To propose a working hypothesis for the mode of action (MoA) of siponimod on SPMS and its differentiation from fingolimod.

Siponimod, an oral, potent, and 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. New preclinical observations help understand its MoA and differentiation from fingolimod, a S1P_1,3,4,5 receptor modulator.

Siponimod was compared with fingolimod using the most recent preclinical results from pharmacokinetic/pharmacodynamic (PK/PD), mechanistic, and disease models.

Besides specific physicochemical characteristics, siponimod differs from fingolimod in three main aspects: narrower target selectivity, no active metabolite, and unique PK/PD profiles in the blood and CNS compartments. Siponimod triggers S1P₁-dependent anti-inflammatory effects on pathogenic lymphocytes and glial cells in the CNS, and S1P₅-dependent pro-repair effects on oligodendrocytes, sparing S1P_3/4-dependent pro-inflammatory effects on astrocytes.

Mechanistically, S1P₁ agonism-induced dose-dependent S1P₁ receptor down-modulation (functional antagonism) is responsible for inhibiting the egress of pathogenic lymphocytes from secondary lymphoid organs. Recent observations suggest that S1P_1,5 receptors in the CNS might be subjected to classical agonism-induced signaling with desensitization, or tachyphylaxis at supramaximal doses that translates into a loss of neuroprotective/pro-remyelination effects at high CNS siponimod or fingolimod-phosphate exposures in various in vivo models. Therefore, an optimal CNS/blood drug exposure ratio (_CNS/bloodDER) is critical for concomitant efficacy in both the blood and CNS (i.e. window for therapeutic efficacy). In this context, a _CNS/bloodDER limited to 6-7 for siponimod versus a _CNS/bloodDER of 20-30 for fingolimod-phosphate, as measured in EAE mice, might reveal potential advantages for siponimod over fingolimod.

In preclinical studies, siponimod differentiates from fingolimod by presenting the pharmacological characteristics required for optimal expression of its dual S1P₁/S1P₅ MoA in both blood and CNS compartments. Quantitative positron emission tomography studies are warranted to assess translation to SPMS.