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.
Medical uses 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.
Pharmacology
Potency and selectivity 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. The prospects for ozanimod (Scripps-Receptos compound RPC1063) depended upon demonstration of comparable or better activity and selectivity relative to fingolimod and other comparators. During the discovery phase of its development, ozanimod was shown to be a selective agonist of the S1P1 and S1P5 receptors. 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. Hence, the study concluded that it had "established... RPC1063 [as] a potent agonist of the S1P1 receptor with additional agonist activity on the S1P5 receptor" with S1P1 activity "similar to other known, less selective S1P receptor agonists".
Mechanism of action, pharmacodynamics The agonism of S1P directly causes its internalization and degradation through the ubiquitin-proteosome pathway. The loss of S1P leads to a decrease in the total lymphocyte count in circulation, specifically CD4+ CCR7+ and CD8+ CCR7+ T cells. The most frequent adverse effects is an increase in liver enzymes (>10% ) and high blood pressure (4%) per product labeling.Kaposi sarcoma of the skin and colon was described in a single case s after treatment with ozanimod for 2 months.
Pharmacokinetics Ozanimod has a high oral bioavailability, a circulating half-life of about 19 hours, and reaches highest blood plasma concentrations after about 6 hours. Ozanimod is dehydrogenated by two CYP enzymes into two active metabolites, all with similar pharmacokinetics. The decrease in lymphocyte count lasts for approximately 14 days after treatment discontinuation. Unlike fingolimod, it does not require phosphorylation for activation, nor does it demonstrate cardiac abnormalities.
History
Ozanimod was invented by Hugh Rosen, Edward Roberts, and colleagues at The Scripps Research Institute, and was subsequently out-licensed in the creation of the startup, Receptos Inc. Celgene Corp acquired Receptos along with its intellectual property in 2015. Bristol Myers Squibb acquired Celgene in 2019 (and with it, ozanimod and the rest of its products and pipeline). The US Food and Drug Administration (FDA) approved ozanimod based on evidence from two clinical trials (Trial 1/NCT02294058 and Trial 2/ NCT02047734) of 1767 subjects with relapsing forms of multiple sclerosis. The trials were conducted at 173 centers in the United States, Belarus, Poland, Russia and Ukraine. Subjects received ozanimod or comparator (interferon β1a, a product approved for the treatment of relapsing forms of multiple sclerosis) for up to one year (in Trial 1) or up to two years (in Trial 2). Neither the subjects nor the health care providers knew which treatment was being given until the trials were completed. The benefit of ozanimod was evaluated based on the percentage of subjects who experienced reduction in disease relapse in comparison to subjects treated with interferon β1a. In May 2021, the FDA approved ozanimod for an additional indication for the treatment of moderately to severely active ulcerative colitis.
Clinical trials
Touchstone Touchstone is a double-blind, placebo controlled phase II clinical for the treatment of ulcerative colitis. 197 patients, ages 18–75, with moderate to severe ulcerative colitis (Mayo Score 6–10) were recruited and assigned either placebo, 0.5 mg or 1 mg of oral ozanimod followed by 1 week of dose escalation. The 1 mg dose showed a slight increase in rate of clinical remission of ulcerative colitits and total lymphocyte decrease as compared to the placebo, with the most common adverse effects being headaches and anemia. The authors noted that limitations on this study included a brief duration and small sample size, meaning they could not assess safety nor efficacy.
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