OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Ozanimod – Zeposia®

DRUG CLASS

Multiple Sclerosis Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Ozanimod	1306760-87-1	C23-H24-N4-O3

ANNOTATED BIBLIOGRAPHY

References updated: 15 July 2021

• Abbreviations: HBV, hepatitis B virus; MRI, magnetic resonance imaging; S1P, sphingosine-1-phosphate.
• Zimmerman HJ. Oncotherapeutic and immunosuppressive agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 697-8.

  (Expert review of hepatotoxicity published in 1999 before the availability of S1P receptor modulators).
• Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013.

  (Multi-authored textbook of hepatotoxicity published in 2013, does not discuss the drugs for multiple sclerosis).
• Krensky AM, Azzi JR, Hafler DA. Immunotherapy for multiple sclerosis. Immunosuppressants and Tolerogens. In, Brunton LL, Halal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 649-52.

  (Textbook of pharmacology and therapeutics).
• FDA Medical Review of NDA for Ozanimod: Pages 92-99. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2020/209899Orig1s000MedR.pdf.

  (FDA website with product labels and medical review of the efficacy and safety of ozanimod mentions that serum aminotransferase elevations above 5 times ULN arose in 10 of 1944 [1%] patients treated with ozanimod and led to dose interruption/discontinuation in ~1%, but careful analysis of specific cases did not find any instance of clinically apparent acute liver injury with jaundice).
• Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, et al. FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387–401. [PubMed: 20089952]

  (Among 1272 patients with relapsing multiple sclerosis treated with fingolimod [0.5 or 1.25 mg daily] or placebo for 24 months, 8.5-12.5% of fingolimod, but only 1.7% of placebo recipients developed ALT elevations above 3 times ULN, and ALT levels fell to normal with or without discontinuation, and serum bilirubin levels did not change).
• Oral fingolimod (gilenya) for multiple sclerosis. Med Lett Drugs Ther. 2010;52(1353-1354):98–9. [PubMed: 21344782]

  (Concise review of mechanism of action, efficacy, safety and costs of fingolimod shortly after is approval for use for multiple sclerosis in the US, mentions that common side effects are headache, cough, diarrhea, back pain and aminotransferase elevations; no mention of clinically apparent liver injury).
• Subei AM, Cohen JA. Sphingosine 1-phosphate receptor modulators in multiple sclerosis. CNS Drugs. 2015;29:565–75. [PMC free article: PMC4554772] [PubMed: 26239599]

  (Review of the function of the S1P receptors [subtypes 1 to 5] and the clinical implications of their differential modulation by different inhibitors).
• Cohen JA, Arnold DL, Comi G, Bar-Or A, Gujrathi S, Hartung JP, Cravets M, et al. RADIANCE Study Group. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15:373–81. [PubMed: 26879276]

  (Among 258 adults with relapsing multiple sclerosis treated with ozanimod [0.5 or 1.0 mg] or placebo once daily for 24 weeks, the accumulative number of brain MRI enhancing lesions were less with ozanimod [1.5] than placebo [11] and adverse event rates were similar, ALT elevations above 3 times the ULN arose in 1.5% vs none on placebo, but no patient required drug discontinuation because of an adverse event).
• Sandborn WJ, Feagan BG, Wolf DC, D'Haens G, Vermeire S, Hanauer SB, Ghosh S, et al. TOUCHSTONE Study Group. Ozanimod induction and maintenance treatment for ulcerative colitis. N Engl J Med. 2016;374:1754–62. [PubMed: 27144850]

  (Among 197 adults with ulcerative colitis treated with ozanimod [0.5 or 1.0 mg] vs placebo once daily for up to 32 weeks, clinical remissions by 8 weeks occurred in 14% and 16% on ozanimod vs 6% on placebo, while adverse event rates were similar in all groups, ALT elevations above 3 times ULN arose in 3% on ozanimod vs none on placebo, but there were no severe hepatic adverse events).
• Filippi M, Bar-Or A, Piehl F, Preziosa P, Solari A, Vukusic S, Rocca MA. Multiple sclerosis. Nat Rev Dis Primers. 2018;4:43. [PubMed: 30410033]

