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Review Article

The Development of the Combination Drug Leukovir® Tablets for the Treatment of Multiple Sclerosis: A Comprehensive Review

Author(s): Elena N. Kalinichenko* and Svetlana V. Babitskaya

Volume 24, Issue 16, 2023

Published on: 30 November, 2023

Page: [1271 - 1281] Pages: 11

DOI: 10.2174/0113894501272301231124074141

open access plus

Abstract

The review is devoted to the development and study of the drug Leukovir® (cladribine+ ribavirin) and its use in the treatment of relapsing-remitting and secondary progressive forms of multiple sclerosis, a chronic neurodegenerative disease aiming the risk reduction of relapse and progression of a disability. In clinical trials Leukovir® has proved to be efficient by up to 56 weeks for the treatment of relapsing-remitting and secondary progressive forms of multiple sclerosis. The drug is registered in the Republic of Belarus. The efficacy, safety and tolerability profile of the drug Leukovir® suggests that it is well suited for disease-modifying therapy of multiple sclerosis. Patients require four 35-day courses of treatment, each consisting of seven days of treatment followed by a break of 28 days. The use of Leukovir® has contributed to the suppression of inflammatory process activity according to MRI data and stabilization of the clinical condition. It has reduced the number of relapses in patients with relapsing-remitting and secondary-progressive forms of multiple sclerosis.

Keywords: multiple sclerosis, Leukovir®, enteric-coated tablets, cladribine, ribavirin, DMTs, clinical trial.

