New treatment perspectives in multiple sclerosis Review article
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Published:
Dec 31, 2021
Keywords:
multiple sclerosis, treatment, clinical trials
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Abstract
Despite progress in the treatment of multiple sclerosis in the last 30 years, therapy of this disease, particularly its progressive subtypes, remains unsatisfactory. In this article, the authors analyzed the Clinical- Trials.gov database in terms of ongoing or completed phase III clinical trials in different multiple sclerosis subtypes. Selected drugs currently in phase II clinical trials were also briefly discussed. The article focused on clinical trials assessing the efficacy and safety of new preparations, such as Bruton’s tyrosine kinase inhibitors, masitinib, or ibudilast. The results of studies with molecules using already known mechanisms of action in this disease as well as with drugs used so far in indications other than multiple sclerosis were also presented. The preliminary results of studies on remyelinating agents in multiple sclerosis, were also discussed.
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References
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2. Wnuk M, Maluchnik M, Perwieniec J et al. Multiple sclerosis incidence and prevalence in Poland: Data from administrative health claims. Mult Scler Relat Disord. 2021; 55: 103162.
3. De Angelis F, John NA, Brownlee WJ. Disease-modifying therapies for multiple sclerosis. BMJ. 2018; 363: k4674.
4. Cao L, Li M, Yao L et al. Siponimod for multiple sclerosis. Cochrane Database Syst Rev. 2021; 11: CD013647.
5. Hartung H-P, Gonsette R, Konig N et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002; 360: 2018-25.
6. Wawrzyniak S, Rzepiński Ł. Is there a new place for mitoxantrone in the treatment of multiple sclerosis? Neurol Neurochir Pol. 2020; 54: 54-61.
7. Piehl F. Current and emerging disease-modulatory therapies and treatment targets for multiple sclerosis. J Intern Med. 2021; 289: 771-91.
8. García-Merino A. Bruton’s tyrosine kinase inhibitors: A new generation of promising agents for multiple sclerosis therapy. Cells. 2021; 10: 2560.
9. Mohamed AJ, Yu L, Bäckesjö C-M et al. Bruton’s tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev. 2009; 228: 58-73.
10. Reich DS, Arnold DL, Vermersch P et al. Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2021; 20: 729-38.
11. Lechner KS, Neurath MF, Weigmann B. Role of the IL-2 inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis. J Mol Med. 2020; 98: 1385-95.
12. Dolgin E. BTK blockers make headway in multiple sclerosis. Nat Biotechnol. 2021; 39: 3-5.
13. Isenberg D, Furie R, Jones NS et al. Efficacy, Safety, and Pharmacodynamic Effects of the Bruton’s Tyrosine Kinase Inhibitor Fenebrutinib (GDC-0853) in Systemic Lupus Erythematosus: Results of a Phase II, Randomized, Double-Blind, Placebo-Controlled Trial. Arthritis Rheumatol. 2021; 73: 1835-46.
14. Montalban X, Arnold DL, Weber MS et al. Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis. N Engl J Med. 2019; 380: 2406-17.
15. Dhillon S. Orelabrutinib: First Approval. Drugs. 2021; 81: 503-7.
16. von Hundelshausen P, Siess W. Bleeding by bruton tyrosine kinase-inhibitors: Dependency on drug type and disease. Cancers (Basel). 2021; 13: 1-33.
17. Dubreuil P, Letard S, Ciufolini M et al. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS One. 2009; 4: e7258.
18. Brown MA, Weinberg RB. Mast cells and innate lymphoid cells: Underappreciated players in CNS autoimmune demyelinating disease. Front Immunol. 2018; 9: 1-14.
19. Vermersch P, Brieva-Ruiz L, Fox RJ et al. Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2022; 9: e1148.
20. Vermersch P, Benrabah R, Schmidt N et al. Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study. BMC Neurol. 2012; 12: 36.
21. Piette F, Belmin J, Vincent H et al. Masitinib as an adjunct therapy for mild-to-moderate Alzheimer’s disease: a randomised, placebo-controlled phase 2 trial. Alzheimers Res Ther. 2011; 3: 16.
22. Mora JS, Genge A, Chio A et al. Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial. Amyotroph Lateral Scler Front Degener. 2020; 21: 5-14.
23. Fox R, Coffey C, Conwit R et al. Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis. N Engl J Med. 2018; 379: 846-55.
24. Cho Y, Crichlow GV, Vermeire JJ et al. Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast. Proc Natl Acad Sci. 2010; 107: 11313-8.
25. Ruiz-Pérez D, Benito J, Polo G et al. The Effects of the Toll-Like Receptor 4 Antagonist, Ibudilast, on Sevoflurane’s Minimum Alveolar Concentration and the Delayed Remifentanil-Induced Increase in the Minimum Alveolar Concentration in Rats. Anesth Analg. 2016; 122: 1370-6.
26. Barkhof F, Hulst HE, Drulovic J et al. Ibudilast in relapsing-remitting multiple sclerosis: A neuroprotectant? Neurology. 2010; 74: 1033-40.
27. Bermel RA, Fedler JK, Kaiser P et al. Optical coherence tomography outcomes from SPRINT-MS, a multicenter, randomized, double-blind trial of ibudilast in progressive multiple sclerosis. Mult Scler J. 2021; 27: 1384-90.
28. Naismith RT, Bermel RA, Coffey CS et al. Effects of Ibudilast on MRI Measures in the Phase 2 SPRINT-MS Study. Neurology. 2021; 96: e491-500.
