Cobenfy: what flexibility did regulators accept, and why?

“We informed the Applicant that based on animal deaths in their 14-day combination study with low and high doses there was now an unknown no observed adverse effect level (NOAEL) and safety margins could not be established to inform dosing.”

“On August 3, 2017, the Division removed the clinical hold acknowledging the Applicant’s commitment to refrain from escalating the dose beyond the initial starting dose until data from the first dose cohort and full study report of the 40-day rat combination study was submitted and reviewed.”

“The Applicant did not submit the study protocol for ECAC concurrence on dose selection. The high dose exceeded the MTD and caused excessive decreases in body weight (↓up to 45%), weight gain (↓up to 70%), and food consumption (↓up to 19%), precluding an adequate assessment for carcinogenic effect at this dose.”

“Xanomeline did not increase the incidence of tumors in rats treated for 2 years via the diet at doses up to 37 mg/kg/day in males and 46/mg/kg/day in females, respectively, which is slightly higher than the xanomeline dose at the MRHD of 125 mg/30 mg xanomeline/trospium, BID, based on body surface area (BSA).”

“Therefore, the TK data are unreliable to use quantitatively, and they are evaluated only from a qualitative perspective. The safety margin calculations listed in the drug label are based on body surface area and not on exposure data.”

“Data from the PK bridging study demonstrated that all three routes of administration in rats provided adequate exposure levels of xanomeline and the important human metabolites relative to the clinical exposure (Table 87).”