications of the inadequate coverage of CC112273 and CC1084037 levels in the above-mentioned studies by amendments of sections 4.4 and 4.6 of the SmPC concerning the embryo-foetal risks and section 4.4 of the SmPC concerning carcinogenic risks (immunosuppressive effects and cutaneous neoplasms).”

“Dr. Toscano concluded that the PPND study is inadequate because of the lack of sufficient exposure to CC1084037 and recommended the metabolite be assessed in a PPND study as a post-marketing requirement.”

“However, the available data demonstrate that ozanimod, administered to pregnant animals, has clear adverse effects on the developing organism, including teratogenicity, which are consistent with the critical role of the S1P1 and S1P5 receptors in embryogenesis (including vascular and neural development) and should discourage use during pregnancy. Therefore, I do not believe the sponsor needs to conduct such a study.”