Advertisement

Updates on efficacy and safety outcomes of new and emerging disease modifying therapies and stem cell therapy for Multiple Sclerosis: A review

  • Sarah Peterson
    Affiliations
    West Virginia University, School of Medicine, Morgantown, WV, USA

    Department of Neurology, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA

    Department of Neurology, University of Cincinnati Medical Center, Cincinnati, OH, USA
    Search for articles by this author
  • Amaris Jalil
    Affiliations
    West Virginia University, School of Medicine, Morgantown, WV, USA

    Department of Neurology, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA
    Search for articles by this author
  • Katherine Beard
    Affiliations
    West Virginia University, School of Medicine, Morgantown, WV, USA

    Department of Neurology, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA
    Search for articles by this author
  • Mihir Kakara
    Affiliations
    Department of Neurology, Perelman School of Medicine, University of Pennsylvania, PA, USA

    Depratment of Neurology, Wayne State University, Detroit, MI, USA
    Search for articles by this author
  • Author Footnotes
    1 ORCID ID: 0000-0001-6844-3287.
    Shitiz Sriwastava
    Correspondence
    Corresponding author at: Department of Neurology, Rockefeller Neuroscience Institute, West Virginia University School of Medicine, Morgantown, WV 26506, USA.
    Footnotes
    1 ORCID ID: 0000-0001-6844-3287.
    Affiliations
    West Virginia University, School of Medicine, Morgantown, WV, USA

    Department of Neurology, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA

    Depratment of Neurology, Wayne State University, Detroit, MI, USA

    West Virginia Clinical and Translational Science Institute, Morgantown, WV, USA

    Division of Multiple Sclerosis and Neuroimmunology, Department of Neurology, McGovern Medical School (UT Health), University of Texas Health Science Center at Houston, Houston, TX, USA
    Search for articles by this author
  • Author Footnotes
    1 ORCID ID: 0000-0001-6844-3287.
Published:August 31, 2022DOI:https://doi.org/10.1016/j.msard.2022.104125

      Highlights

      • We provide an outline of current MS medications in the pipeline including emerging DMTs and stem cell therapy.
      • these new therapies could potentially provide an increasing diversity of treatment options for patients in the future.
      • Many of the therapies discussed such as Evobrutinib, vidofludimus, fenebrutinib, and orelabrutinib offer higher selectivity or potency compared to current available treatments, which could improve overall MS patient satisfaction and quality of life due to theoretically fewer adverse side effects and possible improved efficacy.

      Abstract

      Multiple Sclerosis (MS) is a chronic neurodegenerative autoimmune disorder of the central nervous system (CNS) and the most common cause of serious physical disability in working-age adults. Drug development and research in this field have rapidly evolved over the past two decades, leading to the broad array of treatment options available today. These disease-modifying therapies (DMTs) work through distinct mechanisms of action and exhibit varying safety and efficacy profiles to help manage symptoms and reduce exacerbations in MS patients. Our extensive understanding of this condition has also led to novel approaches, such as the discovery of specific biomarkers that allow us to monitor the therapeutic response towards DMTs. The development of new DMTs continues to progress quickly today, and it can be difficult for clinicians to remain up to date on the most recent advancements and new treatment options for their patients. In this comprehensive review, we provide an outline of current MS medications in the pipeline including emerging DMTs and stem cell therapy, as well as the unique characteristics of these medications, including their indications, pharmacokinetic effects, and the relevant advancements.

      Keywords

      Abbreviations:

      MS (Multiple Sclerosis), RRMS (Relapsing Remitting Multiple Sclerosis), PPMS (Primary Progressive Multiple Sclerosis), RIS (Radiologically isolated syndrome), CIS (Clinical isolated syndrome), DMT (Disease modifying therapy), CNS (Central Nervous System), NEDA (no evidence of disease activity), aHSCT (Autologous Hematopoietic Stem Cell Transplantation), SARS-CoV-2 (Severe Acute Respiratory Distress Syndrome coronavirus 2), CDP (Confirmed disability progression), MSFC (Multiple sclerosis functional composite), SDMT (symbol digit modalities test), EDDS (Expanded disability status scale), TEAEs (Treatment emergent adverse events (TEAEs)), MBP (Myelin basic protein), BTK (Bruton tyrosine kinase), IL (Interleukins), MSQOL-54 (Multiple sclerosis quality of life), ARR (Annualized relapse rate)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Multiple Sclerosis and Related Disorders
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Aly L.
        • Hemmer B.
        • Korn T
        From leflunomide to teriflunomide: drug development and immunosuppressive oral drugs in the treatment of multiple sclerosis.
        Curr. Neuropharmacol. 2017; 15 (PMID: 27928949; PMCID: PMC5652031): 874-891https://doi.org/10.2174/1570159X14666161208151525
      1. Anon, ATX-MS-1467 in Patients With Relapsing Forms of Multiple Sclerosis. Clinicaltrials.gov identifier: NCT01097668. https://clinicaltrials.gov/ct2/show/NCT01097668 ?term=ATX±MS±1467&cond=Multiple±Sclerosis&draw=2&rank=2. Updated February 16, 2015. Accessed April 9, 2022.

