Disease Modifying Strategies in Multiple Sclerosis: New Rays of Hope to Combat Disability?

Carlo Bellanca; Egle Augello; Alice Mariottini; Gabriele Bonaventura; Valentina La Cognata; Giulia Di Benedetto; Anna Cantone; Giuseppe Attaguile; Rosaria Di Mauro; Giuseppina Cantarella; Luca Massacesi; Renato Bernardini

doi:10.2174/1570159X22666240124114126

Disease Modifying Strategies in Multiple Sclerosis: New Rays of Hope to Combat Disability?

Authors: Bellanca C.¹, Augello E.², Mariottini A.³, Bonaventura G.⁴, La Cognata V.⁵, Di Benedetto G.², Cantone A.², Attaguile G.², Di Mauro R.², Cantarella G.², Massacesi L.³, Bernardini R.²
Affiliations:
1. epartment of Biomedical and Biotechnological Sciences (BIOMETEC), Section of Pharmacology, University of Catani
2. Department of Biomedical and Biotechnological Sciences (BIOMETEC), Section of Pharmacology, University of Catania
3. Department of Neurosciences Drugs and Child Health, University of Florence
4. Institute for Biomedical Research and Innovation (IRIB, Italian National Research Council
5. Institute for Biomedical Research and Innovation (IRIB), Italian National Research Council
Issue: Vol 22, No 8 (2024)
Pages: 1286-1326
Section: Neurology
URL: https://hum-ecol.ru/1570-159X/article/view/644858
DOI: https://doi.org/10.2174/1570159X22666240124114126
ID: 644858

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Abstract

Multiple sclerosis (MS) is the most prevalent chronic autoimmune inflammatory- demyelinating disorder of the central nervous system (CNS). It usually begins in young adulthood, mainly between the second and fourth decades of life. Usually, the clinical course is characterized by the involvement of multiple CNS functional systems and by different, often overlapping phenotypes. In the last decades, remarkable results have been achieved in the treatment of MS, particularly in the relapsing- remitting (RRMS) form, thus improving the long-term outcome for many patients. As deeper knowledge of MS pathogenesis and respective molecular targets keeps growing, nowadays, several lines of disease-modifying treatments (DMT) are available, an impressive change compared to the relative poverty of options available in the past. Current MS management by DMTs is aimed at reducing relapse frequency, ameliorating symptoms, and preventing clinical disability and progression. Notwithstanding the relevant increase in pharmacological options for the management of RRMS, research is now increasingly pointing to identify new molecules with high efficacy, particularly in progressive forms. Hence, future efforts should be concentrated on achieving a more extensive, if not exhaustive, understanding of the pathogenetic mechanisms underlying this phase of the disease in order to characterize novel molecules for therapeutic intervention. The purpose of this review is to provide a compact overview of the numerous currently approved treatments and future innovative approaches, including neuroprotective treatments as anti-LINGO-1 monoclonal antibody and cell therapies, for effective and safe management of MS, potentially leading to a cure for this disease.

Keywords

Multiple sclerosis, disease-modifying therapies, clinical trials, approved drugs, off-label treatments, future perspective, stem cells.

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EMA Jayempi. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/jayempi
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A study to evaluate the safety, tolerability, and efficacy of BIIB017 (peginterferon beta-1a) in pediatric participants for the treatment of relapsing-remitting multiple sclerosis. NCT03958877, 2014.
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Phase III Randomized. Double-Blind, Placebo-Controlled Study of Copolymer 1 for Relapsing-Remitting Multiple Sclerosis. Available from: https://clinicaltrials.gov/ct2/show/NCT00004814
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EMA Aubagio. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/aubagio
Sanofi a randomized, double-blind, placebo-controlled, parallel group design study to evaluate the efficacy and safety of teriflunomide in reducing the frequency of relapses and delaying the accumulation of physical disability in subjects with multiple sclerosis with relapses; clinicaltrials.gov. NCT01252355, 2013.
OConnor, P.; Wolinsky, J.S.; Confavreux, C.; Comi, G.; Kappos, L.; Olsson, T.P.; Benzerdjeb, H.; Truffinet, P.; Wang, L.; Miller, A.; Freedman, M.S. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N. Engl. J. Med., 2011, 365(14), 1293-1303. doi: 10.1056/NEJMoa1014656 PMID: 21991951
Sanofi a multi-center double-blind parallel-group placebo-controlled study of the efficacy and safety of teriflunomide in patients with relapsing multiple sclerosis; clinicaltrials.gov. NCT01252355, 2016.
