Ongentys: what flexibility did regulators accept, and why?

“In pregnant rabbits maternal toxicity was evident already at exposure levels far below the human exposure at the recommended daily dose of 50 mg (AUC), while embryo-fetal development was not negatively influenced up to an AUC in the range of the human exposure, resulting in no safety margin either for the does (<1 time) or for the offspring (<1 to 1 time).”

“Due to the fact that opicapone is indicated as adjunctive therapy only to preparations of levodopa/benserazide or levodopa/carbidopa, all products with restricted use during pregnancy (“should not be used during pregnancy without using contraception measures”), or in female patients without childbearing potential, the deficiency of the rabbit study was agreed to be of minor concern and the issue was considered resolved.”

“In the PPND study, effects on neurobehavioral development were not assessed using a complex learning and memory task, such as the Biel or Cincinnati water maze, and were, therefore, marginally acceptable.”

“Adverse development effects of opicapone given in combination with levodopa/carbidopa (LD/CD) were not assessed; however, LD/CD is known to cause visceral and skeletal malformations in rabbits. This information should be included in labeling because opicapone is to be indicated as an adjunct to LD/CD.”

“No juvenile, local tolerance, immunotoxicology or dependence studies have been conducted with Opicapone. The absence of these studies has been adequately justified.”

“Although no sampling of BIA 9-1103 was undertaken, the applicant has sought to address this by extrapolating the expected level of BIA 9-1103 in mice and rats using metabolite exposures observed in other completed TK studies.”

“Relative exposures in mice look on the low side (AUC0-t of 2.81 μg•h/mL at 1000 mg/kg in single dose study), however in the rat (AUC0-t of 35.3 to 182 μg•h/mL ) this has a adequate margin of safety compared to the expected human AUC0-t of 4.00 μg•h/mL. In the end, the toxicological cover for the major human metabolite can be accepted.”