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[1]
Compston A, Coles A. Multiple sclerosis. Lancet 2008; 372(9648): 1502-17.
[http://dx.doi.org/10.1016/S0140-6736(08)61620-7] [PMID: 18970977]
[2]
Didonna A, Oksenberg JR. The genetics of multiple sclerosis. Multiple Sclerosis: Perspectives in Treatment and Pathogenesis. Ian SZ, McLaughlin PJ. Brisbane (AU): Codon Publications 2017.
[http://dx.doi.org/10.15586/codon.multiplesclerosis.2017.ch1]
[3]
Kim W, Patsopoulos NA. Genetics and functional genomics of multiple sclerosis. Semin Immunopathol 2022; 44(1): 63-79.
[http://dx.doi.org/10.1007/s00281-021-00907-3] [PMID: 35022889]
[4]
McGinley MP, Goldschmidt CH, Rae-Grant AD. Diagnosis and treatment of multiple sclerosis. JAMA 2021; 325(8): 765-79.
[http://dx.doi.org/10.1001/jama.2020.26858] [PMID: 33620411]
[5]
Cree BAC. Multiple sclerosis. In: Brust JCM, Ed. Current Diagnosis and Treatment in Neurology. New York: Lange Medical Books/McGraw-Hill Medical 2007.
[6]
Goldenberg MM. Multiple sclerosis review. P&T 2012; 37(3): 175-84.
[PMID: 22605909]
[7]
Al Johani K, Fudah M, Al-Zahrani M. Multiple sclerosis-a demyelinating disorder and its dental considerations-a literature review with own case report. Brain Sci 2023; 13(7): 1009.
[http://dx.doi.org/10.3390/brainsci13071009]
[8]
Wang Z, Kennedy PGE, Dupree C, et al. Antibodies from multiple sclerosis brain identified epstein-barr virus nuclear antigen 1 & 2 epitopes which are recognized by oligoclonal bands. J Neuroimmune Pharmacol 2021; 16(3): 567-80.
[http://dx.doi.org/10.1007/s11481-020-09948-1] [PMID: 32808238]
[9]
Pachner AR. The neuroimmunology of multiple sclerosis: Fictions and facts. Front Neurol 2022; 12: 796378.
[http://dx.doi.org/10.3389/fneur.2021.796378] [PMID: 35197914]
[10]
Trapp BD, Nave KA. Multiple sclerosis: An immune or neurodegenerative disorder? Annu Rev Neurosci 2008; 31(1): 247-69.
[http://dx.doi.org/10.1146/annurev.neuro.30.051606.094313] [PMID: 18558855]
[11]
Cantó E, Oksenberg JR. Multiple sclerosis genetics. Mult Scler 2018; 24(1): 75-9.
[http://dx.doi.org/10.1177/1352458517737371] [PMID: 29307290]
[12]
Delbue S, Carluccio S, Ferrante P. The long and evolving relationship between viruses and multiple sclerosis. Future Virol 2012; 7(9): 871-83.
[http://dx.doi.org/10.2217/fvl.12.78]
[13]
Oskari Virtanen J, Jacobson S. Viruses and multiple sclerosis. CNS Neurol Disord Drug Targets 2012; 11(5): 528-44.
[http://dx.doi.org/10.2174/187152712801661220] [PMID: 22583435]
[14]
Oikonen M, Laaksonen M, Aalto V, et al. Temporal relationship between environmental influenza A and Epstein–Barr viral infections and high multiple sclerosis relapse occurrence. Mult Scler 2011; 17(6): 672-80.
[http://dx.doi.org/10.1177/1352458510394397] [PMID: 21212088]
[15]
Friedman JE, Zabriskie JB, Plank C, et al. A randomized clinical trial of valacyclovir in multiple sclerosis. Mult Scler 2005; 11(3): 286-95.
[http://dx.doi.org/10.1191/1352458505ms1185oa] [PMID: 15957509]
[16]
Bjornevik K, Münz C, Cohen JI, Ascherio A. Epstein–Barr virus as a leading cause of multiple sclerosis: Mechanisms and implications. Nat Rev Neurol 2023; 19(3): 160-71.
[http://dx.doi.org/10.1038/s41582-023-00775-5] [PMID: 36759741]
[17]
Afrasiabi A, Parnell GP, Fewings N, et al. Evidence from genome wide association studies implicates reduced control of Epstein-Barr virus infection in multiple sclerosis susceptibility. Genome Med 2019; 11(1): 26.
[http://dx.doi.org/10.1186/s13073-019-0640-z] [PMID: 31039804]
[18]
Mentis AFA, Dardiotis E, Grigoriadis N, Petinaki E, Hadjigeorgiou GM. Viruses and endogenous retroviruses in multiple sclerosis: From correlation to causation. Acta Neurol Scand 2017; 136(6): 606-16.