Confavreux, C.; OConnor, P.; Comi, G.; Freedman, M.S.; Miller, A.E.; Olsson, T.P.; Wolinsky, J.S.; Bagulho, T.; Delhay, J.L.; Dukovic, D.; Truffinet, P.; Kappos, L. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol., 2014, 13(3), 247-256. doi: 10.1016/S1474-4422(13)70308-9 PMID: 24461574
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Hammer, A.; Waschbisch, A.; Kuhbandner, K.; Bayas, A.; Lee, D.H.; Duscha, A.; Haghikia, A.; Gold, R.; Linker, R.A. The NRF 2 pathway as potential biomarker for dimethyl fumarate treatment in multiple sclerosis. Ann. Clin. Transl. Neurol., 2018, 5(6), 668-676. doi: 10.1002/acn3.553 PMID: 29928650
Havrdova, E.; Hutchinson, M.; Kurukulasuriya, N.C.; Raghupathi, K.; Sweetser, M.T.; Dawson, K.T.; Gold, R. Oral BG-12 (dimethyl fumarate) for relapsing-remitting multiple sclerosis: A review of define and confirm. evaluation of: Gold R, Kappos L, Arnold D, et al. placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012;367:1098-107; and Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012;367:1087-97. Expert Opin. Pharmacother., 2013, 14(15), 2145-2156. doi: 10.1517/14656566.2013.826190 PMID: 23971970
Biogen a randomized, multicenter, double-blind, placebo-controlled, dose-comparison study to determine the efficacy and safety of BG00012 in subjects with relapsing-remitting multiple sclerosis; clinicaltrials.gov. NCT00451451, 2015.
Gold, R.; Kappos, L.; Arnold, D.L.; Bar-Or, A.; Giovannoni, G.; Selmaj, K.; Tornatore, C.; Sweetser, M.T.; Yang, M.; Sheikh, S.I.; Dawson, K.T. Placebocontrolled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N. Engl. J. Med., 2012, 367(12), 1098-1107. doi: 10.1056/NEJMoa1114287 PMID: 22992073
Biogen a randomized, multicenter, placebo-controlled and active reference (Glatiramer Acetate) comparison study to evaluate the efficacy and safety of BG00012 in subjects with relapsing-remitting multiple sclerosis; clinicaltrials.gov. NCT00451451, 2015.
Fox, R.J.; Miller, D.H.; Phillips, J.T.; Hutchinson, M.; Havrdova, E.; Kita, M.; Yang, M.; Raghupathi, K.; Novas, M.; Sweetser, M.T.; Viglietta, V.; Dawson, K.T. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N. Engl. J. Med., 2012, 367(12), 1087-1097. doi: 10.1056/NEJMoa1206328 PMID: 22992072
Aktas, O.; Küry, P.; Kieseier, B.; Hartung, H.P. Fingolimod is a potential novel therapy for multiple sclerosis. Nat. Rev. Neurol., 2010, 6(7), 373-382. doi: 10.1038/nrneurol.2010.76 PMID: 20551946
Brinkmann, V.; Davis, M.D.; Heise, C.E.; Albert, R.; Cottens, S.; Hof, R.; Bruns, C.; Prieschl, E.; Baumruker, T.; Hiestand, P.; Foster, C.A.; Zollinger, M.; Lynch, K.R. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem., 2002, 277(24), 21453-21457. doi: 10.1074/jbc.C200176200 PMID: 11967257
EMA Gilenya Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/gilenya
Novartis a 24-month, double-blind, randomized, multicenter, placebo-controlled, parallel-group study comparing the efficacy and safety of fingolimod 1.25 mg and 0.5 mg administered orally once daily versus placebo in patients with relapsing-remitting multiple sclerosis; clinicaltrials.gov. NCT00731692, 2012.
Novartis a 12-month double-blind, randomized, multicenter, active-controlled, parallel-group study comparing the efficacy and safety of 0.5 mg and 1.25 mg fingolimod (FTY720) administered orally once daily versus interferon ß-1a (avonex) administered im once weekly in patients with relapsing-remitting multiple sclerosis with optional extension phase; clinicaltrials.gov. NCT00670449, 2017.
Kappos, L.; Radue, E.W.; OConnor, P.; Polman, C.; Hohlfeld, R.; Calabresi, P.; Selmaj, K.; Agoropoulou, C.; Leyk, M.; Zhang-Auberson, L.; Burtin, P. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med., 2010, 362(5), 387-401. doi: 10.1056/NEJMoa0909494 PMID: 20089952
Novartis double-blind, randomized, placebo-controlled, parallel-group, multicenter study evaluating the safety,tolerability and effect on MRI lesion parameters of FTY720 vs placebo in patients with relapsing multiple sclerosis including 18 month extension phase. clinicaltrials.gov. 2017.
