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Xiaohe Q&A 33 | Clinical Evaluation and Therapeutic Approaches
Originally published in Chinese on December 4, 2025. This commentary reflects information available as of December 4, 2025.
Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of the central nervous system (CNS). It commonly begins in young adulthood, often between ages 20 and 40, and is more common in women. Frequency varies across geographic regions and populations, with higher prevalence generally observed at higher latitudes.
Relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS) describe the principal disease courses. Radiologically isolated syndrome (RIS) and clinically isolated syndrome (CIS) describe distinct imaging or initial clinical presentations that require appropriate diagnostic assessment. The historical terms “benign” and “malignant” describe disease severity or course rather than equivalent core phenotypes. [1]
Table 1. Clinical presentations and disease courses of MS
Grouping | Type | Clinical and pathological features | Research observations requiring source confirmation |
Initial presentations | RIS | MRI lesions suggestive of demyelination without a corresponding clinical demyelinating event. | Increased HLA-DRB5 and STAT6 expression in the optic chiasm region. |
Initial presentations | CIS | A first clinical demyelinating event lasting at least 24 hours, without otherwise meeting MS diagnostic criteria; subsequent risk varies with MRI, CSF findings and follow-up. | CSF oligoclonal bands; increased CD163 and IGHG1 expression in normal-appearing white matter (NAWM). |
Principal disease courses | RRMS | Relapses alternate with partial or complete recovery; peripheral immune-cell infiltration is prominent in early inflammatory lesions. | Lesional heat-shock proteins HSPA1A/B and increased CXCL12. |
Principal disease courses | SPMS | Progressive disability following an initially relapsing-remitting course; chronic lesions accumulate and tissue repair becomes less effective. | Increased CXCL2 and SNHG15 at lesion margins; increased oligodendrocyte heterogeneity. |
Principal disease courses | PPMS | Progression from onset, commonly presenting after age 40; gray-matter involvement is an important pathological feature. | Gray-matter TNF signaling and selective loss of CUX2-positive neurons. |
Historical descriptors | Benign MS | Relatively little disability after a prolonged disease duration, often assessed after approximately 15 years; the description does not guarantee a stable future course. | Normal methylation of the oligodendrocyte survival-associated gene BCL2L2. |
Historical descriptors | Malignant MS | A rapidly aggressive course with severe disability and involvement of multiple neurological systems. | Increased HLA-family expression and altered STAT6–TGF-β signaling. |
The molecular observations in the final column are research leads presented in this article, rather than established subtype-specific diagnostic tests. Their interpretation depends on the tissue, cohort and experimental methods used.
Annualized relapse rate (ARR), the Expanded Disability Status Scale (EDSS) and magnetic resonance imaging (MRI) are central measures of disease activity and disability. Complementary assessments include the Multiple Sclerosis Functional Composite (MSFC), cerebrospinal fluid (CSF) testing and cognitive measures such as the Symbol Digit Modalities Test (SDMT).
Regular clinical and MRI monitoring supports assessment of no evidence of disease activity (NEDA). The commonly used NEDA-3 definition comprises no relapses, no confirmed disability progression and no new MRI activity. Biomarkers can provide additional information. Functional and cognitive assessments help characterize effects on daily life and quality of life. [2]
MS development encompasses established B-cell-directed treatment, investigational approaches to B-cell function and immune reconstitution, modulation of innate immunity, and strategies for neural repair. Table 2 retains the categories and representative programs discussed here, with mechanisms and historical status clarified where evidence is available. Status refers to information available by December 4, 2025.
