EXTH-77. ONC201 EXHIBITS PASSIVE DIFFUSION AND BROAD DISTRIBUTION IN THE CENTRAL NERVOUS SYSTEM

Abstract

Abstract Imipridone ONC201 is an investigational agent in phase II clinical trials for H3 K27M-mutant diffuse midline glioma with evidence of durable objective responses and clinical symptom improvements as a single agent. The systemic pharmacokinetics of ONC201 and its ability to achieve target concentrations in supratentorial glioblastoma have been demonstrated in clinical trials; however, its clearance and distribution in midline structures and other areas of the central nervous system (CNS) haven’t been evaluated. A quantitative whole-body autoradiography study was conducted in Long-Evans rats with a single dose of [14C]-ONC201. [14C]-ONC201-related material was rapidly distributed throughout the body, with concentrations peaking at 1h for most tissues. The endocrine, metabolic/excretory, ocular and gastrointestinal tract tissues contained the highest distribution of [14C]-ONC201-derived radioactivity. Importantly, [14C]-ONC201 material was distributed evenly across brain substructures, including the meninges and midline structures of the brain; all tissues had a half-life of 1.4–7.9h, with the exception of the meninges (2397.3h). Given the uniform distribution throughout the CNS, we evaluated the permeability and efflux potential of ONC201 in bidirectional transport assays using human Caco-2 cell monolayers. ONC201 displayed high permeability in the apical to basolateral direction with apparent permeability values of 23–31×10–6 cm/s at 7–700μM. In the basolateral to apical direction, apparent permeability values were 11–24 × 10–6 cm/s. The efflux ratio values were 0.46–0.79 for ONC201, suggesting that ONC201 is not a substrate of efflux transporters. However, ONC201 exerted inhibitory potential on MDR1- (90.6%) and BCRP-mediated (81.6%) transport at 200mM. In summary, ONC201 exhibits passive diffusion without being effluxed, which may enable its rapid and wide distribution throughout the CNS. This distribution profile suggests that the compound may achieve therapeutic concentrations throughout the CNS with oral administration and that investigation of additional CNS tumors will not be hindered by drug delivery to specific anatomic structures.