      2. Anon, Phase 1/2 Study to Evaluate the Safety and Efficacy of ATA188 in Subjects With Progressive Multiple Sclerosis - EMBOLD. Clinicaltrials.gov identifier: NCT03283826. https://clinicaltrials.gov/ct2/show/record/NCT03283826 ?term=ATA-188&draw=2&rank=1&view=record. Published September 14, 2017. Accessed April 9, 2022.

      3. Anon, ATX-MS-1467 in Multiple Sclerosis. Clinicaltrials.gov identifier: NCT01973491. https://clinicaltrials.gov/ct2/show/study/NCT01973491? term=ATX±MS±1467&cond=Multiple±Sclerosis&draw=2&rank=1. Updated July 2, 2017. Accessed April 9, 2022.

      4. Anon, Efficacy and safety of masitinib in the treatment of progressive multiple sclerosis. Clinicaltrials.gov identifier: NCT01433497. https://clinicaltrials.gov/ct2/show/record/NCT01433497?term=masitinib&cond=Multiple+Sclerosis&draw=1&rank=2. Updated April 8, 2020. Accessed February 4, 2022.

      5. Anon, Safety, Tolerability and Activity Study of Ibudilast in Subjects With Progressive Multiple Sclerosis. Clinicaltrials.gov identifier: NCT01982942. https://www.clinicaltrials.gov/ct2/show/study/NCT01982942 ?term=ibudilast&cond=multiple±sclerosis&draw=2&rank=1. Updated July 28, 2020. Accessed April 9, 2022.

      6. Anon, Clene Nanomedicine I. Clene nanomedicine Presents Updated Blinded Interim Data from the visionary-MS Phase 2 study. Clene Nanomedicine Presents Updated Blinded Interim Data from the VISIONARY-MS Phase 2 Study. https://www.prnewswire.com/news-releases/clene-nanomedicine-presents-updated-blinded-interim-data-from-the-visionary-ms-phase-2-study-301128025.html. Published September 11, 2020. Accessed May 2, 2022.

      7. Anon, Best Available Therapy Versus Autologous Hematopoetic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS). Clinicaltrials.gov identifier: NCT04047628. https://www.clinicaltrials.gov/ct2/show/study/NCT04047628 ?term=04047628&draw=2&rank=1.Updated December 22, 2021a. Accessed March 5, 2022.

      8. Anon, RCT Comparing Autologous Hematopoietic Stem Cell Transplantation Versus Alemtuzumab in MS (RAM-MS). Clinicaltrials.gov identifier: NCT03477500. https://clinicaltrials.gov/ct2/show/NCT03477500 ?term=03477500&draw=2&rank=1. Updated February 10, 2021b. Accessed March 5, 2022.

      9. Anon, Autologous Stem Cell Transplantation Versus alemtuzumab, Ocrelizumab Or Cladribine in Relapsing-Remitting Multiple Sclerosis (STAR-MS). ISRCTN identifier: ISRCTN88667898. https://www.isrctn.com/ISRCTN88667898. Updated August 2, 2021c. Accessed March 8, 2022.

      10. Anon, Ocrelizumab Or Alemtuzumab Compared With Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis - a Phase-2 Randomised Controlled Trial (COAST). Clinicaltrials.gov identifier: NCT04971005. https://clinicaltrials.gov/ct2/show/NCT04971005. Updated October 5, 2021d Accessed March 5, 2022.