[http://dx.doi.org/10.1111/ane.12775] [PMID: 28542724]
[19]
Sedighi S, Gholizadeh O, Yasamineh S, et al. Comprehensive investigations relationship between viral infections and multiple sclerosis pathogenesis. Curr Microbiol 2023; 80(1): 15.
[http://dx.doi.org/10.1007/s00284-022-03112-z] [PMID: 36459252]
[20]
Kennedy PGE. An overview of viral infections of the nervous system in the immunosuppressed. J Neurol 2021; 268(8): 3026-30.
[http://dx.doi.org/10.1007/s00415-020-10265-z] [PMID: 33048220]
[21]
Vasileiou ES, Fitzgerald KC. Multiple sclerosis pathogenesis and updates in targeted therapeutic approaches. Curr Allergy Asthma Rep 2023; 23(9): 481-96.
[http://dx.doi.org/10.1007/s11882-023-01102-0] [PMID: 37402064]
[22]
Tavazzi E, Rovaris M, La Mantia L. Drug therapy for multiple sclerosis. CMAJ 2014; 186(11): 833-40.
[http://dx.doi.org/10.1503/cmaj.130727] [PMID: 24756629]
[23]
Weinstock-Guttman B, Jacobs LD. What is new in the treatment of multiple sclerosis? Drugs 2000; 59(3): 401-10.
[http://dx.doi.org/10.2165/00003495-200059030-00002] [PMID: 10776827]
[24]
Vargas DL, Tyor WR. Update on disease-modifying therapies for multiple sclerosis. J Investig Med 2017; 65(5): 883-91.
[http://dx.doi.org/10.1136/jim-2016-000339] [PMID: 28130412]
[25]
Oreja-Guevara C, Ramos-Cejudo J, Aroeira LS, Chamorro B, Diez-Tejedor E. TH1/TH2 Cytokine profile in relapsing-remitting multiple sclerosis patients treated with Glatiramer acetate or Natalizumab. BMC Neurol 2012; 12(1): 95.
[http://dx.doi.org/10.1186/1471-2377-12-95] [PMID: 22989378]
[26]
Frohman EM, Shah A, Eggenberger E, Metz L, Zivadinov R, Stüve O. Corticosteroids for multiple sclerosis: I. Application for treating exacerbations. Neurotherapeutics 2007; 4(4): 618-26.
[http://dx.doi.org/10.1016/j.nurt.2007.07.008] [PMID: 17920542]
[27]
Myhr KM, Mellgren SI. Corticosteroids in the treatment of multiple sclerosis. Acta Neurol Scand 2009; 120(189): 73-80.
[http://dx.doi.org/10.1111/j.1600-0404.2009.01213.x] [PMID: 19566504]
[28]
Saied A, Elsaid N, Azab A. Long term effects of corticosteroids in multiple sclerosis in terms of the “no evidence of disease activity” (NEDA) domains. Steroids 2019; 149: 108401.
[http://dx.doi.org/10.1016/j.steroids.2019.04.006] [PMID: 31100292]
[29]
Montalban X, Sastre-Garriga J, Tintoré M, et al. A single-center, randomized, double-blind, placebo-controlled study of interferon beta-1b on primary progressive and transitional multiple sclerosis. Mult Scler 2009; 15(10): 1195-205.
[http://dx.doi.org/10.1177/1352458509106937] [PMID: 19797261]
[30]
Gómez-Figueroa E, Gutierrez-Lanz E, Alvarado-Bolaños A, et al. Cyclophosphamide treatment in active multiple sclerosis. Neurol Sci 2021; 42(9): 3775-80.
[http://dx.doi.org/10.1007/s10072-021-05052-1] [PMID: 33452657]
[31]
Wolinsky JS. Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: A randomized, double-blinded, placebo-controlled clinical trial. Ann Neurol 1990; 27(6): 591-605.
[http://dx.doi.org/10.1002/ana.410270603] [PMID: 2193613]
[32]
Boyko A, Boyko O. Cladribine tablets’ potential role as a key example of selective immune reconstitution therapy in multiple sclerosis. Degener Neurol Neuromuscul Dis 2018; 8: 35-44.
[http://dx.doi.org/10.2147/DNND.S161450] [PMID: 30050387]
[33]
Gholamzad M, Ebtekar M, Ardestani MS, et al. A comprehensive review on the treatment approaches of multiple sclerosis: currently and in the future. Inflamm Res 2019; 68(1): 25-38.
[http://dx.doi.org/10.1007/s00011-018-1185-0] [PMID: 30178100]
[34]