29. Fox E, Lovett-Racke AE, Gormley M et al. A phase 2 multicenter study of ublituximab, a novel glycoengineered anti-CD20 monoclonal antibody, in patients with relapsing forms of multiple sclerosis. Mult Scler J. 2021; 27: 420-9.
30. Steinman L, Fox E, Hartung H-P et al. Efficacy and safety of ublituximab versus teriflunomide in relapsing multiple sclerosis: Results of the Phase 3 ULTIMATE I and II trials. Neurology. 2021; 96(15 suppl): 4494.
31. Wray S, Then Bergh F, Wundes A et al. Efficacy and Safety Outcomes with Diroximel Fumarate After Switching from Prior Therapies or Continuing on DRF: Results from the Phase 3 EVOLVE-MS-1 Study. Adv Ther. 2022; 39(4): 1810-31.
32. Muehler A, Peelen E, Kohlhof H et al. Vidofludimus calcium, a next generation DHODH inhibitor for the Treatment of relapsing-remitting multiple sclerosis. Mult Scler Relat Disord. 2020; 43: 102129.
33. Kappos L, Fox RJ, Burcklen M et al. Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study. JAMA Neurol. 2021; 78: 558.
34. Mamani-Matsuda M, Cosma A, Weller S et al. The human spleen is a major reservoir for long-lived vaccinia virus-specific memory B cells. Blood. 2008; 111: 4653-9.
35. Hauser SL, Bar-Or A, Cohen JA et al. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med. 2020; 383: 546-57.
36. Burt RK, Balabanov R, Burman J et al. Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis. JAMA. 2019; 321: 165.
37. Bose G, Thebault S, Rush CA et al. Autologous hematopoietic stem cell transplantation for multiple sclerosis: A current perspective. Mult Scler J. 2021; 27: 167-73.
38. Mohammadi R, Aryan A, Omrani MD et al. Autologous hematopoietic stem cell transplantation (Ahsct): An evolving treatment avenue in multiple sclerosis. Biol Targets Ther. 2021; 15: 53-9.
39. Sormani MP, Muraro PA, Schiavetti I et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis. Neurology. 2017; 88: 2115-22.
40. Arrambide G, Iacobaeus E, Amato M et al. Aggressive multiple sclerosis (2): Treatment. Mult Scler. 2020; 26: 1045-63.
41. Harris VK, Stark J, Vyshkina T et al. Phase I Trial of Intrathecal Mesenchymal Stem Cell-derived Neural Progenitors in Progressive Multiple Sclerosis. EBioMedicine. 2018; 29: 23-30.
42. Suuring M, Moreau A. Regulatory macrophages and tolerogenic dendritic cells in myeloid regulatory cell-based therapies. Int J Mol Sci. 2021; 22: 7970.
43. Quirant-Sánchez B, Mansilla MJ, Navarro-Barriuso J et al. Combined therapy of vitamin d3-tolerogenic dendritic cells and interferon-β in a preclinical model of multiple sclerosis. Biomedicines. 2021; 9: 1758.
44. Tourbah A, Lebrun-Frenay C, Edan G et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Mult Scler J. 2016; 22: 1719-31.
45. Motte J, Gold R. High-dose biotin in multiple sclerosis: the end of the road. Lancet Neurol. 2020; 19: 965-6.
46. Cree BAC, Cutter G, Wolinsky JS, Freedman MS et al. Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2020; 19: 988-97.
47. Gifford JL, Sadrzadeh SMH, Naugler C. Biotin interference: Underrecognized patient safety risk in laboratory testing. Can Fam Physician. 2018; 64: 370.
48. Goldschmidt CH, Cohen JA. The Rise and Fall of High-Dose Biotin to Treat Progressive Multiple Sclerosis. Neurotherapeutics. 2020; 17: 968-70.
49. Cadavid D, Mellion M, Hupperts R et al. Safety and efficacy of opicinumab in patients with relapsing multiple sclerosis (SYNERGY): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2019; 18: 845-56.
50. Ahmed Z, Fulton D, Douglas MR. Opicinumab: is it a potential treatment for multiple sclerosis? Ann Transl Med. 2020; 8: 892.
51. Hanf KJM, Arndt JW, Liu YT et al. Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site. MAbs. 2020; 12: 1-14.
52. Chataway J, Schuerer N, Alsanousi A et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (M-STAT): A randomised, placebo-controlled, phase 2 trial. Lancet. 2014; 383: 2213-21.
53. van der Most PJ, Dolga AM, Nijholt IM et al. Statins: Mechanisms of neuroprotection. Prog Neurobiol. 2009; 88: 64-75.
54. Giannopoulos S, Katsanos AH, Tsivgoulis G et al. Statins and Cerebral Hemodynamics. J Cereb Blood Flow Metab. 2012; 32: 1973-6.
55. Green AJ, Gelfand JM, Cree BA et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017; 390: 2481-9.
56. Dziedzic A, Saluk-Bijak J, Miller E et al. Metformin as a potential agent in the treatment of multiple sclerosis. Int J Mol Sci. 2020; 21: 1-19.
57. Negrotto L, Farez MF, Correale J. Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple Sclerosis. JAMA Neurol. 2016; 73: 520.
58. Brown D, Moezzi D, Dong Y et al. Combination of Hydroxychloroquine and Indapamide Attenuates Neurodegeneration in Models Relevant to Multiple Sclerosis. Neurotherapeutics. 2021; 18: 387-400.
59. Rankin KA, Mei F, Kim K et al. Selective estrogen receptor modulators enhance CNS remyelination independent of estrogen receptors. J Neurosci. 2019; 39: 2184-94.
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