      11. Anon, Study to Assess the Efficacy and Safety of Ublituximab in Participants With Relapsing Forms of Multiple Sclerosis (RMS) (ULTIMATE II). Clinicaltrials.gov identifier: NCT03277248. https://clinicaltrials.gov/ct2/show/results/NCT03277248?term=Ublituximab&recrs=e&phase=2&draw=2&rank=1. Updated December 6, 2021e. Accessed April 30, 2022.

      12. Anon, Study to Assess the Efficacy and Safety of Ublituximab in Participants With Relapsing Forms of Multiple Sclerosis (RMS) (ULTIMATE 1). Clinicaltrials.gov identifier: NCT0327726. https://clinicaltrials.gov/ct2/show/results/NCT03277261?term=Ublituximab&recrs=e&phase=2&draw=2&rank=2. Updated December 6, 2021f. Accessed April 30, 2022.

      13. Anon, MRI Trial to Explore the Efficacy and Safety of IMU-838 in Relapsing Remitting Multiple Sclerosis (EMPHASIS). Clinicaltrials.gov identifier: NCT03846219. https://clinicaltrials.gov/ct2/show/record/NCT03846219?view=record. Updated February 11, 2022 g. Accessed May 2, 2022.

      14. Anon, Funding and Awards. National Institute for Health Research. https://www.fundingawards.nihr.ac.uk/award/16/126/26. Accessed March 5, 2022.

      15. Anon, Study of Evobrutinib in Participants With RMS (evolutionRMS 1). Clinicaltrials.gov identifier: NCT04338022..

      16. Anon, Study of Evobrutinib in Participants With RMS (evolutionRMS 2). Clinicaltrials.gov identifier: NCT04338061. https://clinicaltrials.gov/ct2/show/NCT04338022?cond=Evobrutinib&phase=2&draw=2&rank=3. Updated April 27, 2022c Accessed April 30, 2022.

      17. Anon, Study to Evaluate the Efficacy, Safety, and Tolerability of IMU-838 in Patients With Relapsing Multiple Sclerosis (ENSURE-1). Clinicaltrials.gov identifier: NCT05134441. https://clinicaltrials.gov/ct2/show/NCT05134441. Updated April 13, 2022d Accessed May 2, 2022.

      18. Anon, Study to Evaluate the Efficacy, Safety and Tolerability of IMU-838 in Patients With Relapsing Multiple Sclerosis (ENSURE-2). Clinicaltrials.gov identifier: NCT05201638. https://clinicaltrials.gov/ct2/show/NCT05201638 ?term=IMU-838&cond=multiple±sclerosis&phase=2&draw=2&rank=2. Updated April 7, 2022e. Accessed May 2, 2022.

      19. Anon, Study to Evaluate Efficacy, Safety, and Tolerability of IMU-838 in Patients With Progressive Multiple Sclerosis (CALLIPER). Clinicaltrials.gov identifier: NCT05054140. https://clinicaltrials.gov/ct2/show/NCT05054140?term=IMU-838&draw=2&rank=1. Updated April 13, 2022f. Accessed May 2, 2022.

      20. Anon, A Study To Evaluate The Efficacy And Safety Of Fenebrutinib Compared With Ocrelizumab In Adult Participants With Primary Progressive Multiple Sclerosis (FENtrepid). Clinicaltrials.gov identifier: NCT04544449. https://clinicaltrials.gov/ct2/show/NCT04544449. Updated April 29, 2022 h. Accessed May 2, 2022.

      21. Anon, Study To Evaluate The Efficacy And Safety Of Fenebrutinib Compared With Teriflunomide In Relapsing Multiple Sclerosis (RMS) (FENhance). Clinicaltrials.gov identifier: NCT04586023. https://clinicaltrials.gov/ct2/show/NCT04586023 ?term=NCT04586023&draw=2&rank=1. Updated April 29, 2022i. Accessed May 2, 2022.

      22. Anon, A Study To Evaluate The Efficacy And Safety Of Fenebrutinib Compared With Teriflunomide In Relapsing Multiple Sclerosis (RMS) (FENhance). Clinicaltrials.gov identifier: NCT04586010. https://clinicaltrials.gov/ct2/show/NCT04586010 ?term=NCT04586010&draw=2&rank=1. Updated April 29, 2022j. Accessed May 2, 2022.

      23. Anon, A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of Orelabrutinib in Patients With Relapsing-Remitting Multiple Sclerosis to Evaluate Efficacy, Safety, Tolerability, Pharmacokinetics, and Biological Activity. Clinicaltrials.gov identifier: NCT04711148. https://clinicaltrials.gov/ct2/show/record/NCT04711148 ?term=orelabrutinib&cond=Multiple±Sclerosis&draw=2&rank=1. Updated February 1, 2022k. Accessed April 5, 2022.