Kappos, L.; Antel, J.; Comi, G.; Montalban, X.; OConnor, P.; Polman, C.H.; Haas, T.; Korn, A.A.; Karlsson, G.; Radue, E.W. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N. Engl. J. Med., 2006, 355(11), 1124-1140. doi: 10.1056/NEJMoa052643 PMID: 16971719
Gergely, P.; Nuesslein-Hildesheim, B.; Guerini, D.; Brinkmann, V.; Traebert, M.; Bruns, C.; Pan, S.; Gray, N.S.; Hinterding, K.; Cooke, N.G.; Groenewegen, A.; Vitaliti, A.; Sing, T.; Luttringer, O.; Yang, J.; Gardin, A.; Wang, N.; Crumb, W.J., Jr; Saltzman, M.; Rosenberg, M.; Wallström, E. The selective sphingosine 1‐phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species‐specific effects on heart rate. Br. J. Pharmacol., 2012, 167(5), 1035-1047. doi: 10.1111/j.1476-5381.2012.02061.x PMID: 22646698
Chun, J.; Hartung, H.P. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin. Neuropharmacol., 2010, 33(2), 91-101. doi: 10.1097/WNF.0b013e3181cbf825 PMID: 20061941
Tavares, A.; Barret, O.; Alagille, D.; Morley, T.; Papin, C.; Maguire, R.; Briard, E.; Auberson, Y.; Tamagnan, G. Brain distribution of MS565, an imaging analogue of siponimod (BAF312), in nonhuman primates (P1.168). Neurology, 2014, 82.
Brana, C.; Frossard, M.J.; Pescini Gobert, R.; Martinier, N.; Boschert, U.; Seabrook, T.J. Immunohistochemical detection of sphingosine-1-phosphate receptor 1 and 5 in human multiple sclerosis lesions. Neuropathol. Appl. Neurobiol., 2014, 40(5), 564-578. doi: 10.1111/nan.12048 PMID: 23551178
Kappos, L.; Li, D.K.B.; Stüve, O.; Hartung, H.P.; Freedman, M.S.; Hemmer, B.; Rieckmann, P.; Montalban, X.; Ziemssen, T.; Hunter, B.; Arnould, S.; Wallström, E.; Selmaj, K. Safety and efficacy of siponimod (BAF312) in patients with relapsing-remitting multiple sclerosis. JAMA Neurol., 2016, 73(9), 1089-1098. doi: 10.1001/jamaneurol.2016.1451 PMID: 27380540
EMA Mayzent. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/mayzent
Novartis Pharmaceuticals. Novartis pharmaceuticals a dose blinded extension study to the CBAF312A2201 study to evaluate long-term safety, tolerability and efficacy of BAF312 given orally once daily in patients with relapsing-remitting multiple sclerosis; clinicaltrials.gov. NCT00879658, 2018.
Novartis Pharmaceuticals. Novartis pharmaceuticals a multicenter, randomized, double-blind, parallel-group, placebo-controlled variable treatment duration study evaluating the efficacy and safety of siponimod (BAF312) in patients with secondary progressive multiple sclerosis followed by extended treatment with open-label BAF312.; clinicaltrials.gov. NCT01665144, 2022.
Kappos, L.; Bar-Or, A.; Cree, B.A.C.; Fox, R.J.; Giovannoni, G.; Gold, R.; Vermersch, P.; Arnold, D.L.; Arnould, S.; Scherz, T.; Wolf, C.; Wallström, E.; Dahlke, F.; Achiron, A.; Achtnichts, L.; Agan, K.; Akman-Demir, G.; Allen, A.B.; Antel, J.P.; Antiguedad, A.R.; Apperson, M.; Applebee, A.M.; Ayuso, G.I.; Baba, M.; Bajenaru, O.; Balasa, R.; Balci, B.P.; Barnett, M.; Bass, A.; Becker, V.U.; Bejinariu, M.; Bergh, F.T.; Bergmann, A.; Bernitsas, E.; Berthele, A.; Bhan, V.; Bischof, F.; Bjork, R.J.; Blevins, G.; Boehringer, M.; Boerner, T.; Bonek, R.; Bowen, J.D.; Bowling, A.; Boyko, A.N.; Boz, C.; Bracknies, V.; Braune, S.; Brescia Morra, V.; Brochet, B.; Brola, W.; Brownstone, P.K.; Brozman, M.; Brunet, D.; Buraga, I.; Burnett, M.; Buttmann, M.; Butzkueven, H.; Cahill, J.; Calkwood, J.C.; Camu, W.; Cascione, M.; Castelnovo, G.; Centonze, D.; Cerqueira, J.; Chan, A.; Cimprichova, A.; Cohan, S.; Comi, G.; Conway, J.; Cooper, J.A.; Corboy, J.; Correale, J.; Costell, B.; Cottrell, D.A.; Coyle, P.K.; Craner, M.; Cui, L.; Cunha, L.; Czlonkowska, A.; da Silva, A.M.; de Sa, J.; de