Nexletol: what flexibility did regulators accept, and why?

“In conclusion, safety margins established from the 26-week rat and 52-week monkey studies support the proposed 180 mg/day dose of bempedoic acid and correspond to at least <1 and 13 times the clinical exposure at the human dose of 180 mg, respectively, based on AUC exposures at the nonclinical no observed adverse effect levels (NOAELs).”

“The low safety margin in rodent studies is due to dose-limiting, rodent-specific PPARD-related effects that occurred at low multiples of clinical exposures. The monkey is considered more representative of the potential human responses than rodents for PPARD-mediated effects.”

“The NOAEL is established as 10 mg/kg/day (at doses resulting in exposures below the clinical exposure, based on AUC) considering the absence of effect on growth and neurobehavior in juvenile rats treated at the high dose (10 mg/kg/day) tested.”

“However, the absence of a safety margin is not of clinical concern, because the toxicological profile of bempedoic acid in juvenile rats was comparable to that observed in adult rats.”

“The low safety margins identified from fertility, embryo-fetal and pre-and postnatal development studies conducted in rat (Table 47) are considered acceptable, because the adverse effects were only observed at maternally toxic doses.”