Multiple sclerosis future or investigational therapies
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D., Julinka Auta Fernandes
Overview
Investigational therapies for multiple sclerosis (MS) include new immune-targeting drugs, repurposed drugs and combinations intended to promote myelin repair, and experimental cellular therapies. Research aims include controlling inflammatory disease activity, protecting nerve cells, and restoring function. These are distinct objectives: an effect on an imaging or laboratory marker does not by itself establish prevention or reversal of disability.[1]
This microchapter covers selected investigational approaches, with sources reviewed on 1 September 2026. Guideline and consensus recommendations are distinguished from published trials, trial protocols, registry records, and preliminary conference or sponsor reports. Inclusion does not imply approval or a recommendation for routine treatment. Development status is specific to the MS indication and may change.
Future or Investigational Therapies
Investigational immune-targeting drugs
Novel drugs are being studied to interrupt immune pathways involved in MS. Their effects on inflammatory lesions, clinical attacks, and disability must be assessed separately.
| Investigational agent | Therapeutic approach | Evidence and development status |
|---|---|---|
| Fenebrutinib | Oral, noncovalent, reversible Bruton's tyrosine kinase (BTK) inhibitor, targeting signaling involved in B-cell and myeloid-cell activation. | In the published phase 2 FENopta trial, involving 109 participants with relapsing MS, fenebrutinib reduced new gadolinium-enhancing brain lesions compared with placebo over 12 weeks. Liver-enzyme elevations occurred in some participants.[2] Phase 3 development includes FENhance in relapsing MS and FENtrepid in primary progressive MS, using active comparators.[3][4] |
| Remibrutinib | Oral, selective BTK inhibitor investigated for modulation of immune-cell activation. | The phase 3 REMODEL-1 and REMODEL-2 trials compared remibrutinib with teriflunomide in relapsing MS. Their design was described in a 2023 conference abstract, which should not be interpreted as an efficacy-results publication.[5] A separate registered phase 3 study, REMASTER, evaluates secondary progressive MS.[6] |
| Frexalimab | Monoclonal antibody against CD40 ligand (CD40L), intended to interrupt immune-cell costimulation. | A published phase 2 trial found fewer new gadolinium-enhancing lesions on magnetic resonance imaging (MRI) at 12 weeks compared with placebo. The study did not establish long-term disability benefit.[7] Phase 3 programmes address relapsing MS (FREXALT) and nonrelapsing secondary progressive MS (FREVIVA).[8][9] |
| Vidofludimus calcium | Oral dihydroorotate dehydrogenase inhibitor investigated for effects on activated lymphocytes and MS disease activity. | Published phase 2 EMPhASIS results demonstrated reduced MRI lesion activity at the effective study doses. These findings do not establish a long-term effect on disability.[10] The phase 3 ENSURE programme evaluates efficacy and safety in relapsing MS.[11] |
Recent phase 3 development reports
The following dated reports update development status. They are preliminary conference or sponsor reports, not guideline endorsements or full peer-reviewed trial reports.
- Fenebrutinib: At Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2026, FENtrepid was reported to have met its primary non-inferiority endpoint against ocrelizumab for composite confirmed disability progression in primary progressive MS; this does not establish superiority.[12] At American Academy of Neurology (AAN) 2026, FENhance 1 and 2 were reported to have reduced annualized relapse rates and MRI lesion activity compared with teriflunomide in relapsing MS. The reported disability-progression comparisons did not establish superiority. Safety reports included liver-enzyme elevations and an imbalance in fatal events, with more deaths in the fenebrutinib groups than in comparator groups. These observations require assessment of the complete benefit-risk profile; an imbalance alone does not establish drug causation. Fenebrutinib remains investigational for MS.[13][12]
- Remibrutinib: On 1 September 2026, the sponsor announced that REMODEL-1 and REMODEL-2 met their primary endpoints, with lower annualized relapse rates and fewer inflammatory MRI lesions than with teriflunomide. The announcement described a favorable safety profile, but detailed results were scheduled for conference presentation and require full publication and independent assessment. Remibrutinib remains investigational for MS; the topline announcement is not a treatment recommendation.[14]
Remyelination and neuroprotection
Remyelination research aims to restore myelin around damaged nerve fibers, including by promoting maturation of oligodendrocyte precursor cells. Neuroprotective approaches aim to preserve nerve cells and axons. Repurposed medicines and combination treatments are being investigated for these purposes.[1]
- Clemastine: The repurposed antihistamine clemastine was evaluated in the randomized Assessment of Clemastine Fumarate as a Remyelinating Agent in Multiple Sclerosis (ReBUILD) trial. Shortening of visual-evoked-potential latency provided a signal consistent with improved conduction and possible remyelination, but did not establish clinically meaningful reversal of disability.[15]