      24. Anon, Clene Nanomedicine. Pipeline. Clene Inc. https://clene.com/pipeline/. Accessed May 2, 2022.

      25. Anon, Nanocrystalline Gold to Treat Remyelination Failure in Chronic Optic Neuropathy In Multiple Sclerosis (VISIONARY-MS). Clinicaltrials.gov identifier: NCT03536559. https://clinicaltrials.gov/ct2/show/NCT03536559. Updated March 11, 2022n. Accessed May 2, 2022.

      26. Anon, A Multi-Center, Open-Label Long-Term Extension Study of CNM-Au8 In Patients With Stable Relapsing Multiple Sclerosis (VISIONMS-LTE). Clinicaltrials.gov identifier: NCT04626921. https://clinicaltrials.gov/ct2/show/study/NCT04626921?term=CNM+AU8&cond=Multiple+Sclerosis&draw=2&rank=1. Updated March 11, 2022. Accessed May 2, 2022.

      27. Anon, 31P-MRS Imaging to Assess the Effects of CNM-Au8 On Impaired Neuronal Redox State in Multiple Sclerosis. (REPAIR-MS). Clinicaltrials.gov identifier: NCT03993171. Clinicaltrials.gov identifier: NCT03993171. https://clinicaltrials.gov/ct2/show/NCT03993171. Updated January 26, 2022 m. Accessed May 2, 2022.

