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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Siponimod

Last Update: January 13, 2020.

OVERVIEW

Introduction

Siponimod is an orally available immunomodulatory drug used to treat relapsing forms of multiple sclerosis. Siponimod is associated with transient serum enzyme elevations during therapy but has not been linked to instances of clinically apparent liver injury with jaundice, although experience with its use has been limited.

Background

Siponimod (si pon’ i mod) is an immunomodulatory agent used in the treatment of multiple sclerosis that is believed to act by modulating sphingosine-1-phosphate (S1P) receptors. Siponimod is a derivative of myriocin, a metabolite of the fungus Isaria sinclairii and is a structural analogue of sphingosine. Related in structure to fingolimod, the first S1P receptor inhibitor approved for use in multiple sclerosis, siponimod appears to have greater selectivity of S1P receptors 1 and 5, and thus might have equivalent potency but fewer off-target side effects. Once phosphorylated intracellularly, siponimod acts as a S1P receptor antagonist which renders T and B cells insensitive to signals necessary for egress from lymphoid tissue. In animal models of multiple sclerosis, siponimod resulted in reduced recirculation of autoaggressive lymphocytes to the central nervous system. Subsequently, in several large, randomized controlled trials, siponimod was shown to reduce relapse rates and improve neuro-radiologic outcomes in adult patients with relapsing multiple sclerosis. Siponimod was approved for use in the United States in 2019 and is available in tablets of 0.25 and 2 mg under the brand name Mayzent. The recommended maintenance dose in adults is 2 mg orally once daily. Common side effects are lymphopenia, headache, diarrhea, cough, rhinorrhea and back and abdominal pain. Rare, but potentially severe adverse events include severe viral, bacterial or fungal infections, atrial arrhythmias and bradycardia, macular edema, decrease in pulmonary function, progressive multifocal leukoencephalopathy (PML), and embryonal-fetal toxicity.

Hepatotoxicity

In large controlled trials of siponimod in patients with multiple sclerosis, serum ALT elevations were common, typically arising during the first 3 months and persisting throughout the treatment period. The elevations were generally mild and asymptomatic, and they returned to baseline values within 3 months of stopping. Aminotransferase elevations above 3 times upper limit of normal (ULN) were reported in 6% to 8% of siponimod recipients compared to less than 2% of placebo recipients. In these prelicensure clinical trials, there were no cases of acute hepatitis or clinically apparent liver injury but elevations in liver tests led to discontinuation in 1% if subjects. Thus, mild-to-moderate and transient serum enzyme elevations during therapy are not uncommon, but clinically apparent liver injury with jaundice due to siponimod has not been reported, although the clinical experience with its use has been limited.

Likelihood score: E* (suspected but unproven cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which siponimod might cause liver injury is not known. It is extensively metabolized by liver via the cytochrome P450 system, predominantly CYP 2C9 and 3A4 and drug-drug interactions with agents that induce or inhibit these enzymes are likely to occur.

Outcome and Management

While chronic therapy with siponimod can be associated with mild-to-moderate serum aminotransferase elevations, it has not been linked to any cases of clinically apparent liver injury. Because of the frequency of enzyme elevations detected during therapy, the product label for siponimod recommends obtaining baseline liver tests before initiation of treatment. However, no specific recommendations for monitoring liver tests during treatment have been made. There is no known cross sensitivity of the hepatic injury from siponimod with other agents used to treat multiple sclerosis. Because of the similarity in chemical structure and mechanism of action, there may be cross sensitivity to side effects with fingolimod.

Drug Class: Multiple Sclerosis Agents

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Siponimod – Mayzent®

DRUG CLASS

Multiple Sclerosis Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NOMOLECULAR FORMULASTRUCTURE
Siponimod1230487-00-9C29-H35-F3-N2-O3image 172113595 in the ncbi pubchem database

