Siponimod (BAF312) penetrates, distributes, and acts in the central nervous system: Preclinical insights

BACKGROUND: Siponimod (BAF312), a selective S1P(1)/S1P(5) agonist, reduces disability progression in secondary progressive MS. Recent observations suggest it could act via S1P(1)/S1P(5)-dependent anti-inflammatory and pro-myelination effects on CNS-resident cells. OBJECTIVE: Generate preclinical evidence confirming siponimod's CNS penetration and activity. METHODS: Siponimod's CNS penetration and distribution was explored in rodents and non-human primates (NHPs) using: Liquid Chromatography coupled to tandem Mass Spectrometry (LC-MS/MS), quantitative whole-body autoradiography (QWBA) using (14)C-radiolabeled siponimod or non-invasive single-photon emission CT (SPECT) with a validated (123)I-radiolabeled siponimod analog. Functional CNS activity was investigated by S1P(1) receptor quantification in brain homogenates. RESULTS: In mice/rats, siponimod treatments achieved dose-dependent efficacy and dose-proportional increase in drug blood levels, with mean brain/blood drug-exposure ratio ((Brain/Blood)DER) of 6–7. Efficacy in rat brain tissues was revealed by a dose-dependent reduction in brain S1P(1) levels. QWBA distribution analysis in rats indicated that [(14)C]siponimod related radioactivity could readily penetrate CNS, with particularly high uptakes in white matter of cerebellum, corpus callosum, and medulla oblongata versus lower exposures in other areas such as olfactory bulb. SPECT monitoring in NHPs revealed CNS distribution with a (brain/blood)DER of ∼6, as in rodents. CONCLUSION: Findings demonstrate siponimod's CNS penetration and distribution across species, with high translational potential to human.