Abstract Details

Title Siponimod Penetrates, Distributes and Acts on the Central Nervous System: Translational Insights

Topic Multiple Sclerosis

Presentation(s) P13 - Poster Session 13 (5:30 PM-6:30 PM)

Poster/Presentation
Number 9-015

Objective Consolidate translational evidence to establish the CNS penetration and action of siponimod.

Background Siponimod, a potent, oral, selective sphingosine 1-phosphate (S1P_1,5) receptor modulator, is the first disease-modifying therapy proven to reduce disability progression, cognitive decline, and total brain volume loss versus placebo in patients with typical SPMS. The mechanism of action of siponimod is believed to involve both S1P₁-dependent anti-inflammatory effects on pathogenic lymphocytes and glial cells in the CNS, and S1P₅-dependent pro-repair effects on oligodendrocytes.

Design/Methods Siponimod CNS penetration and/or action were explored in healthy mice, rats, non-human primates (NHP) and SPMS patients from the Phase 3 EXPAND study. This was done via liquid chromatography-mass spectrometry measurements of siponimod in blood, plasma, brain homogenates and/or CSF samples; down-modulation assays of S1P₁ receptors in brain homogenates; and Quantitative Whole Body Autoradiography (QWBA) using [¹⁴C]siponimod or non-invasive single-photon emission computed tomography (SPECT) using a previously validated ¹²³I radiolabeled imaging analog for siponimod.

Results In mice, a siponimod-loaded diet over 10 days achieved dose-proportional steady-state levels of siponimod in blood, concomitant with 6- to 8-fold higher levels in brain homogenates. This was similar in siponimod-treated rats (oral gavage, 7 days), together with a siponimod CSF/plasma ratio of 0.0025 and a dose-dependent down-modulation of brain S1P₁ receptors, as indicated by S1P₁ protein levels measured in brain homogenates. QWBA distribution analysis in rats indicated the highest concentrations of siponimod-related radioactivity in the CNS in the spinal cord, cerebellum (white matter), choroid plexus, medulla oblongata, and corpus callosum. SPECT monitoring in NHP revealed CNS distribution of siponimod with a brain/blood ratio of 6–8, as in mice. Of the EXPAND population (N=1651), 9 (5 siponimod-treated; 4 placebo-treated) consented to CSF sampling at the end of treatment; all 5 siponimod-treated patients had siponimod (low nM range) in their CSF.

Conclusions Results suggest CNS penetration and distribution of siponimod across species.

Authors/Disclosures
Marc Bigaud PRESENTER	Marc Bigaud has received personal compensation for serving as an employee of Novartis Pharma.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Anna Schubart (Novartis Institutes of BioMedical Research)	No disclosure on file
	No disclosure on file

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Abstract Details