        • Apostolidis S.A.
        • Kakara M.
        • Painter M.M.
        • Goel R.R.
        • Mathew D.
        • Lenzi K.
        • Rezk A.
        • Patterson K.R.
        • Espinoza D.A.
        • Kadri J.C.
        • Markowitz D.M.
        • E Markowitz C.
        • Mexhitaj I.
        • Jacobs D.
        • Babb A.
        • Betts M.R.
        • Prak E.T.L.
        • Weiskopf D.
        • Grifoni A.
        • Lundgreen K.A.
        • Gouma S.
        • Sette A.
        • Bates P.
        • Hensley S.E.
        • Greenplate A.R.
        • Wherry E.J.
        • Li R.
        Bar-Or A. Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy.
        Nat. Med. 2021; 27 (Epub 2021 Sep 14. PMID: 34522051; PMCID: PMC8604727): 1990-2001https://doi.org/10.1038/s41591-021-01507-2
        • Bayas A.
        • Gold R.
        Lessons from 10 years of interferon beta-1b (Betaferon/Betaseron) treatment.
        J. Neurol. 2003; 250 (IV3-8PMID: 14712395)https://doi.org/10.1007/s00415-003-1402-8
        • Beard K.
        • Sriwastava S.
        Insight in booster COVID-19 vaccine and disease modifying therapy in multiple sclerosis.
        J. Neurol. Sci. 2021; 430 (Epub 2021 Oct 19. PMID: 34688988; PMCID: PMC8523307)120034https://doi.org/10.1016/j.jns.2021.120034
        • Boffa G.
        • et al.
        Long-term clinical outcomes of hematopoietic stem cell transplantation in multiple sclerosis.
        Neurology. 2021; 97: 203https://doi.org/10.1212/WNL.0000000000011825
        • Chataway J.
        • Martin K.
        • Barrell K.
        • Sharrack B.
        • Stolt P.
        • Wraith D.C.
        • ATX-MS1467 Study Group
        Effects of ATX-MS-1467 immunotherapy over 16 weeks in relapsing multiple sclerosis.
        Neurology. 2018; 90 (Epub 2018 Feb 21. PMID: 29467307): e955-e962https://doi.org/10.1212/WNL.0000000000005118
        • Ciotti J.R.
        • Valtcheva M.V.
        • Cross A.H.
        Effects of MS disease-modifying therapies on responses to vaccinations: a review.
        Mult Scler Relat Disord. 2020; 45 (OctEpub 2020 Aug 1. PMID: 32769063; PMCID: PMC7395588)102439https://doi.org/10.1016/j.msard.2020.102439
        • Darlington P.J.
        • Touil T.
        • Doucet J.S.
        • Gaucher D.
        • Zeidan J.
        • Gauchat D.
        • Corsini R.
        • Kim H.J.
        • Duddy M.
        • Jalili F.
        • Arbour N.
        • Kebir H.
        • Chen J.
        • Arnold D.L.
        • Bowman M.
        • Antel J.
        • Prat A.
        • Freedman M.S.
        • Atkins H.
        • Sekaly R.
        • Cheynier R.
        • Bar-Or A.
        • Canadian MS/BMT Study Group
        Diminished Th17 (not Th1) responses underlie multiple sclerosis disease abrogation after hematopoietic stem cell transplantation.
        Ann. Neurol. 2013; 73 (Epub 2013 Mar 5. PMID: 23463494): 341-354https://doi.org/10.1002/ana.23784
        • Darlington P.J.
        • Stopnicki B.
        • Touil T.
        • Doucet J.S.
        • Fawaz L.
        • Roberts M.E.
        • Boivin M.N.
        • Arbour N.
        • Freedman M.S.
        • Atkins H.L.
        • Bar-Or A.
        Natural killer cells regulate Th17 cells after autologous hematopoietic stem cell transplantation for relapsing remitting multiple sclerosis.
        Front. Immunol. 2018; 9 (PMID: 29867923; PMCID: PMC5951114): 834https://doi.org/10.3389/fimmu.2018.00834
        • Dhillon S.
        Orelabrutinib: first approval.
        Drugs. 2021; 81 (Epub 2021 Mar 11. PMID: 33704654): 503-507https://doi.org/10.1007/s40265-021-01482-5
        • Faissner S.
        • Gold R.
        Efficacy and safety of the newer multiple sclerosis drugs approved since 2010.
        CNS Drugs. 2018; 32 (Erratum in: CNS Drugs. 2018 May;32(5):469-471. PMID: 29600441): 269-287https://doi.org/10.1007/s40263-018-0488-6
        • Fox R.J.
        • Coffey C.S.
        • Conwit R.
        • Cudkowicz M.E.
        • Gleason T.
        • Goodman A.
        • Klawiter E.C.