Zhuravleva MV, Davydovskaya MV, Luchinina EV, Shelekhova TV, Kurguzova DO, Serebrova SY. Comparison of the clinical benefits of second-line drugs modifying the course of multiple sclerosis. Zh Nevrol Psikhiatr Im S S Korsakova 2020; 120(8): 148-53.
[http://dx.doi.org/10.17116/jnevro2020120081148] [PMID: 32929938]
[35]
Eriksson I, Komen J, Piehl F, Malmström RE, Wettermark B, von Euler M. The changing multiple sclerosis treatment landscape: Impact of new drugs and treatment recommendations. Eur J Clin Pharmacol 2018; 74(5): 663-70.
[http://dx.doi.org/10.1007/s00228-018-2429-1] [PMID: 29429031]
[36]
Mancinelli CR, De Rossi N, Capra R. Ocrelizumab for the treatment of multiple sclerosis: Safety, efficacy, and pharmacology. Ther Clin Risk Manag 2021; 17: 765-76.
[http://dx.doi.org/10.2147/TCRM.S282390] [PMID: 34354358]
[37]
Platzbecker K, Wentzell N, Kollhorst B, Haug U. Fingolimod, teriflunomide and cladribine for the treatment of multiple sclerosis in women of childbearing age: Description of drug utilization and exposed pregnancies in Germany. Mult Scler Relat Disord 2022; 67: 104184.
[http://dx.doi.org/10.1016/j.msard.2022.104184] [PMID: 36174258]
[38]
Azari H, Karimi E, Shekari M, et al. Construction of a lncRNA–miRNA–mRNA network to determine the key regulators of the Th1/Th2 imbalance in multiple sclerosis. Epigenomics 2021; 13(22): 1797-815.
[http://dx.doi.org/10.2217/epi-2021-0296] [PMID: 34726075]
[39]
Ma X, Ma R, Zhang M, Qian B, Wang B, Yang W. Recent progress in multiple sclerosis treatment using immune cells as targets. Pharmaceutics 2023; 15(3): 728.
[http://dx.doi.org/10.3390/pharmaceutics15030728] [PMID: 36986586]
[40]
Sipe JC. Cladribine for multiple sclerosis: Review and current status. Expert Rev Neurother 2005; 5(6): 721-7.
[http://dx.doi.org/10.1586/14737175.5.6.721] [PMID: 16274330]
[41]
Jacobs BM, Ammoscato F, Giovannoni G, Baker D, Schmierer K. Cladribine: Mechanisms and mysteries in multiple sclerosis. J Neurol Neurosurg Psychiatry 2018; 89(12): 1266-71.
[http://dx.doi.org/10.1136/jnnp-2017-317411] [PMID: 29991490]
[42]
Giovannoni G. Cladribine to treat relapsing forms of multiple sclerosis. Neurotherapeutics 2017; 14(4): 874-87.
[http://dx.doi.org/10.1007/s13311-017-0573-4] [PMID: 29168160]
[43]
Karussis D, Petrou P. Immune reconstitution therapy (IRT) in multiple sclerosis: The rationale. Immunol Res 2018; 66(6): 642-8.
[http://dx.doi.org/10.1007/s12026-018-9032-5] [PMID: 30443887]
[44]
Comi G, Cook S, Giovannoni G, et al. Effect of cladribine tablets on lymphocyte reduction and repopulation dynamics in patients with relapsing multiple sclerosis. Mult Scler Relat Disord 2019; 29: 168-74.
[http://dx.doi.org/10.1016/j.msard.2019.01.038] [PMID: 30885375]
[45]
Cook S, Leist T, Comi G, et al. Safety of cladribine tablets in the treatment of patients with multiple sclerosis: An integrated analysis. Mult Scler Relat Disord 2019; 29: 157-67.
[http://dx.doi.org/10.1016/j.msard.2018.11.021] [PMID: 30885374]
[46]
Rammohan K, Coyle PK, Sylvester E, et al. The development of cladribine tablets for the treatment of multiple sclerosis: A comprehensive review. Drugs 2020; 80(18): 1901-28.
[http://dx.doi.org/10.1007/s40265-020-01422-9] [PMID: 33247831]
[47]
Baker D, Pryce G, Herrod SS, Schmierer K. Potential mechanisms of action related to the efficacy and safety of cladribine. Mult Scler Relat Disord 2019; 30: 176-86.
[http://dx.doi.org/10.1016/j.msard.2019.02.018] [PMID: 30785074]
[48]
Kalinichenko E, Ponteleeva I, Golubeva M. Immunotropic activity of a new cladribine/ribavirin-based composition. Ann Pharmacol Pharm 2020; 5(6): 1196.