Seze, J.; Debouverie, M.; Debruyne, J.; Decoo, D.; Defer, G.; Derfuss, T.; Deri, N.H.; Dihenia, B.; Dioszeghy, P.; Donath, V.; Dubois, B.; Duddy, M.; Duquette, P.; Edan, G.; Efendi, H.; Elias, S.; Emrich, P.J.; Estruch, B.C.; Evdoshenko, E.P.; Faiss, J.; Fedyanin, A.S.; Feneberg, W.; Fermont, J.; Fernandez, O.F.; Ferrer, F.C.; Fink, K.; Ford, H.; Ford, C.; Francia, A.; Freedman, M.; Frishberg, B.; Galgani, S.; Garmany, G.P.; Gehring, K.; Gitt, J.; Gobbi, C.; Goldstick, L.P.; Gonzalez, R.A.; Grandmaison, F.; Grigoriadis, N.; Grigorova, O.; Grimaldi, L.M.E.; Gross, J.; Gross-Paju, K.; Gudesblatt, M.; Guillaume, D.; Haas, J.; Hancinova, V.; Hancu, A.; Hardiman, O.; Harmjanz, A.; Heidenreich, F.R.; Hengstman, G.J.D.; Herbert, J.; Herring, M.; Hodgkinson, S.; Hoffmann, O.M.; Hofmann, W.E.; Honeycutt, W.D.; Hua, L.H.; Huang, D.; Huang, Y.; Huang, D.R.; Hupperts, R.; Imre, P.; Jacobs, A.K.; Jakab, G.; Jasinska, E.; Kaida, K.; Kalnina, J.; Kaprelyan, A.; Karelis, G.; Karussis, D.; Katz, A.; Khabirov, F.A.; Khatri, B.; Kimura, T.; Kister, I.; Kizlaitiene, R.; Klimova, E.; Koehler, J.; Komatineni, A.; Kornhuber, A.; Kovacs, K.; Koves, A.; Kozubski, W.; Krastev, G.; Krupp, L.B.; Kurca, E.; Lassek, C.; Laureys, G.; Lee, L.; Lensch, E.; Leutmezer, F.; Li, H.; Linker, R.A.; Linnebank, M.; Liskova, P.; Llanera, C.; Lu, J.; Lutterotti, A.; Lycke, J.; Macdonell, R.; Maciejowski, M.; Maeurer, M.; Magzhanov, R.V.; Maida, E-M.; Malciene, L.; Mao-Draayer, Y.; Marfia, G.A.; Markowitz, C.; Mastorodimos, V.; Matyas, K.; Meca-Lallana, J.; Merino, J.A.G.; Mihetiu, I.G.; Milanov, I.; Miller, A.E.; Millers, A.; Mirabella, M.; Mizuno, M.; Montalban, X.; Montoya, L.; Mori, M.; Mueller, S.; Nakahara, J.; Nakatsuji, Y.; Newsome, S.; Nicholas, R.; Nielsen, A.S.; Nikfekr, E.; Nocentini, U.; Nohara, C.; Nomura, K.; Odinak, M.M.; Olsson, T.; van Oosten, B.W.; Oreja-Guevara, C.; Oschmann, P.; Overell, J.; Pachner, A.; Panczel, G.; Pandolfo, M.; Papeix, C.; Patrucco, L.; Pelletier, J.; Piedrabuena, R.; Pless, M.; Polzer, U.; Pozsegovits, K.; Rastenyte, D.; Rauer, S.; Reifschneider, G.; Rey, R.; Rizvi, S.A.; Robertson, D.; Rodriguez, J.M.; Rog, D.; Roshanisefat, H.; Rowe, V.; Rozsa, C.; Rubin, S.; Rusek, S.; Saccà, F.; Saida, T.; Salgado, A.V.; Sanchez, V.E.F.; Sanders, K.; Satori, M.; Sazonov, D.V.; Scarpini, E.A.; Schlegel, E.; Schluep, M.; Schmidt, S.; Scholz, E.; Schrijver, H.M.; Schwab, M.; Schwartz, R.; Scott, J.; Selmaj, K.; Shafer, S.; Sharrack, B.; Shchukin, I.A.; Shimizu, Y.; Shotekov, P.; Siever, A.; Sigel, K-O.; Silliman, S.; Simo, M.; Simu, M.; Sinay, V.; Siquier, A.E.; Siva, A.; Skoda, O.; Solomon, A.; Stangel, M.; Stefoski, D.; Steingo, B.; Stolyarov, I.D.; Stourac, P.; Strassburger-Krogias, K.; Strauss, E.; Stuve, O.; Tarnev, I.; Tavernarakis, A.; Tello, C.R.; Terzi, M.; Ticha, V.; Ticmeanu, M.; Tiel-Wilck, K.; Toomsoo, T.; Tubridy, N.; Tullman, M.J.; Tumani, H.; Turcani, P.; Turner, B.; Uccelli, A.; Urtaza, F.J.O.; Vachova, M.; Valikovics, A.; Walter, S.; Van Wijmeersch, B.; Vanopdenbosch, L.; Weber, J.R.; Weiss, S.; Weissert, R.; Vermersch, P.; West, T.; Wiendl, H.; Wiertlewski, S.; Wildemann, B.; Willekens, B.; Visser, L.H.; Vorobeychik, G.; Xu, X.; Yamamura, T.; Yang, Y.N.; Yelamos, S.M.; Yeung, M.; Zacharias, A.; Zelkowitz, M.; Zettl, U.; Zhang, M.; Zhou, H.; Zieman, U.; Ziemssen, T. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): A double-blind, randomised, phase 3 study. Lancet, 2018, 391(10127), 1263-1273. doi: 10.1016/S0140-6736(18)30475-6 PMID: 29576505
Lassiter, G.; Melancon, C.; Rooney, T.; Murat, A.M.; Kaye, J.S.; Kaye, A.M.; Kaye, R.J.; Cornett, E.M.; Kaye, A.D.; Shah, R.J.; Viswanath, O.; Urits, I. Ozanimod to treat relapsing forms of multiple sclerosis: A comprehensive review of disease, drug efficacy and side effects. Neurol. Int., 2020, 12(3), 89-108. doi: 10.3390/neurolint12030016 PMID: 33287177
