Ogsiveo: what flexibility did regulators accept, and why?

“A rat 2-year carcinogenicity study was not conducted given that non-melanoma skin cancers have been reported in humans treated with nirogacestat and the fact that human systemic exposures exceed those that can be achieved in animal toxicology studies due to low tolerance in the rat and excess of toxicological findings.”

“It is accepted not to perform a 2-year rat carcinogenicity study since the results of such study would not add to the clinical safety assessment.”

“Based on the severity of the embryo‐fetal toxicities, and the known requirement for the Notch pathway for normal embryo implantation and development, the weight of evidence provides justification for not conducting the definitive embryo‐fetal toxicity studies in rats and in rabbits, as well as not conducting the rat peri‐ and post‐natal development study.”

“Further embryo-foetal toxicity studies in rats and rabbits as well as a pre- and post-natal development (PPND)-study in the rat is not warranted.”

“Conduct of additional general toxicology studies were not required based on FDA feedback received at the end‐of‐Phase 1 meeting; therefore, the 6‐month rat and 9‐month dog studies with nirogacestat were not conducted.”

“Considering the toxicological findings in multiple organs across all tested species at no exposure margins to the clinical exposure further non-clinical toxicity studies of longer duration is not considered to add to the clinical safety assessment.”

“The exposure margins based on NOAEL/LOAEL observed in all repeat-dose studies performed in the rat, dog and mouse, reproductive toxicity studies performed in the rat, as well as the carcinogenicity study performed in the TgRasH2 mouse are considerable below 1, indicating a lack of safety margins to the adverse effects observed in the non-clinical studies.”

“It is agreed that additional studies in animals are not warranted as significant findings relevant for risk assessment and risk mitigation in humans already is identified.”

“Considering the clinical context (unmet medical need for a severe condition with a beneficial clinical profile), the clinical judgement that long term treatment is unlikely, that both impurities are considered to have relatively low mutagenic potential, a product specific acceptable intake limit of 20 μg/day (corresponding to 66,667 ppb/day based on a maximum daily dose of 300 mg) for the sum of ASYM-136911 and ASYM-136912 was proposed.”

“The NcWP has been consulted on the product specific limit proposed by the applicant and concluded that the theoretical excess cancer risk (TECR) for total NDSRI (ASYM 136911 + ASYM 136912) levels is near or below the acceptable TECR of 1:100,000 for 7 years of treatment duration or less.”