  (Review of the pathogenesis, clinical features, natural history, management and therapy of multiple sclerosis).
• Siponimod (Mayzent)--a new drug for multiple sclerosis. Med Lett Drugs Ther. 2019;61(1571):70–2. [PubMed: 31169805]

  (Concise review of the mechanism of action, clinical efficacy, safety and costs of siponimod in comparison to other agents used to treat multiple sclerosis; mentions that serum aminotransferase elevations can occur with siponimod therapy and that patients should be tested for liver function tests and have CYP 2C9 genotype testing before starting treatment).
• Al-Salama ZT. Siponimod: first global approval. Drugs. 2019;79:1009–15. [PubMed: 31144287]

  (Review of the mechanism of action, history of development, clinical efficacy and safety of siponimod; mentions the common side effects include headache, hypertension, aminotransferase elevations, peripheral edema, nausea, dizziness, diarrhea, bradycardia and musculoskeletal pain, but that the aminotransferase levels were rarely severely elevated).
• Cohen JA, Comi G, Arnold DL, Bar-Or A, Selmaj KW, Steinman L, Havrdová EK, et al. RADIANCE Trial Investigators. Efficacy and safety of ozanimod in multiple sclerosis: Dose-blinded extension of a randomized phase II study. Mult Scler. 2019;25:1255–62. [PMC free article: PMC6681431] [PubMed: 30043658]

  (In a two year extension study of ozanimod [0.5 or 1.0 mg once daily] in 247 adults with relapsing multiple sclerosis [Cohen 2016], 5% of patients developed ALT or AST elevations above 3 times ULN and 4 subjects [1.6%] required drug discontinuation for ALT elevations above 5 times ULN, but all resolved rapidly and none developed symptoms or jaundice).
• Comi G, Kappos L, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, Hartung HP, et al. SUNBEAM Study Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 2019;18:1009–20. [PubMed: 31492651]

  (Among 1346 adults with relapsing multiple sclerosis treated with ozanimod [0.5 or 1.0 mg orally once daily] or interferon beta [30 µg intramuscularly once weekly] for at least 12 months, the annual relapse rate was less with ozanimod [0.18 and 0.24] than interferon beta [0.35], and while adverse event rates were less with ozanimod, ALT elevations above 3 times ULN arose in 3.0% vs 2.2% and discontinuations for ALT elevations in 0.6% vs 0.2%, but there were no cases of clinically apparent liver injury with jaundice).
• Cohen JA, Comi G, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, Hartung HP, et al. RADIANCE Trial Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019;18:1021–33. [PubMed: 31492652]

  (Among 1313 adults with relapsing multiple sclerosis treat with oral ozanimod [0.5 or 1.0 mg daily] or intramuscular interferon beta 1a [30 µg weekly], annualized relapse rates over 2 years were lower with ozanimod, while adverse event rates and discontinuations were more frequent with interferon beta, and ALT elevations above 3 times ULN arose in 6.3% on ozanimod vs 4.5% on interferon beta, although there were no instances of clinically apparent liver injury with jaundice).
• Lamb YN. Ozanimod: first approval. Drugs. 2020;80:841–8. [PubMed: 32385738]

  (Review of the mechanism of action, pharmacology, clinical efficacy and safety of ozanimod shortly after its approval for use in multiple sclerosis in the US mentions that ALT and AST elevations arose in 10% of patients treated in large controlled trials in comparison to 5% in patients receiving interferon beta-1a; no mention of clinically apparent hepatotoxicity).
• Feagan BG, Sandborn WJ, Danese S, Wolf DC, Liu WJ, Hua SY, Minton N, et al. Ozanimod induction therapy for patients with moderate to severe Crohn's disease: a single-arm, phase 2, prospective observer-blinded endpoint study. Lancet Gastroenterol Hepatol. 2020;5:819–28. [PubMed: 32553149]

  (Among 69 patients with active Crohn disease treated with ozanimod [1 mg daily] for 12 weeks, improvements occurred in clinical, endoscopic and histologic features, and adverse events were largely due to the underlying disease; 7% of patients had ALT elevations, 4% rising to above 3 times the ULN, but none were associated with jaundice or required drug discontinuation).
• Ozanimod (Zeposia) for multiple sclerosis. Med Lett Drugs Ther. 2020;62(1605):132–4. [PubMed: 32970043]