- Important safety finding: In a different population with disability progression independent of clinical attacks, the clemastine arm of Targeting Residual Activity by Precision, Biomarker-Guided Combination Therapies of Multiple Sclerosis (TRAP-MS) was stopped after 3 of 9 participants met prespecified safety stopping criteria. The 2025 publication reported accelerated disability accumulation. This small study raises a clinically important safety concern and argues against unsupervised use of clemastine for myelin repair.[16]
- Metformin plus clemastine: The Cambridge Centre for Myelin Repair trial Two (CCMR Two) investigated the combination of metformin and clemastine to promote myelin repair, using visual-evoked-potential and MRI outcomes. Its published phase 2a protocol describes the rationale and methods, not efficacy results.[17] In their report of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2025 presentation, the Cambridge investigators described improved visual-evoked-potential latency but no demonstrated improvement in visual function or disability over six months. These are preliminary conference findings, not an established functional benefit; fatigue and diarrhea were reported, and long-term efficacy and safety remain uncertain.[18]
Experimental cell-based therapies
Chimeric antigen receptor T-cell therapies
Chimeric antigen receptor (CAR) T-cell approaches use genetically modified T cells to recognize selected immune-cell targets. Investigational MS strategies include targeting CD19-expressing B cells and B-cell maturation antigen (BCMA)-expressing cells. Published experience includes small early studies; these cannot establish comparative efficacy or long-term safety.[19][20]
The 2026 German Society of Neurology living guideline, statement D55 (strong consensus), makes no general recommendation to treat MS with CAR T cells because benefits and risks require evaluation in clinical trials. Important risks include cytokine-release syndrome, immune effector cell-associated neurotoxicity, and longer-term immune complications. Studies require centers experienced in both MS and cellular immunotherapy.[21]
Mesenchymal stromal cells and related cell products
Mesenchymal stromal/stem cells and derived products are investigated for immunomodulatory and tissue-supporting effects. Different cell sources, manufacturing methods, and routes of administration produce distinct interventions; findings from one product cannot automatically be generalized to another.[22]
- The randomized Mesenchymal Stem Cells for Multiple Sclerosis (MESEMS) trial did not demonstrate a reduction in gadolinium-enhancing brain lesions with intravenous autologous mesenchymal stromal cells compared with placebo.[23]
- The 2026 Study of Mesenchymal Autologous Stem Cells as Regenerative Treatment for Multiple Sclerosis (SMART-MS) trial, involving 18 participants with progressive MS, did not detect a neuroregenerative effect on its primary evoked-potential outcome after intrathecal cell administration. Adverse events suggested localized inflammation, including a case of chronic pain attributed to arachnoiditis. These findings reinforce the need for careful product-specific safety evaluation.[24]
European Society for Blood and Marrow Transplantation (EBMT)/Joint Accreditation Committee of the International Society for Cell and Gene Therapy and EBMT (JACIE) guidance recommends that mesenchymal stromal-cell treatment for MS be restricted to clinical trials in appropriately accredited centers; routine treatment is not supported by established safety and efficacy evidence.[22]
Neural stem and progenitor cells
Neural stem/progenitor-cell approaches are investigated for local immune modulation, support of damaged neural tissue, and possible repair. A published open-label phase 1 study evaluated transplantation in progressive MS. Such early studies primarily assess feasibility and safety and cannot establish that the intervention restores neurological function or prevents disability progression.[25]
Antigen-specific immune tolerance
Antigen-specific approaches aim to restore immune tolerance to disease-associated antigens while preserving protective immune responses. Investigational methods include myelin peptide-loaded tolerogenic dendritic cells and autologous peptide-coupled blood cells. A phase 1b study of tolerogenic dendritic cells provided initial safety and immunological observations, not proof of clinical efficacy.[26] The Peptide-coupled Red Blood Cells for the Treatment of Multiple Sclerosis (RED4MS) research programme has evaluated autologous red blood cells coupled to myelin peptides as an experimental therapeutic tolerance strategy.[27]
Evaluation of investigational therapies
Evidence assessment should distinguish prespecified primary outcomes from exploratory findings, and randomized comparisons from uncontrolled observations. Investigational cellular therapies require appropriate regulatory and ethical oversight, informed consent, and long-term safety follow-up. Current trial status and eligibility should be verified with the trial registry and study center; registration alone is not an endorsement of a treatment.[1][22]
References
- ↑ 1.0 1.1 1.2 Scolding NJ, Pasquini M, Reingold SC, Cohen JA (2017). "Cell-based therapeutic strategies for multiple sclerosis". Brain. 140 (11): 2776–2796. doi:10.1093/brain/awx154. PMID 29053779.
