Ekterly: which tox species, and why?

“the Applicant characterized the toxicity profile of sebetralstat with general toxicity studies in dogs (up to 4 weeks), and rats and monkeys (4 weeks, 13 weeks, and long-term dosing at durations up to 6 months).”

“Pharmacology studies sufficiently justified the choice of species for toxicology investigations. The monkey, mouse and rat turned out to be the most relevant species (IC50 of 5.07 nM, 13.9 nM and 69.8 nM respectively).”

“In the 26-week study, daily oral gavage administration of 30, 100, or 300 mg/kg/day was clinically well tolerated, with no sebetralstat-related deaths.”

“To support the marketing authorisation, the applicant performed GLP-compliant repeat-dose studies in Crl:WI(Han) rats and in Cynomolgus NHP via oral route for up to 26 weeks.”

“A full set of developmental and reproductive toxicity studies were performed in rats and rabbits.”

“A statement regarding carcinogenicity has been implemented in SmPC in section 5.3. to reflect the lack of carcinogenicity based on a 26-week study in rasH2-Tg transgenic mice and a 104-week study in rats.”

“Regarding species selection, rabbits cannot be considered as pharmacologically active species since PD data showed IC50 values higher than 40,000 nM regarding inhibition of rabbit plasma kallikrein enzyme”