Scott, F.L.; Clemons, B.; Brooks, J.; Brahmachary, E.; Powell, R.; Dedman, H.; Desale, H.G.; Timony, G.A.; Martinborough, E.; Rosen, H.; Roberts, E.; Boehm, M.F.; Peach, R.J. Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity. Br. J. Pharmacol., 2016, 173(11), 1778-1792. doi: 10.1111/bph.13476 PMID: 26990079
Tran, J.Q.; Hartung, J.P.; Peach, R.J.; Boehm, M.F.; Rosen, H.; Smith, H.; Brooks, J.L.; Timony, G.A.; Olson, A.D.; Gujrathi, S.; Frohna, P.A. Results from the firstinhuman study with ozanimod, a Novel, selective sphingosine-1-phosphate receptor modulator. J. Clin. Pharmacol., 2017, 57(8), 988-996. doi: 10.1002/jcph.887 PMID: 28398597
Lamb, Y.N. Ozanimod: First Approval. Drugs, 2020, 80(8), 841-848. doi: 10.1007/s40265-020-01319-7 PMID: 32385738
EMA Zeposia. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/zeposia
Celgene a phase 2/3, multi-center, randomized, double-blind, placebo-controlled (Part A) and double-blind, double-dummy, active-controlled (Part B), parallel group study to evaluate the efficacy and safety of RPC1063 administered orally to relapsing multiple sclerosis patients; clinicaltrials.gov. 2021.
Celgene a phase 3, multi-center, randomized, double-blind, double-dummy, active controlled, parallel group study to evaluate the efficacy and safety of RPC1063 administered orally to relapsing multiple sclerosis patients; clinicaltrials.gov. NCT01628393, 2020.
Cohen, J.A.; Comi, G.; Selmaj, K.W.; Bar-Or, A.; Arnold, D.L.; Steinman, L.; Hartung, H.P.; Montalban, X.; Kubala Havrdová, E.; Cree, B.A.C.; Sheffield, J.K.; Minton, N.; Raghupathi, K.; Huang, V.; Kappos, L. Safety and efficacy of ozanimod versus interferon beta1a in relapsing multiple sclerosis (RADIANCE): A multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol., 2019, 18(11), 1021-1033. doi: 10.1016/S1474-4422(19)30238-8 PMID: 31492652
Cohen, J.A.; Comi, G.; Arnold, D.L.; Bar-Or, A.; Selmaj, K.W.; Steinman, L.; Havrdová, E.K.; Cree, B.A.C.; Montalbán, X.; Hartung, H.P.; Huang, V.; Frohna, P.; Skolnick, B.E.; Kappos, L. Efficacy and safety of ozanimod in multiple sclerosis: Dose-blinded extension of a randomized phase II study. Mult. Scler., 2019, 25(9), 1255-1262. doi: 10.1177/1352458518789884 PMID: 30043658
Comi, G.; Kappos, L.; Selmaj, K.W.; Bar-Or, A.; Arnold, D.L.; Steinman, L.; Hartung, H.P.; Montalban, X.; Kubala Havrdová, E.; Cree, B.A.C.; Sheffield, J.K.; Minton, N.; Raghupathi, K.; Ding, N.; Cohen, J.A. 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(11), 1009-1020. doi: 10.1016/S1474-4422(19)30239-X PMID: 31492651
Baldin, E.; Lugaresi, A. Ponesimod for the treatment of relapsing multiple sclerosis. Expert Opin. Pharmacother., 2020, 21(16), 1955-1964. doi: 10.1080/14656566.2020.1799977 PMID: 32808832
DAmbrosio, D.; Steinmann, J.; Brossard, P.; Dingemanse, J. Differential effects of ponesimod, a selective S1P 1 receptor modulator, on blood-circulating human T cell subpopulations. Immunopharmacol. Immunotoxicol., 2015, 37(1), 103-109. doi: 10.3109/08923973.2014.993084 PMID: 25519470
EMA Ponvory. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/ponvory
Markham, A. Ponesimod: First approval. Drugs, 2021, 81(8), 957-962. doi: 10.1007/s40265-021-01523-z PMID: 33939119
Olsson, T.; Boster, A.; Fernández, O.; Freedman, M.S.; Pozzilli, C.; Bach, D.; Berkani, O.; Mueller, M.S.; Sidorenko, T.; Radue, E.W.; Melanson, M. Oral ponesimod in relapsingremitting multiple sclerosis: A randomised phase II trial. J. Neurol. Neurosurg. Psychiatry., 2014, 85(11), 1198-1208. doi: 10.1136/jnnp-2013-307282 PMID: 24659797
Actelion multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study to evaluate the efficacy, safety, and tolerability of three doses of ACT-128800, an oral s1p1 receptor agonist, administered for twenty-four weeks in patients with relapsing-remitting multiple sclerosis; clinicaltrials.gov. NCT01006265, 2022.
