Ponesimod for treating relapsing–remitting multiple sclerosis (MS)

Ponesimod is a selective and rapidly reversible sphingosine-1-phosphate receptor Type 1 (S1P1) modulator (1,2)

• S1P1 receptor is one of five known G protein-coupled receptors with nanomolar affinity for the lysophospholipid sphingosine-1-phosphate (S1P), which is generated through physiologic metabolism of the cell membrane constituent sphingomyelin by all cells
  • S1P receptors, including S1P1 receptor, are widely expressed in many tissues
    • S1P1 receptor expression on lymphocytes controls their egress from thymus and secondary lymphoid organs

Ponesimod presents distinctive features compared to fingolimod, including selectivity for S1P1, a shorter half-life, and consequently a faster lymphocyte count normalization upon treatment discontinuation (within less than a week) in comparison to fingolimod (1-2 months) (1)

• SIP1 receptor modulators disrupt the interaction of the physiologic S1P ligand with S1P1 receptors by promoting initial activation followed by sustained internalization and desensitization of S1P1 receptor
  • causes internalization of S1P1 receptors on lymphocytes, which results in blocking lymphocyte egress from lymphoid tissues into the circulation, thus reducing peripheral lymphocyte count in a dose-dependent manner
    • pathogenic lymphocytes are sequestered in peripheral lymphoid organs, thus preventing their infiltration into the site of inflammation (i.e., the central nervous system [CNS] in MS) (1)

NICE state (3):

• Ponesimod is recommended for treating relapsing-remitting multiple sclerosis with active disease defined by clinical or imaging features in adults, only if the company provides ponesimod according to the commercial arrangement
• "..Clinical trial evidence shows that people who have ponesimod have fewer relapses than people who have teriflunomide.."

Reference:

1. Pouzol L, Piali L, Bernard CC, Martinic MM, Steiner B, Clozel M. Therapeutic Potential of Ponesimod Alone and in Combination with Dimethyl Fumarate in Experimental Models of Multiple Sclerosis. Innov Clin Neurosci. 2019;16(3-4):22-30.
2. D'Ambrosio D, Freedman MS, Prinz J. Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases. Ther Adv Chronic Dis. 2016;7(1):18-33. doi:10.1177/2040622315617354
3. NICE (February 2022). Ponesimod for treating relapsing-remitting multiple sclerosis