[49]
Kalinichenko EN, Kuzmicki BB, Golubeva MB. Immunosuppressive composition. BY Patent 15534, 2012.
[50]
Kalinichenko EN, Ponteleeva IV, Golubeva MB. Pharmacokinetic study and toxicity of leukovir: A new combined drug for the treatment of multiple sclerosis. Adv Biol Chem 2022; 12(1): 1-15.
[http://dx.doi.org/10.4236/abc.2022.121001]
[51]
Azodi S, Jacobson S. Cytokine therapies in neurological disease. Neurotherapeutics 2016; 13(3): 555-61.
[http://dx.doi.org/10.1007/s13311-016-0455-1] [PMID: 27388288]
[52]
Hermann R, Karlsson MO, Novakovic AM, Terranova N, Fluck M, Munafo A. The clinical pharmacology of cladribine tablets for the treatment of relapsing multiple sclerosis. Clin Pharmacokinet 2019; 58(3): 283-97.
[http://dx.doi.org/10.1007/s40262-018-0695-9] [PMID: 29987837]
[53]
Chtioui H, Millius C, Lämmle B, Lauterburg BH. Concomitant treatment with lamivudine renders cladribine inactive by inhibition of its phosphorylation. Br J Haematol 2009; 144(1): 136-7.
[http://dx.doi.org/10.1111/j.1365-2141.2008.07432.x] [PMID: 19016729]
[54]
Laugel B, Borlat F, Galibert L, et al. Cladribine inhibits cytokine secretion by T cells independently of deoxycytidine kinase activity. J Neuroimmunol 2011; 240-241: 52-7.
[http://dx.doi.org/10.1016/j.jneuroim.2011.09.010] [PMID: 22035961]
[55]
Kraus SHP, Luessi F, Trinschek B, et al. Cladribine exerts an immunomodulatory effect on human and murine dendritic cells. Int Immunopharmacol 2014; 18(2): 347-57.
[http://dx.doi.org/10.1016/j.intimp.2013.11.027] [PMID: 24316255]
[56]
Jensen K, Johnson LAA, Jacobson PA, et al. Cytotoxic purine nucleoside analogues bind to A1, A2A, and A3 adenosine receptors. Naunyn Schmiedebergs Arch Pharmacol 2012; 385(5): 519-25.
[http://dx.doi.org/10.1007/s00210-011-0719-6] [PMID: 22249336]
[57]
Novitskiy SV, Ryzhov S, Zaynagetdinov R, et al. Adenosine receptors in regulation of dendritic cell differentiation and function. Blood 2008; 112(5): 1822-31.
[http://dx.doi.org/10.1182/blood-2008-02-136325] [PMID: 18559975]
[58]
Fissolo N, Calvo-Barreiro L, Eixarch H, et al. Immunomodulatory effects associated with cladribine treatment. Cells 2021; 10(12): 3488.
[http://dx.doi.org/10.3390/cells10123488] [PMID: 34943995]
[59]
Likchachev SA, Kalinichenko EN, Nedzved GK, Buniak A. Evaluate the efficacy and safety of leykovir in the treatment of patients with multiple sclerosis. Actual Problems of Neurology and Neurosurgery. Minsk: Peer-Reviewed Collection of Scientific Papers 2014; 17: pp. 5-15.
[60]
Kalinichenko EN, Kuzmitsky BB, Likhachev SA, Zubbritsky SM. Clinical trials of the innovative drug Leikovir for the treatment of multiple sclerosis. International Scientific and Practical Conference "Belarus Medications. At: Minsk, Belarus. 2014.November, 27-28;
[61]
Instruction for the medical use of the drug Leukovir®. Available from: https://www.vidal.by/poisk_preparatov/leukovir.html
[62]
Mikhailopulo IA, Zinchenko AI, Kazimierczuk Z, Barai VN, Bokut SB, Kalinichenko EN. Synthesis of 2-Chloro-2′-Deoxyadenosine by Microbiological Transglycosylation. Nucleosides Nucleotides 1993; 12(3-4): 417-22.
[http://dx.doi.org/10.1080/07328319308017836]
[63]
Barai VN, Zinchenko AI, Eroshevskaya LA, Kalinichenko EN, Kulak TI, Mikhailopulo IA. A universal biocatalyst for the preparation of base- and sugar-modified nucleosides via an enzymatic transglycosylation. Helv Chim Acta 2002; 85(7): 1901.
[http://dx.doi.org/10.1002/1522-2675(200207)85:7<1901::AID-HLCA1901>3.0.CO;2-C]
[64]
Chudinov MV. Ribavirin and its analogs: Сan you teach an old dog new tricks? Fine Chemical Technologies 2019; 14(4): 7-23.