- ↑ Bar-Or A, Dufek M, Budincevic H, et al. (2025). "Safety and efficacy of fenebrutinib in relapsing multiple sclerosis (FENopta): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial and open-label extension study". Lancet Neurol. 24 (8): 656–666. doi:10.1016/S1474-4422(25)00174-7. PMID 40683275 Check
|pmid=value (help). - ↑ Hoffmann-La Roche. "A Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Teriflunomide in Adult Participants With Relapsing Multiple Sclerosis (FENhance): NCT04586010". ClinicalTrials.gov. U.S. National Library of Medicine. Retrieved 2026-09-01.
- ↑ Hoffmann-La Roche. "A Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Ocrelizumab in Adult Participants With Primary Progressive Multiple Sclerosis: NCT04544449". ClinicalTrials.gov. U.S. National Library of Medicine. Retrieved 2026-09-01.
- ↑ Wiendl H, Airas L, Chitnis T, et al. (2023). "Phase 3 REMODEL I/II Trials: Efficacy, Safety, and Tolerability of Remibrutinib in Patients with Relapsing Multiple Sclerosis [conference abstract]". Mult Scler Relat Disord. 80: 105315. doi:10.1016/j.msard.2023.105315.
- ↑ Novartis Pharmaceuticals. "A Study to Evaluate the Efficacy and Safety of Remibrutinib in Secondary Progressive Multiple Sclerosis: NCT07225504". ClinicalTrials.gov. U.S. National Library of Medicine. Retrieved 2026-09-01.
- ↑ Vermersch P, Granziera C, Mao-Draayer Y, et al. (2024). "Inhibition of CD40L with Frexalimab in Multiple Sclerosis". N Engl J Med. 390 (7): 589–600. doi:10.1056/NEJMoa2309439. PMID 38354138 Check
|pmid=value (help). - ↑ Sanofi. "Efficacy and Safety Studies of Frexalimab in Adults With Relapsing Forms of Multiple Sclerosis: NCT06141473". ClinicalTrials.gov. U.S. National Library of Medicine. Retrieved 2026-09-01.
- ↑ Sanofi. "Efficacy and Safety Study of Frexalimab (SAR441344) in Adults With Nonrelapsing Secondary Progressive Multiple Sclerosis (FREVIVA): NCT06141486". ClinicalTrials.gov. U.S. National Library of Medicine. Retrieved 2026-09-01.
- ↑ Fox RJ, Wiendl H, Wolf C, et al. (2024). "Safety and Dose-Response of Vidofludimus Calcium in Relapsing Multiple Sclerosis: Extended Results of a Placebo-Controlled Phase 2 Trial". Neurol Neuroimmunol Neuroinflamm. 11 (3): e200208. doi:10.1212/NXI.0000000000200208. PMID 38662979 Check
|pmid=value (help). - ↑ Immunic AG. "Study to Evaluate the Efficacy, Safety, and Tolerability of IMU-838 in Patients With Relapsing Multiple Sclerosis (ENSURE-1): NCT05134441". ClinicalTrials.gov. U.S. National Library of Medicine. Retrieved 2026-09-01.
- ↑ 12.0 12.1 Roche (2026-02-07). "Roche's fenebrutinib is the first investigational medicine in over a decade that reduces disability progression in primary progressive multiple sclerosis (PPMS)". Roche. Retrieved 2026-09-01.
- ↑ Roche (April 2026). "Roche's fenebrutinib significantly reduced relapses versus standard of care to approximately one every 17 years in RMS". Roche. Retrieved 2026-09-01.
