Background: S969 is a first-in-class oral small molecule designed to transcriptionally upregulate α7β1 integrin, a structural disease modifier for Duchenne muscular dystrophy (DMD). Accurate prediction of human pharmacokinetics (PK) and optimal clinical dosing requires a comprehensive understanding of hepatic clearance across multiple species. This study evaluates the absorption, distribution, metabolism, and excretion (ADME) profile of S969 to facilitate allometric scaling for first-in-human trials.
Methods: The in vitro clearance rate of S969 was assessed using liver microsomes (0.1mg/mL) and cryopreserved hepatocytes (0.7 million viable cells/mL) across five species: CD-1 mouse, Sprague-Dawley rat, Beagle dog, Cynomolgus monkey, and human. Metabolic stability, expressed as the percentage of parent compound remaining, was measured via HPLC-MS/MS over 60 to 120 minutes. The half-life (T1/2) and apparent intrinsic clearance (CLint) were calculated assuming first-order kinetics.
Results: S969 demonstrated significant species-specific variability in metabolic stability. In human liver microsomes, the compound exhibited a T1/2 between 332 and 554.5 minutes, markedly longer than the T1/2 observed in monkeys (137.9–152.3 min), dogs (131.4–146.5 min), rats (144.8–198.6 min), and mice (29.5–31.6 min). Comparative hepatocyte analysis confirmed this trend, with human T1/2 exceeding 240 minutes, while animal models ranged from 46.7 to 81.0 minutes. This represents a >10-fold reduction in clearance rates in humans compared to the primary rodent model. These in vitro predictions align with preliminary in vivo serum PK data, supporting favorable metabolic stability for human administration.
Conclusions: S969 exhibits high metabolic stability in human hepatic models, suggesting a longer half-life and lower clearance than predicted by standard animal models. These data inform the projected human dose range of 5–30 mg/kg/day for forthcoming clinical trials. S969 is currently in IND-enabling development as a mutation-agnostic therapy for DMD.