        • Matsuda K.
        • McGovern M.
        • Naismith R.T.
        • Ashokkumar A.
        • Barnes J.
        • Ecklund D.
        • Klingner E.
        • Koepp M.
        • Long J.D.
        • Natarajan S.
        • Thornell B.
        • Yankey J.
        • Bermel R.A.
        • Debbins J.P.
        • Huang X.
        • Jagodnik P.
        • Lowe M.J.
        • Nakamura K.
        • Narayanan S.
        • Sakaie K.E.
        • Thoomukuntla B.
        • Zhou X.
        • Krieger S.
        • Alvarez E.
        • Apperson M.
        • Bashir K.
        • Cohen B.A.
        • Coyle P.K.
        • Delgado S.
        • Dewitt L.D.
        • Flores A.
        • Giesser B.S.
        • Goldman M.D.
        • Jubelt B.
        • Lava N.
        • Lynch S.G.
        • Moses H.
        • Ontaneda D.
        • Perumal J.S.
        • Racke M.
        • Repovic P.
        • Riley C.S.
        • Severson C.
        • Shinnar S.
        • Suski V.
        • Weinstock-Guttman B.
        • Yadav V.
        • Zabeti A.
        • NN102/SPRINT-MS Trial Investigators
        Phase 2 Trial of Ibudilast in progressive multiple sclerosis.
        N. Engl. J. Med. 2018; 379 (PMID: 30157388; PMCID: PMC6172944): 846-855https://doi.org/10.1056/NEJMoa1803583
        • Fox E.
        • Lovett-Racke A.E.
        • Gormley M.
        • Liu Y.
        • Petracca M.
        • Cocozza S.
        • Shubin R.
        • Wray S.
        • Weiss M.S.
        • Bosco J.A.
        • Power S.A.
        • Mok K.
        • Inglese M.
        A phase 2 multicenter study of ublituximab, a novel glycoengineered anti-CD20 monoclonal antibody, in patients with relapsing forms of multiple sclerosis.
        Mult. Scler. 2021; 27 (Epub 2020 Apr 30. PMID: 32351164; PMCID: PMC7897779): 420-429https://doi.org/10.1177/1352458520918375
        • Ge F.
        • Lin H.
        • Li Z.
        • Chang T.
        Efficacy and safety of autologous hematopoietic stem-cell transplantation in multiple sclerosis: a systematic review and meta-analysis.
        Neurol Sci. 2019; 40 (Epub 2018 Dec 10. PMID: 30535563): 479-487https://doi.org/10.1007/s10072-018-3670-1
        • Hartung D.M.
        Health economics of disease-modifying therapy for multiple sclerosis in the United States.
        Ther Adv Neurol Disord. 2021; 14 (PMID: 33643441; PMCID: PMC7894590)1756286420987031https://doi.org/10.1177/1756286420987031
        • 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.
        • EXPAND Clinical Investigators
        Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study.
        Lancet. 2018 Mar 31; 391 (Epub 2018 Mar 23. Erratum in: Lancet. 2018 Nov 17;392(10160):2170. PMID: 29576505): 1263-1273https://doi.org/10.1016/S0140-6736(18)30475-6
        • Kappos L.
        • Arnold D.L.
        • Bar-Or A.
        • Camm A.J.
        • Derfuss T.
        • Sprenger T.
        • Davies M.
        • Piotrowska A.
        • Ni P.
        • Harada T.
        Two-year results from a phase 2 extension study of oral amiselimod in relapsing multiple sclerosis.
        Mult. Scler. 2018 Oct; 24 (Epub 2017 Sep 15. PMID: 28911260; PMCID: PMC6196590): 1605-1616https://doi.org/10.1177/1352458517728343
        • Klineova S.
        • Lublin F.D.
        Clinical course of multiple sclerosis.
        Cold Spring Harb. Perspect. Med. 2018; 8 (PMID: 29358317; PMCID: PMC6120692)a028928https://doi.org/10.1101/cshperspect.a028928
        • Lassmann H.
        • Brück W.
        • Lucchinetti C.F.
        The immunopathology of multiple sclerosis: an overview.
        Brain Pathol. 2007; 17 (doi: 10.1111/j.1750-3639.2007.00064.x. PMID: 17388952; PMCID: PMC8095582): 210-218
        • Mancardi G.
        • Sormani M.P.
        • Muraro P.A.
        • Boffa G.
        • Saccardi R.
        Intense immunosuppression followed by autologous haematopoietic stem cell transplantation as a therapeutic strategy in aggressive forms of multiple sclerosis.
        Mult. Scler. 2018; 24 (Epub 2017 Nov 10. PMID: 29125439): 245-255https://doi.org/10.1177/1352458517742532