- ↑ Novartis (2026-09-01). "Novartis remibrutinib, a high-efficacy oral BTK inhibitor, significantly reduces relapse rates and shows favorable safety profile in Phase III RMS trials". Novartis. Retrieved 2026-09-01.
- ↑ Green AJ, Gelfand JM, Cree BA, et al. (2017). "Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial". Lancet. 390 (10111): 2481–2489. doi:10.1016/S0140-6736(17)32346-2. PMID 29029896.
- ↑ Kocot J, Kosa P, Ashida S, et al. (2025). "Clemastine fumarate accelerates accumulation of disability in progressive multiple sclerosis by enhancing pyroptosis". J Clin Invest. 135 (10): e183941. doi:10.1172/JCI183941.
- ↑ Riboni-Verri G, McMurran CE, Mukherjee T, et al. (2025). "The Cambridge Centre for Myelin Repair trial Two (CCMR Two): a trial protocol for a phase 2a, randomised, double-blind, placebo-controlled clinical trial of the ability of the combination of metformin and clemastine to promote remyelination in people with relapsing-remitting multiple sclerosis already on disease-modifying therapy". Trials. 26 (1): 562. doi:10.1186/s13063-025-09254-2. PMID 41361285 Check
|pmid=value (help). - ↑ Cambridge Clinical MS Research Group (2025-09-26). "CCMR Two Results Presented During Late Breaking Abstracts Session at ECTRIMS 2025". Cambridge Clinical MS Research. Retrieved 2026-09-01.
- ↑ Fischbach F, Richter J, Pfeffer LK, et al. (2024). "CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis". Med. 5 (6): 550–558.e2. doi:10.1016/j.medj.2024.03.002. PMID 38554710 Check
|pmid=value (help). - ↑ Qin C, Dong MH, Zhou LQ, et al. (2025). "Anti-BCMA CAR-T therapy in patients with progressive multiple sclerosis". Cell. 188 (23): 6414–6423.e11. doi:10.1016/j.cell.2025.09.020. PMID 41101309 Check
|pmid=value (help). - ↑ Hemmer B, Gehring K; et al. (2026-04-27). "Diagnose und Therapie der Multiplen Sklerose, Neuromyelitis-optica-Spektrum-Erkrankung (NMOSD) und MOG-IgG-assoziierten Erkrankung (MOGAD): S2k-Leitlinie, Living Guideline, Version 9.0" (PDF). AWMF Registry Number 030-050 (in German). Deutsche Gesellschaft für Neurologie. Retrieved 2026-09-01.
- ↑ 22.0 22.1 22.2 Sharrack B, Saccardi R, Alexander T, et al. (2020). "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 Transplant. 55 (2): 283–306. doi:10.1038/s41409-019-0684-0.
- ↑ Uccelli A, Laroni A, Ali R, et al. (2021). "Safety, tolerability, and activity of mesenchymal stem cells versus placebo in multiple sclerosis (MESEMS): a phase 2, randomised, double-blind crossover trial". Lancet Neurol. 20 (11): 917–929. doi:10.1016/S1474-4422(21)00301-X. PMID 34687636 Check
|pmid=value (help). - ↑ Kvistad CE, Kråkenes T, Holmøy T, et al. (2026). "Intrathecal Mesenchymal Stem Cells in Progressive Multiple Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial (SMART-MS)". Neurology. 106 (10): e214915. doi:10.1212/WNL.0000000000214915. PMID 42081777 Check
|pmid=value (help). - ↑ Genchi A, Brambilla E, Sangalli F, et al. (2023). "Neural stem cell transplantation in patients with progressive multiple sclerosis: an open-label, phase 1 study". Nat Med. 29 (1): 75–85. doi:10.1038/s41591-022-02097-3. PMID 36624312 Check
|pmid=value (help). - ↑ Zubizarreta I, Florez-Grau G, Vila G, et al. (2019). "Immune tolerance in multiple sclerosis and neuromyelitis optica with peptide-loaded tolerogenic dendritic cells in a phase 1b trial". Proc Natl Acad Sci U S A. 116 (17): 8463–8470. doi:10.1073/pnas.1820039116. PMID 30962374.
- ↑ Cellerys AG. "Peptide-coupled Red Blood Cells for the Treatment of Multiple Sclerosis (RED4MS): NCT06430671". ClinicalTrials.gov. U.S. National Library of Medicine. Retrieved 2026-09-01.