Mayzent: what flexibility did regulators accept, and why?

“Concentrations of metabolites M3 and M17 were not directly assessed in pivotal repeat-dose toxicity studies. Instead, levels in these studies were inferred based on the ratio of metabolite to parent observed in non-GLP PK and exploratory studies in relevant species, and no method validation has been submitted for the methods of analysis used to determine metabolite concentrations in these studies.”

“Although the approach was not in line with ICH S3A guidance, the CHMP agreed with the provided justification for this approach and that the safety of metabolites M3 and M17 were adequately qualified in pivotal non-clinical repeat-dose toxicity studies.”

“Hence, no safety margin could be determined at the NOAEL for embryo-foetal development with respect to clinical exposure at the 2 mg daily dose (0.2 fold the exposure level), whereas the NOAEL for maternal toxicity of 1 mg/kg/day corresponds to a margin of exposure of 1.7 fold.”

“In view of the observed embryonic malformations and the lack of any safety margins, the use of siponimod during pregnancy and by women of childbearing potential not using effective contraception has been contraindicated in line with fingolimod.”

“On a body surface area basis, NOAELs were <0.24 and 720 mg/m2 for guinea pig and monkey, respectively. The human dose is 0.3 mg/m2, resulting in no safety margin.”

“Safety margins to toxicities observed with administration of siponimod are adequate (lung), can be monitored (cardiovascular), or are described in the labeling (reproductive and development, and carcinogenicity).”

“A post-marketing requirement for a juvenile animal toxicology study is recommended to support clinical development of siponimod in the pediatric population under PREA.”