Litfulo: what flexibility did regulators accept, and why?

“According to the applicant, the margins between the clinical exposure and the exposures in the lowest dose group at which ritlecitinib-related axonal dystrophies were observed (rostral cerebellar vermis at 10 mg/kg/day, study 20099163) are only 6.0-fold in terms of Cmax and 7.4-fold in terms of AUC24.”

“Therefore, upon CHMP’s request, a warning was added in section 4.4 of the SmPC, and a summary of the axonal dystrophy findings in dogs was included in the section 5.3 of the SmPC. Furthermore, given the limited availability of long-term clinical safety data, this safety concern will be followed-up post-approval (see clinical safety and RMP sections below).”

“While ritlecitinib was unequivocally an in vitro aneugen, the in vivo relevance of this finding is considered to be low, especially as aneugenicity is generally considered to be a threshold effect and as in vitro aneugenicity was only observed at exceedingly high supra-therapeutic exposures.”

“This notion was supported by the in vivo micronucleus rat study 14GR132, in which no increases in micronucleated cells were observed in test-article groups at relevant exposures.”

“However, the very small sample size of 4 beagle dogs, actually 3 in the GLP-compliant study, since the data of one dog could not be evaluated, poses an issue with the informative value of the results.”

“Although the results of these cardiovascular safety studies in beagle dogs can be regarded as supportive information only, possible CV effects are not expected with ritlecitinib due to selectivity towards JAK3.”