[http://dx.doi.org/10.32362/2410-6593-2019-14-4-7-23]
[65]
Tarasiuk A, Skierski J, Kazimierczuk Z. Stability of 2-chloro-2′-deoxyadenosine at various pH and temperature. Arch Immunol Ther Exp 1994; 42(1): 13-5.
[PMID: 7503627]
[66]
Baranzini SE, Hauser SL. Large-scale gene-expression studies and the challenge of multiple sclerosis. Genome Biol 2002; 3(10): reviews1027.
[67]
Milicevic I, Pekovic S, Subasic S, et al. Ribavirin reduces clinical signs and pathological changes of experimental autoimmune encephalomyelitis in Dark Agouti rats. J Neurosci Res 2003; 72(2): 268-78.
[http://dx.doi.org/10.1002/jnr.10552] [PMID: 12672002]
[68]
Bozic I, Savic D, Jovanovic M, et al. Low-dose ribavirin treatments attenuate neuroinflammatory activation of BV-2 Cells by interfering with inducible nitric oxide synthase. Anal Cell Pathol 2015; 2015: 1-8.
[http://dx.doi.org/10.1155/2015/923614] [PMID: 26413464]
[69]
Kast RE. Ribavirin in cancer immunotherapies: Controlling nitric oxide helps generate cytotoxic lymphocyte. Cancer Biol Ther 2002; 1(6): 626-30.
[http://dx.doi.org/10.4161/cbt.310] [PMID: 12642684]
[70]
Braun-Sand SB, Peetz M. Inosine monophosphate dehydrogenase as a target for antiviral, anticancer, antimicrobial and immunosuppressive therapeutics. Future Med Chem 2010; 2(1): 81-92.
[http://dx.doi.org/10.4155/fmc.09.147] [PMID: 21426047]
[71]
Beaucourt S, Vignuzzi M. Ribavirin: A drug active against many viruses with multiple effects on virus replication and propagation. Molecular basis of ribavirin resistance. Curr Opin Virol 2014; 8: 10-5.
[http://dx.doi.org/10.1016/j.coviro.2014.04.011] [PMID: 24846716]
[72]
Kuzmitsky BB, Golubeva MB, Kalinichenko EN, Zinchenko A. Leukovir - a rational dosage form for multiple sclerosis. Bioregulators: research and application, issue 3: collection of scientific papers. Usanov SA. Minsk: IBOCH NAS of Belarus 2014; pp. 47-60.
[73]
Kalinichenko EN, Likhachev SA, Bunyak AG. Drug Product with a Prolonged Action for the Treatment of Multiple Sclerosis (Options). Patent EurAsEC. 201800465 (BY), 2018.
[74]
Kalinichenko EN, Kuzmitsky BB, Likhachev SA, Zubbritsky SM. Clinical studies of the innovative drug Leucovir for the treatment of multiple sclerosis. All-Russian Scientific and Practical Conference “Topical Issues in Research and Treatment of Multiple Sclerosis. St. Petersburg (RF). 2019.October 04-05, 2019;
[75]
Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 2010; 362(5): 416-26.
[http://dx.doi.org/10.1056/NEJMoa0902533] [PMID: 20089960]
[76]
Zavalishin IA, Peresedova AV, Stoĭda NI, et al. A comparative analysis of rebif 22-mcg and copaxone efficacy in multiple sclerosis. Zh Nevrol Psikhiatr Im S S Korsakova 2006; 3: 111-5.
[PMID: 17172245]
[77]
Arends RJ, Wang D, Buurman M, et al. Comparison of Copaxone® and Synthon’s therapeutically equivalent glatiramer acetate. Pharmazie 2019; 74(8): 449-61.
[PMID: 31526436]
[78]
Flechter S, Vardi J, Pollak L, Rabey JM. Comparison of glatiramer acetate (Copaxone®) and interferon β-1b (Betaferon®) in multiple sclerosis patients: An open-label 2-year follow-up. J Neurol Sci 2002; 197(1-2): 51-5.
[http://dx.doi.org/10.1016/S0022-510X(02)00047-3] [PMID: 11997066]
[79]
SPC. Mavenclad®. 2023. Available from: https://www.ema.europa.eu/en/documents/product-information/mavenclad-epar-product-information_en.pdf
[80]
Giovannoni G, Mathews J. Cladribine tablets for relapsing–remitting multiple sclerosis: A clinician’s review. Neurol Ther 2022; 11(2): 571-95.
[http://dx.doi.org/10.1007/s40120-022-00339-7] [PMID: 35318617]

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