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Ozanimod
Ozanimod, sold under the brand name Zeposia, is an immunomodulatory medication for the treatment of relapsing multiple sclerosis and ulcerative colitis. It acts as a sphingosine-1-phosphate receptor (S1PR) agonist, sequestering lymphocytes to peripheral lymphoid organs and away from their sites of chronic inflammation.
The most common adverse reactions are upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.
Ozanimod was approved for medical use in the United States in March 2020, in the European Union in May 2020, and in Australia in July 2020.
In the United States, ozanimod is indicated for the treatment of adults with relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease; and with moderately to severely active ulcerative colitis.
In the European Union and in Australia, ozanimod is indicated for the treatment of adults with relapsing remitting multiple sclerosis.
The principle of autoimmune therapy based on targeting S1P receptors was established through the clinical work performed during development of fingolimod (trade name Gilenya), a non‐selective S1P modulator.[better source needed] The prospects for ozanimod (Scripps-Receptos compound RPC1063) depended upon demonstration of comparable or better activity and selectivity relative to fingolimod and other comparators.[citation needed] During the discovery phase of its development, ozanimod was shown to be a selective agonist of the S1P1 and S1P5 receptors.[non-primary source needed] Specifically, in a discovery research report, ozanimod's equal potency and improved selectivity for S1P1 and S1P5 receptor family members were determined though a combination of inhibition, binding, and signalling assays for the S1P1, S1P2, S1P3, S1P4, and S1P5 receptor types alongside the same tests with fingolimod and other compounds.
Potency for ozanimod as an agonist of the S1P1 receptor type was established through observed sub-nanomolar EC50 values in GTPγS binding and cAMP inhibition assays, and for the S1P5 type through an observed nanomolar EC50 value in the GTPγS binding assay. Measured alongside its binding to the S1P2, S1P3, and S1P4 receptor types, these concentration-response results supported a conclusion of an improved selectivity profile, with selectivity of S1P1 over S1P5 receptors at 27‐fold, and selectivity for S1P1 over S1P2, S1P3, and S1P4 receptors greater than 10,000‐fold.
Also, these assays allowed comparison of ozanimod potency against and selectivity for S1P1 over other S1 receptors, relative to related S1 active agents siponimod and the phosphorylated (prodrug) forms of fingolimod and mocravimod, where ozanimod was similar to these comparators in S1P1 potency, but had the elevated selectivities stated above (versus fingolimod being potent in stimulating S1P3, S1P4, and S1P5, siponimod potent with a S1P5 form, and mocravimod active in some way against S1P3, S1P4, and S1P5), making its selectivity profile an improvement over all of these.
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Ozanimod
Ozanimod, sold under the brand name Zeposia, is an immunomodulatory medication for the treatment of relapsing multiple sclerosis and ulcerative colitis. It acts as a sphingosine-1-phosphate receptor (S1PR) agonist, sequestering lymphocytes to peripheral lymphoid organs and away from their sites of chronic inflammation.
The most common adverse reactions are upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.
Ozanimod was approved for medical use in the United States in March 2020, in the European Union in May 2020, and in Australia in July 2020.
In the United States, ozanimod is indicated for the treatment of adults with relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease; and with moderately to severely active ulcerative colitis.
In the European Union and in Australia, ozanimod is indicated for the treatment of adults with relapsing remitting multiple sclerosis.
The principle of autoimmune therapy based on targeting S1P receptors was established through the clinical work performed during development of fingolimod (trade name Gilenya), a non‐selective S1P modulator.[better source needed] The prospects for ozanimod (Scripps-Receptos compound RPC1063) depended upon demonstration of comparable or better activity and selectivity relative to fingolimod and other comparators.[citation needed] During the discovery phase of its development, ozanimod was shown to be a selective agonist of the S1P1 and S1P5 receptors.[non-primary source needed] Specifically, in a discovery research report, ozanimod's equal potency and improved selectivity for S1P1 and S1P5 receptor family members were determined though a combination of inhibition, binding, and signalling assays for the S1P1, S1P2, S1P3, S1P4, and S1P5 receptor types alongside the same tests with fingolimod and other compounds.
Potency for ozanimod as an agonist of the S1P1 receptor type was established through observed sub-nanomolar EC50 values in GTPγS binding and cAMP inhibition assays, and for the S1P5 type through an observed nanomolar EC50 value in the GTPγS binding assay. Measured alongside its binding to the S1P2, S1P3, and S1P4 receptor types, these concentration-response results supported a conclusion of an improved selectivity profile, with selectivity of S1P1 over S1P5 receptors at 27‐fold, and selectivity for S1P1 over S1P2, S1P3, and S1P4 receptors greater than 10,000‐fold.
Also, these assays allowed comparison of ozanimod potency against and selectivity for S1P1 over other S1 receptors, relative to related S1 active agents siponimod and the phosphorylated (prodrug) forms of fingolimod and mocravimod, where ozanimod was similar to these comparators in S1P1 potency, but had the elevated selectivities stated above (versus fingolimod being potent in stimulating S1P3, S1P4, and S1P5, siponimod potent with a S1P5 form, and mocravimod active in some way against S1P3, S1P4, and S1P5), making its selectivity profile an improvement over all of these.