        • McGinley M.P.
        • Cohen J.A.
        Sphingosine 1-phosphate receptor modulators in multiple sclerosis and other conditions.
        Lancet. 2021; 398 (Epub 2021 Jun 24. Erratum in: Lancet. 2021 Sep 25;398(10306):1132. PMID: 34175020): 1184-1194https://doi.org/10.1016/S0140-6736(21)00244-0
        • McGinley M.P.
        • Goldschmidt C.H.
        • AD R.-G.
        Diagnosis and treatment of multiple sclerosis: a review.
        JAMA. 2021; 325 (Erratum in: JAMA. 2021 Jun 1;325(21):2211. PMID: 33620411): 765-779https://doi.org/10.1001/jama.2020.26858
        • Moberly J.B.
        • Ford D.M.
        • Zahir H.
        • Chen S.
        • Mochizuki T.
        • Truitt K.E.
        • Vollmer T.L.
        Pharmacological effects of CS-0777, a selective sphingosine 1-phosphate receptor-1 modulator: results from a 12-week, open-label pilot study in multiple sclerosis patients.
        J. Neuroimmunol. 2012; 246 (Epub 2012 Mar 31. PMID: 22465063): 100-107https://doi.org/10.1016/j.jneuroim.2012.03.007
        • Montalban X.
        • Hauser S.L.
        • Kappos L.
        • Arnold D.L.
        • Bar-Or A.
        • Comi G.
        • de Seze J.
        • Giovannoni G.
        • Hartung H.P.
        • Hemmer B.
        • Lublin F.
        • Rammohan K.W.
        • Selmaj K.
        • Traboulsee A.
        • Sauter A.
        • Masterman D.
        • Fontoura P.
        • Belachew S.
        • Garren H.
        • Mairon N.
        • Chin P.
        • Wolinsky J.S.
        • ORATORIO Clinical Investigators
        Ocrelizumab versus Placebo in primary progressive multiple sclerosis.
        N. Engl. J. Med. 2017; 376 (Epub 2016 Dec 21. PMID: 28002688): 209-220https://doi.org/10.1056/NEJMoa1606468
        • Montalban X.
        • Arnold D.L.
        • Weber M.S.
        • Staikov I.
        • Piasecka-Stryczynska K.
        • Willmer J.
        • Martin E.C.
        • Dangond F.
        • Syed S.
        • Wolinsky J.S.
        Evobrutinib Phase 2 Study Group. Placebo-controlled trial of an oral BTK inhibitor in multiple sclerosis.
        N. Engl. J. Med. 2019; 380 (Epub 2019 May 10. PMID: 31075187): 2406-2417https://doi.org/10.1056/NEJMoa1901981
        • Montalban X.
        • Arnold D.L.
        • Bar-Or A.
        • Cross A.H.
        • Havrdova E.K.
        • Stuve O.
        • Weber M.S.
        • Wiendl H.
        • Wolinsky J.S.
        • Syed S.
        • Mandel M.
        • Martin E.C.
        • Patrick V.
        Rationale and design of two phase 3 randomized controlled trials (evolution RMS 1&2) evaluating the Bruton’s Tyrosine Kinase inhibitor evobrutinib in patients with relapsing multiple sclerosis (4071). 2020, AAN Enterprises.
        Neurology. 2020; 94: 4071
        • Muehler A.
        • Peelen E.
        • Kohlhof H.
        • Gröppel M.
        • Vitt D.
        Vidofludimus calcium, a next generation DHODH inhibitor for the Treatment of relapsing-remitting multiple sclerosis.
        Mult. Scler. Relat. Disord. 2020; 43 (Epub 2020 May 6. PMID: 32428844)102129https://doi.org/10.1016/j.msard.2020.102129
        • Muraro P.A.
        • et al.
        Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients.
        J. Exp. Med. 2005; 201 (Epub 2005 Feb 28. PMID: 15738052; PMCID: PMC2212822): 805-816https://doi.org/10.1084/jem.20041679
        • Muraro P.A.
        • Martin R.
        • Mancardi G.L.
        • Nicholas R.
        • Sormani M.P.
        • Saccardi R.
        Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis.
        Nat. Rev. Neurol. 2017; 13 (Epub 2017 Jun 16. PMID: 28621766): 391-405https://doi.org/10.1038/nrneurol.2017.81
      28. NIH National Library of Medicine. Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton's tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168). ClinicalTrials.gov identifier: NCT04410978. https://clinicaltrials.gov/ct2/show/NCT04410978. Published June 1, 2020. Accessed March 6, 2022.