Kappos, L.; Fox, R.J.; Burcklen, M.; Freedman, M.S.; Havrdová, E.K.; Hennessy, B.; Hohlfeld, R.; Lublin, F.; Montalban, X.; Pozzilli, C.; Scherz, T.; DAmbrosio, D.; Linscheid, P.; Vaclavkova, A.; Pirozek-Lawniczek, M.; Kracker, H.; Sprenger, T. Ponesimod compared with teriflunomide in patients with relapsing multiple sclerosis in the active-comparator phase 3 optimum study. JAMA Neurol., 2021, 78(5), 558-567. doi: 10.1001/jamaneurol.2021.0405 PMID: 33779698
Actelion multicenter, randomized, double-blind, parallel-group, active-controlled, superiority study to compare the efficacy and safety of ponesimod to teriflunomide in subjects with relapsing multiple sclerosis; clinicaltrials.gov. NCT02425644, 2023.
Stüve, O.; Bennett, J.L. Pharmacological properties, toxicology and scientific rationale for the use of natalizumab (Tysabri) in inflammatory diseases. CNS Drug Rev., 2007, 13(1), 79-95. doi: 10.1111/j.1527-3458.2007.00003.x PMID: 17461891
Sheremata, W.A.; Minagar, A.; Alexander, J.S.; Vollmer, T. The role of alpha-4 integrin in the aetiology of multiple sclerosis: Current knowledge and therapeutic implications. CNS Drugs, 2005, 19(11), 909-922. doi: 10.2165/00023210-200519110-00002 PMID: 16268663
Biogen a randomized, double-blind, placebo-controlled, parallel-group, multicenter study to determine the safety and efficacy of natalizumab in subjects with relapsing-remitting multiple sclerosis; clinicaltrials.gov. NCT01440101, 2017.
Polman, C.H.; OConnor, P.W.; Havrdova, E.; Hutchinson, M.; Kappos, L.; Miller, D.H.; Phillips, J.T.; Lublin, F.D.; Giovannoni, G.; Wajgt, A.; Toal, M.; Lynn, F.; Panzara, M.A.; Sandrock, A.W. A randomized, placebocontrolled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med., 2006, 354(9), 899-910. doi: 10.1056/NEJMoa044397 PMID: 16510744
Miller, D.H.; Soon, D.; Fernando, K.T.; MacManus, D.G.; Barker, G.J.; Yousry, T.A.; Fisher, E.; OConnor, P.W.; Phillips, J.T.; Polman, C.H.; Kappos, L.; Hutchinson, M.; Havrdova, E.; Lublin, F.D.; Giovannoni, G.; Wajgt, A.; Rudick, R.; Lynn, F.; Panzara, M.A.; Sandrock, A.W. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology, 2007, 68(17), 1390-1401. doi: 10.1212/01.wnl.0000260064.77700.fd PMID: 17452584
Biogen a randomized, double-blind, placebo-controlled, parallel-group, multicenter study to determine the safety and efficacy of natalizumab, when added to avonex® (Interferon Beta-1a), in subjects with relapsing-remitting multiple sclerosis; clinicaltrials.gov. NCT00030966, 2009.