ANNOTATED BIBLIOGRAPHY

References updated: 13 January 2020

  • 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 siponimod).
  • 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: Center for Drug Evaluation and Research. 209884Orig1s000. Clinical Review(s). pp: 166-73.
  • https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000MedR.pdf.
    (FDA website with product labels and medical review of the efficacy and safety of siponimod; mentions that serum aminotransferase elevations are common during siponimod therapy occurring in almost half of patients but are typically mild and resolve rapidly with stopping and that serious hepatotoxicity was not encountered; ALT elevations above 3 times the ULN occurred in 6-8% of subjects).
  • 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).
  • Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, Pelletier J, et al. TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402–15. [PubMed: 20089954]
    (Among 1280 patients with relapsing multiple sclerosis treated with fingolimod [0.5 or 1.25 mg daily] or interferon beta [30 mg weekly] for 12 months, relapse rates were lower, but ALT elevations above 3 times ULN were more common with fingolimod [7% and 8%] than interferon beta [2%], although there were no clinically apparent episodes of liver injury).
  • 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).
  • New drugs for relapsing multiple sclerosis. Med Lett Drugs Ther. 2012;54(1403):89–91. [PubMed: 23183318]
    (Concise review of efficacy, safety and costs of new disease modifying drugs for multiple sclerosis lists side effects in a table including "transaminase elevations" for interferon beta, fingolimod and teriflunomide and "hepatotoxicity" for natalizumab, but not for glatiramer or mitoxantrone).
  • Oh J, O'Connor PW. Safety, Tolerability, and Efficacy of Oral Therapies for Relapsing-Remitting Multiple Sclerosis. CNS Drugs. 2013;27:591–609. [PubMed: 23801528]
    (Review of efficacy and safety or oral agents for multiple sclerosis, including fingolimod, teriflunomide, dimethyl fumarate, laquinimod and cladribine, none of which have raised major issues of hepatotoxicity).
  • Kappos L. Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial. Neurology. 2015;84:1582–91. O.Connor P, Radue E-W, Polman C, Hohlfeld R, Selmaj K, Ritter S, et al. [PMC free article: PMC4408283] [PubMed: 25795646]
    (Among 920 patients with multiple sclerosis enrolled in an extension study of fingolimod [0.5 vs 1.25 mg daily], beneficial effects were sustained and no new safety concerns arose, serum enzyme elevations occurring in 13% and 19% of subjects during the first and 7% and 8% during the second year of fingolimod therapy).
  • Selmaj K, Li DK, Hartung HP, Hemmer B, Kappos L, Freedman MS, Stüve O, et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol. 2013;12:756–67. [PubMed: 23764350]
    (Among 297 patients with relapsing multiple sclerosis treated with siponimod [0.25, 0.50,1.25, 2 or 10 mg] or placebo once daily for 6 months, there was a dose related increase in clinical responses and higher rates of adverse events including ALT elevations [0% to 6-8%], but levels were rarely above 3 times ULN and there were no hepatic serious adverse events).
  • English C, Aloi JJ. New FDA-approved disease-modifying therapies for multiple sclerosis. Clin Ther. 2015;37:691–715. [PubMed: 25846320]
    (Systematic review of efficacy and safety of the newer disease modifying therapies of multiple sclerosis lists ALT elevations as adverse events associated with fingolimod, teriflunomide and dimethyl fumarate, but not peginterferon beta or alemtuzumab).
  • Kappos L, Li DK, Stüve O, Hartung HP, Freedman MS, Hemmer B, Rieckmann P, et al. Safety and Efficacy of siponimod (BAF312) in patients with relapsing-remitting multiple sclerosis: dose-blinded, randomized extension of the phase 2 BOLD study. JAMA Neurol. 2016;73:1089–98. [PubMed: 27380540]
    (Among 252 patients with relapsing multiple sclerosis continued in an extension of a phase 2 study of siponimod [Selmaj 2013], there was a dose related increase in ALT elevations [2% to 17%] but there were no hepatic serious adverse events).
  • Hammond ER. Perspectives on safety and efficacy-the BOLD phase 2 extension study of siponimod in relapsing-remitting multiple sclerosis. JAMA Neurol. 2016;73:1052–4. [PubMed: 27380179]
    (Editorial in response to the analyses of efficacy and safety of siponimod in an extension study [Kappos 2016]).
  • Shakeri-Nejad K, Aslanis V, Veldandi UK, Gardin A, Zaehringer A, Dodman A, Su Z, et al. Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with different levels of hepatic impairment: a single-dose, open-label, parallel-group study. Int J Clin Pharmacol Ther. 2017;55:41–53. [PubMed: 27443658]
    (Single dose studies of siponimod done in 40 subjects found little difference in pharmacokinetics among patients with or without hepatic impairment).
  • Kappos L, Bar-Or A, Cree BAC, Fox RJ, Giovannoni G, Gold R, Vermersch P, et al. EXPAND Clinical Investigators. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391(10127):1263–73. [PubMed: 29576505]
    (Among 1645 patients with secondary progressive multiple sclerosis enrolled in a controlled trial for up to 3 years, disability progression was less frequent with siponimod than placebo [26% vs 32%] but liver related “investigations” were more common [12% vs 4%], although none resulted in clinically apparent liver injury with jaundice ).
  • Jin Y, Borell H, Gardin A, Ufer M, Huth F, Camenisch G. In vitro studies and in silico predictions of fluconazole and CYP2C9 genetic polymorphism impact on siponimod metabolism and pharmacokinetics. Eur J Clin Pharmacol. 2018;74:455–64. [PMC free article: PMC5849655] [PubMed: 29273968]
    (In vitro metabolic studies using human liver microsomes demonstrated possible functional consequences of CYP2C9*2/*2 and CYP2C9*3/*3 polymorphisms on the metabolism of siponimod which predict significant reductions in clearance and possible drug accumulation to toxic levels).
  • 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).

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