        • Oh J.
        • Cohen S.
        • Isenberg D.
        • Maurer M.
        • Galanter J.
        • Chu T.
        • Teterina A.
        • Goodyear A.
        • Mandel C.
        • Lee C.
        • Tuckwell K.
        • Lim J.
        • Vanevski K.
        • Giovannoni G.
        The safety of fenebrutinib in a large population of patients with diverse autoimmune indications supports investigation in multiple sclerosis (MS).
        Neurology. 2021; 96: 4564
        • Pender M.P.
        • Csurhes P.A.
        • Smith C.
        • Beagley L.
        • Hooper K.D.
        • Raj M.
        • Coulthard A.
        • Burrows S.R.
        • Khanna R.
        Epstein-Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis.
        Mult. Scler. 2014; 20 (Epub 2014 Feb 3. PMID: 24493474; PMCID: PMC4230458): 1541-1544https://doi.org/10.1177/1352458514521888
        • Reich D.S.
        • Arnold D.L.
        • Vermersch P.
        • Bar-Or A.
        • Fox R.J.
        • Matta A.
        • Turner T.
        • Wallström E.
        • Zhang X.
        • Mareš M.
        • Khabirov F.A.
        • Traboulsee A.
        Tolebrutinib Phase 2b Study Group. 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 (PMID: 34418400; PMCID: PMC8434816): 729-738https://doi.org/10.1016/S1474-4422(21)00237-4
        • Robinson A.P.
        • Zhang J.Z.
        • Titus H.E.
        • Karl M.
        • Merzliakov M.
        • Dorfman A.R.
        • Karlik S.
        • Stewart M.G.
        • Watt R.K.
        • Facer B.D.
        • Facer J.D.
        • Christian N.D.
        • Ho K.S.
        • Hotchkin M.T.
        • Mortenson M.G.
        • Miller R.H.
        • Miller S.D.
        Nanocatalytic activity of clean-surfaced, faceted nanocrystalline gold enhances remyelination in animal models of multiple sclerosis.
        Sci. Rep. 2020; 10 (PMID: 32041968; PMCID: PMC7010780): 1936https://doi.org/10.1038/s41598-020-58709-w
        • Rotstein D.L.
        • Healy B.C.
        • Malik M.T.
        • Chitnis T.
        • Weiner H.L.
        Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort.
        JAMA Neurol. 2015; 72 (PMID: 25531931): 152-158https://doi.org/10.1001/jamaneurol.2014.3537
        • Sharrack B.
        • European Society for Blood and Marrow Transplantation (EBMT)Autoimmune Diseases Working Party (ADWP)
        • the Joint Accreditation Committee of the International Society for Cellular Therapy (ISCT) and EBMT (JACIE)
        Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE).
        Bone Marrow Transpl. 2020; 55 (doi: 10.1038/s41409-019-0684-0. Epub 2019 Sep 26. PMID: 31558790; PMCID: PMC6995781): 283-306
        • Sriwastava S.
        • Kataria S.
        • Srivastava S.
        • Kazemlou S.
        • Gao S.
        • Wen S.
        • Saber H.
        • Tripathi R.
        • Sheikh Z.
        • Peterson S.
        • Gwinn R.
        • Bernitsas E.
        Disease-modifying therapies and progressive multifocal leukoencephalopathy in multiple sclerosis: a systematic review and meta-analysis.
        J. Neuroimmunol. 2021; 360 (Epub 2021 Sep 15. PMID: 34547511)577721https://doi.org/10.1016/j.jneuroim.2021.577721
        • Steinman L.
        • Fox E.
        • Hartung H.-P.
        • Alvarez E.
        • Qian P.
        • Wray S.
        • Robertson D.
        • Huang D.
        • Selmaj K.
        • Wynn D.
        • Weiss M.
        • Bosco J.
        • Power S.
        • Mok K.
        • Cree; B.
        Efficacy and safety of ublituximab versus teriflunomide in relapsing multiple sclerosis: results of the Phase 3 ULTIMATE I and II trials 2021, AAN Enterprises.
        Neurology. 2021; 96: 4494
        • TaŞKapilioĞLu Ö.
        Recent advances in the treatment for multiple sclerosis; current new drugs specific for multiple sclerosis.
        Noro Psikiyatr Ars. 2018; 55 (PMID: 30692849; PMCID: PMC6278629): S15-S20https://doi.org/10.29399/npa.23402
        • Tortorella C.
        • Aiello A.
        • Gasperini C.
        • Agrati C.
        • Castilletti C.
        • Ruggieri S.
        • Meschi S.
        • Matusali G.
        • Colavita F.
        • Farroni C.
        • Cuzzi G.
        • Cimini E.
        • Tartaglia E.
        • Vanini V.
        • Prosperini L.
        • Haggiag S.
        • Galgani S.
        • Quartuccio M.E.
        • Salmi A.
        • Repele F.
        • Altera A.M.G.
        • Cristofanelli F.
        • D’Abramo A.
        • Bevilacqua N.
        • Corpolongo A.
        • Puro V.
        • Vaia F.
        • Capobianchi M.R.
        • Ippolito G.
        • Nicastri E.
        • Goletti D.
        • INMI COVID-19 Vaccine Study Group
        Humoral- and T-cell-specific immune responses to SARS-CoV-2 mRNA vaccination in patients with MS using different disease-modifying therapies.
        Neurology. 2022; 98 (Epub 2021 Nov 22. PMID: 34810244; PMCID: PMC8826460): e541-e554https://doi.org/10.1212/WNL.0000000000013108
        • Vermersch P.
        • Benrabah R.
        • Schmidt N.
        • Zéphir H.
        • Clavelou P.
        • Vongsouthi C.
        • Dubreuil P.
        • Moussy A.
        • Hermine O.
        Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study.
        BMC Neurol. 2012; 12 (PMID: 22691628; PMCID: PMC3467179): 36https://doi.org/10.1186/1471-2377-12-36
        • Weber M.
        • Harp C.
        • Bremer M.
        • Goodyear A.
        • Crawford J.
        • Johnson A.
        • Bar-Or A.
        Fenebrutinib demonstrates the highest potency of Bruton Tyrosine Kinase inhibitors (BTKis) in phase 3 clinical development for multiple sclerosis (MS).
        Neurol. 2021; 96: 4437