Rudick, R.A.; Stuart, W.H.; Calabresi, P.A.; Confavreux, C.; Galetta, S.L.; Radue, E.W.; Lublin, F.D.; Weinstock-Guttman, B.; Wynn, D.R.; Lynn, F.; Panzara, M.A.; Sandrock, A.W. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N. Engl. J. Med., 2006, 354(9), 911-923. doi: 10.1056/NEJMoa044396 PMID: 16510745
EMA Tysabri Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/tysabri
Clerico, M.; Artusi, C.A.; Di Liberto, A.; Rolla, S.; Bardina, V.; Barbero, P.; De Mercanti, S.F.; Durelli, L. Long-term safety evaluation of natalizumab for the treatment of multiple sclerosis. Expert Opin. Drug Saf., 2017, 16(8), 963-972. doi: 10.1080/14740338.2017.1346082 PMID: 28641055
Major, E.O.; Yousry, T.A.; Clifford, D.B. Pathogenesis of progressive multifocal leukoencephalopathy and risks associated with treatments for multiple sclerosis: A decade of lessons learned. Lancet Neurol., 2018, 17(5), 467-480. doi: 10.1016/S1474-4422(18)30040-1 PMID: 29656742
Ruck, T.; Bittner, S.; Wiendl, H.; Meuth, S. Alemtuzumab in multiple sclerosis: Mechanism of action and beyond. Int. J. Mol. Sci., 2015, 16(7), 16414-16439. doi: 10.3390/ijms160716414 PMID: 26204829
Hale, G. The CD52 antigen and development of the CAMPATH antibodies. Cytotherapy, 2001, 3(3), 137-143. doi: 10.1080/146532401753174098 PMID: 12171721
Ginaldi, L.; De Martinis, M.; Matutes, E.; Farahat, N.; Morilla, R.; Dyer, M.J.S.; Catovsky, D. Levels of expression of CD52 in normal and leukemic B and T cells : Correlation with in vivo therapeutic responses to Campath-1H. Leuk. Res., 1998, 22(2), 185-191. doi: 10.1016/S0145-2126(97)00158-6 PMID: 9593475
Gribben, J.G.; Hallek, M. Rediscovering alemtuzumab: Current and emerging therapeutic roles. Br. J. Haematol., 2009, 144(6), 818-831. doi: 10.1111/j.1365-2141.2008.07557.x PMID: 19183194
Alireza, M.; J Steven, A.; Mohammad Ali, S.; Robert, Z. Alemtuzumab and multiple sclerosis: Therapeutic application. Expert Opin. Biol. Ther., 2010, 10(3), 421-429. doi: 10.1517/14712591003586806 PMID: 20095876
Watanabe, T.; Masuyama, J.; Sohma, Y.; Inazawa, H.; Horie, K.; Kojima, K.; Uemura, Y.; Aoki, Y.; Kaga, S.; Minota, S.; Tanaka, T.; Yamaguchi, Y.; Kobayashi, T.; Serizawa, I. CD52 is a novel costimulatory molecule for induction of CD4+ regulatory T cells. Clin. Immunol., 2006, 120(3), 247-259. doi: 10.1016/j.clim.2006.05.006 PMID: 16797237
Rao, S.P.; Sancho, J.; Campos-Rivera, J.; Boutin, P.M.; Severy, P.B.; Weeden, T.; Shankara, S.; Roberts, B.L.; Kaplan, J.M. Human peripheral blood mononuclear cells exhibit heterogeneous CD52 expression levels and show differential sensitivity to alemtuzumab mediated cytolysis. PLoS One, 2012, 7(6), e39416. doi: 10.1371/journal.pone.0039416 PMID: 22761788
EMA Lemtrada Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/lemtrada
Genzyme, a sanofi company a phase II, randomized, open-label, three-arm study comparing low- and high-dose alemtuzumab and high-dose subcutaneous interferon beta-1a (Rebif®) in patients with early, active relapsing-remitting multiple sclerosis; clinicaltrials.go. NCT00050778, 2015.
CAMMS223 Trial Investigators. Alemtuzumab vs. Interferon Beta-1a in early multiple sclerosis. N. Engl. J. Med., 2008, 359(17), 1786-1801. doi: 10.1056/NEJMoa0802670
Coles, A.J.; Fox, E.; Vladic, A.; Gazda, S.K.; Brinar, V.; Selmaj, K.W.; Skoromets, A.; Stolyarov, I.; Bass, A.; Sullivan, H.; Margolin, D.H.; Lake, S.L.; Moran, S.; Palmer, J.; Smith, M.S.; Compston, D.A.S. Alemtuzumab more effective than interferon -1a at 5-year follow-up of CAMMS223 clinical Trial. Neurology, 2012, 78(14), 1069-1078. doi: 10.1212/WNL.0b013e31824e8ee7 PMID: 22442431
Genzyme, a sanofi company a phase 3 randomized, rater-blinded study comparing two annual cycles of intravenous alemtuzumab to three-times weekly subcutaneous interferon Beta-1a (Rebif®) in treatment-naïve patients with relapsing-remitting multiple sclerosis; clinicaltrials.gov. NCT00530348, 2014.
Genzyme, a sanofi company a phase 3, randomized, rater- and dose-blinded study comparing two annual cycles of intravenous low- and high-dose alemtuzumab to three-times weekly subcutaneous interferon beta 1a (Rebif®) in patients with relapsing remitting multiple sclerosis who have relapsed on therapy; clinicaltrials.gov. NCT00548405, 2017.