  (Concise review of the mechanism of action, clinical efficacy, toxicity and costs of ozanimod shortly after its approval for use in relapsing multiple sclerosis in the US mentions that ozanimod is associated with ALT and AST elevations and that therapy lowers lymphocyte counts and increases the risk of infections including herpes zoster).
• Lu MC, Shih YL, Hsieh TY, Lin JC. Flare of hepatitis B virus after fingolimod treatment for relapsing and remitting multiple sclerosis. J Formos Med Assoc. 2020;119:886–7. [PubMed: 31679907]

  (Letter describing 41 year old Taiwanese woman with relapsing multiple sclerosis and inactive HBsAg carrier state who developed reactivation of hepatitis B after 35 months of treatment with fingolimod [ALT 385 U/L, HBV DNA 8 log₁₀ IU/mL, bilirubin not given] who responded to tenofovir, with resolution of ALT elevations and decrease of HBV DNA levels to undetectable despite continuation of fingolimod).
• Drugs for multiple sclerosis. Med Lett Drugs Ther. 2021;63(1620):42–8. [PubMed: 33976089]

  (Concise review of the relative clinical efficacy, safety and costs of drugs for relapsing multiple sclerosis including parenteral agents [such as interferon-beta, glatiramer acetate, natalizumab, alemtuzumab, ocreliumab, ofatumumab, rituximab and mitoxantrone] and the oral agents [such as the S1P receptor modulators, cladribine, fumarates, and teriflunomide], many of which are associated with serum ALT elevations and several have been reported to cause clinically apparent liver injury or reactivation of hepatitis B).
• Selmaj KW, Cohen JA, Comi G, Bar-Or A, Arnold DL, Steinman L, Hartung HP, et al. Ozanimod in relapsing multiple sclerosis: pooled safety results from the clinical development program. Mult Scler Relat Disord. 2021;51:102844. [PubMed: 33892317]

  (Analysis of treatment emergent adverse events from pooled results of 5 preregistration trials in 2631 patients who received ozanimod for a mean of 32 months, identified no serious opportunistic infections, 37 cases of herpes zoster and 40 of oral herpes; elevations in ALT arose in 5% which were above 3 times the ULN in 3.9%, but with no clear temporal pattern and with no case of severe drug induced liver injury).
• Sandborn WJ, Feagan BG, Hanauer S, Vermeire S, Ghosh S, Liu WJ, Petersen A, et al. Long-term efficacy and safety of ozanimod in moderately to severely active ulcerative colitis: results from the open-label extension of the randomized, phase 2 TOUCHSTONE Study. J Crohns Colitis. 2021;15:1120–9. [PMC free article: PMC8256627] [PubMed: 33438008]

  (Among 170 patients with ulcerative colitis who participated in a placebo controlled trial and were then enrolled in an open-label extension study of ozanimod [1 mg daily], clinical improvements were frequent and usually sustained; ALT elevations arose in 3.5% of subjects, but “no clinically significant elevations in hepatic transaminases and no evidence of serious hepatocellular injury were observed”).
• McGinley MP, Cohen JA. Sphingosine 1-phosphate receptor modulators in multiple sclerosis and other conditions. Lancet 2021 Jun 24: S0140-6736(21)00244-0. Epub ahead of print. [PubMed: 34175020]

  (Review of the function of S1P receptors and the mechanism of action of S1P receptor modulators in affecting lymphocyte tracking out of lymph nodes into the circulation and tissues; fingolimod is a nonspecific modulator affecting all 5 forms of S1P receptors, whereas siponimod and ozanimod act predominantly on S1P receptors 1 and 5 and ponesimod against S1P receptor-1 alone, the activity against S1P receptor-1 accounting for most of the beneficial effects in multiple sclerosis and the restricted specificity perhaps accounting for the lower rate of cardiac, lung and eye adverse events driven mostly by the inhibition of the other S1P receptor subtypes).