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

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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.

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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.

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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.

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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.

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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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/10.1002/jcph.887] [PMID: 28398597]

Lamb, Y.N. Ozanimod: First Approval. Drugs, 2020, 80(8), 841-848.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/10.1080/14656566.2020.1799977] [PMID: 32808832]

D’Ambrosio, 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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.; D’Ambrosio, 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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.; O’Connor, 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.
[http://dx.doi.org/10.1056/NEJMoa044397] [PMID: 16510744]

Miller, D.H.; Soon, D.; Fernando, K.T.; MacManus, D.G.; Barker, G.J.; Yousry, T.A.; Fisher, E.; O’Connor, 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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/10.3390/ijms160716414] [PMID: 26204829]

Hale, G. The CD52 antigen and development of the CAMPATH antibodies. Cytotherapy, 2001, 3(3), 137-143.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.; O’Connor, 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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
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