Cohen, J.A.; Coles, A.J.; Arnold, D.L.; Confavreux, C.; Fox, E.J.; Hartung, H.P.; Havrdova, E.; Selmaj, K.W.; Weiner, H.L.; Fisher, E.; Brinar, V.V.; Giovannoni, G.; Stojanovic, M.; Ertik, B.I.; Lake, S.L.; Margolin, D.H.; Panzara, M.A.; Compston, D.A.S. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: A randomised controlled phase 3 trial. Lancet, 2012, 380(9856), 1819-1828. doi: 10.1016/S0140-6736(12)61769-3 PMID: 23122652
Coles, A.J.; Twyman, C.L.; Arnold, D.L.; Cohen, J.A.; Confavreux, C.; Fox, E.J.; Hartung, H.P.; Havrdova, E.; Selmaj, K.W.; Weiner, H.L.; Miller, T.; Fisher, E.; Sandbrink, R.; Lake, S.L.; Margolin, D.H.; Oyuela, P.; Panzara, M.A.; Compston, D.A.S. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: A randomised controlled phase 3 trial. Lancet, 2012, 380(9856), 1829-1839. doi: 10.1016/S0140-6736(12)61768-1 PMID: 23122650
EMA MabThera. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/mabthera
Genentech, Inc.. Genentech, inc. a phase ii, randomized, double-blind, parallel-group, placebo-controlled, multicenter study to evaluate the safety and efficacy of rituximab (Mabthera/Rituxan) in adults with relapsing remitting multiple sclerosis; clinicaltrials.gov. NCT00097188, 2014.
Hauser, S.L.; Waubant, E.; Arnold, D.L.; Vollmer, T.; Antel, J.; Fox, R.J.; Bar-Or, A.; Panzara, M.; Sarkar, N.; Agarwal, S.; Langer-Gould, A.; Smith, C.H. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med., 2008, 358(7), 676-688. doi: 10.1056/NEJMoa0706383 PMID: 18272891
A Study to Evaluate the Safety and Efficacy of Rituximab in Adults With Primary Progressive Multiple Sclerosis (OLYMPUS), Available at: https://clinicaltrials.gov/study/NCT00087529
Hawker, K.; OConnor, P.; Freedman, M.S.; Calabresi, P.A.; Antel, J.; Simon, J.; Hauser, S.; Waubant, E.; Vollmer, T.; Panitch, H.; Zhang, J.; Chin, P.; Smith, C.H. Rituximab in patients with primary progressive multiple sclerosis: Results of a randomized double-blind placebo-controlled multicenter trial. Ann. Neurol., 2009, 66(4), 460-471. doi: 10.1002/ana.21867 PMID: 19847908
Sorensen, P.S.; Blinkenberg, M. The potential role for ocrelizumab in the treatment of multiple sclerosis: Current evidence and future prospects. Ther. Adv. Neurol. Disord., 2016, 9(1), 44-52. doi: 10.1177/1756285615601933 PMID: 26788130
Genovese, M.C.; Kaine, J.L.; Lowenstein, M.B.; Giudice, J.D.; Baldassare, A.; Schechtman, J.; Fudman, E.; Kohen, M.; Gujrathi, S.; Trapp, R.G.; Sweiss, N.J.; Spaniolo, G.; Dummer, W. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: A phase I/II randomized, blinded, placebo-controlled, dose-ranging study. Arthritis Rheum., 2008, 58(9), 2652-2661. doi: 10.1002/art.23732 PMID: 18759293
Kausar, F.; Mustafa, K.; Sweis, G.; Sawaqed, R.; Alawneh, K.; Salloum, R.; Badaracco, M.; Niewold, T.B.; Sweiss, N.J. Ocrelizumab: A step forward in the evolution of B-cell therapy. Expert Opin. Biol. Ther., 2009, 9(7), 889-895. doi: 10.1517/14712590903018837 PMID: 19463076
Morschhauser, F.; Marlton, P.; Vitolo, U.; Lindén, O.; Seymour, J.F.; Crump, M.; Coiffier, B.; Foà, R.; Wassner, E.; Burger, H.U.; Brennan, B.; Mendila, M. Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/refractory follicular lymphoma. Ann. Oncol., 2010, 21(9), 1870-1876. doi: 10.1093/annonc/mdq027 PMID: 20157180
Li, R.; Patterson, K.R.; Bar-Or, A.; Reassessing, B. Reassessing B cell contributions in multiple sclerosis. Nat. Immunol., 2018, 19(7), 696-707. doi: 10.1038/s41590-018-0135-x PMID: 29925992
Sabatino, J.J., Jr; Pröbstel, A.K.; Zamvil, S.S. B cells in autoimmune and neurodegenerative central nervous system diseases. Nat. Rev. Neurosci., 2019, 20(12), 728-745. doi: 10.1038/s41583-019-0233-2 PMID: 31712781
Hoffmann-La Roche. Hoffmann-la roche a randomized, double-blind, double-dummy, parallel-group study to evaluate the efficacy and safety of ocrelizumab in comparison to interferon beta-1a (Rebif®) in patients with relapsing multiple sclerosis; clinicaltrials.gov. NCT01412333, 2022.
Hoffmann-La Roche. A Randomized, double-blind, double-dummy, parallel-group study to evaluate the efficacy and safety of ocrelizumab in comparison to interferon beta-1a (Rebif) in patients with relapsing multiple sclerosis; clinicaltrials.gov NCT01412333, 2022.
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Disease Modifying Strategies in Multiple Sclerosis: New Rays of Hope to Combat Disability?

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