A Comprehensive Pharmacological and Clinical Monograph on Ponesimod

I. Executive Summary

Ponesimod, marketed under the brand name Ponvory, is an orally administered, small molecule drug classified as a selective sphingosine 1-phosphate (S1P) receptor modulator.[1] It is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.[1] The development of ponesimod was driven by the need for a more selective agent than the first-in-class S1P modulator, fingolimod, whose off-target activity at the S1P3 receptor was associated with certain adverse effects.[1]

The primary mechanism of action of ponesimod involves high-affinity agonism at the S1P receptor subtype 1 (S1P1) on lymphocytes. This interaction leads to the internalization and functional antagonism of the receptor, effectively sequestering lymphocytes within secondary lymphoid organs.[2] By preventing the egress of these immune cells into the peripheral circulation, ponesimod reduces the infiltration of autoaggressive lymphocytes into the central nervous system (CNS), thereby mitigating the inflammatory processes that drive MS pathology.[6] Its high selectivity for S1P1 over other S1P receptor subtypes is a key pharmacological feature intended to optimize its benefit-risk profile.[2]