Table 2. Representative therapeutic approaches and programs
Category | Mechanism and features | Representative therapy and historical status | Population or development rationale |
Established B-cell depletion | Anti-CD20 antibody depleting CD20-positive B cells. | Ofatumumab; approved subcutaneous therapy. [3] | Relapsing forms of MS; self-administration offers convenience. |
g-NK cell therapy | Allogeneic FcεRIγ-deficient natural killer cells; studied with antibody treatment. | IDP-023; phase 1b study with IL-2 and ocrelizumab. [4] | Refractory primary and secondary progressive MS; safety and biological activity under evaluation. |
B-cell functional modulation | Co-engagement of CD19 and FcγRIIb inhibits B-cell activity without depletion. | Obexelimab; phase 2 MoonStone. Initial results announced October 2025; 24-week results then expected in Q1 2026. [5] | Relapsing MS; functional regulation of B cells. |
BTK inhibition | Modulates B-cell and myeloid-cell signaling; CNS activity depends on the molecule. | Tolebrutinib, evobrutinib and orelabrutinib; individual programs have distinct development histories. Evobrutinib phase 3 trials did not meet their primary endpoints. [6] | Relapsing or progressive MS, depending on program; peripheral and CNS immune mechanisms. |
CAR-T cell therapy | CD19-directed depletion intended to enable sustained changes in B-cell immunity. | YTB323; early clinical investigation. | Refractory or highly active MS; benefit–risk profile remains under evaluation. |
Autologous stem-cell transplantation | Conditioning followed by autologous hematopoietic stem-cell transplantation (aHSCT) to support immune reconstitution. | aHSCT; an option for selected patients. | Carefully selected patients with highly active disease. |
CSF-1R inhibition | Investigational modulation of microglial survival or function. | AXS-02; program identity and early clinical status require confirmation. | Proposed progressive MS approach targeting innate immune and neurodegenerative processes. |
Neural protection and repair | Elezanumab binds repulsive guidance molecule A (RGMa), a regulator of neural regeneration. | Elezanumab; phase 2 RADIUS-R and RADIUS-P studies did not meet their primary endpoints. [7] | Investigated for functional recovery in relapsing and progressive MS. |
Other inflammatory pathways | Oral IL-17AA/AF pathway inhibition. | Zenas investigational program; preclinical, with clinical entry planned for 2026. [5] | Potential oral approach to inflammatory activity; MS benefit requires clinical evaluation. |
Other inflammatory pathways | Oral, brain-penetrant TYK2 inhibition, targeting cytokine signaling through the JAK–STAT pathway. | Zenas investigational program; preclinical, with clinical entry planned for 2026. [5] | Potential peripheral and CNS immune modulation. |
For repair strategies, oligodendrocyte precursor cell (OPC) differentiation and remyelination are important biological objectives. Program-specific mechanisms and clinical outcomes should guide interpretation of their contribution to functional recovery.
Experimental autoimmune encephalomyelitis (EAE) models are evaluated through complementary neurological, pathological and immune readouts.
1. Clinical scoring. Behavior-based scoring of neurological deficits and disease severity is a core efficacy endpoint.
2. Histopathology. Hematoxylin and eosin (H&E) staining assesses inflammatory-cell infiltration in the spinal cord. Luxol Fast Blue (LFB) staining evaluates demyelination. Immunofluorescence using glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (IBA1) helps characterize astrocytic and microglial responses, interpreted with morphology, distribution and quantitative measures.
3. Immunology and molecular biology. Enzyme-linked immunosorbent assay (ELISA), quantitative PCR (qPCR), flow cytometry, Western blotting and transcriptomic sequencing provide complementary mechanistic and pharmacodynamic information.
HKeyBio develops EAE models through a strategy spanning multiple species, strains, mechanisms and disease-course phenotypes. Its portfolio includes cynomolgus macaque, mouse and rat models designed to address different questions in MS-oriented research.
Table 3. HKeyBio EAE model portfolio
Species and strain | EAE model | Model characteristics |
Cynomolgus macaque | MOG35–55-induced EAE | T-cell-dominant |
Cynomolgus macaque | MOG1–125-induced EAE | B-cell and T-cell involvement |
C57BL/6 mouse | MOG1–125-induced B-cell-dependent EAE | B-cell and T-cell involvement |
C57BL/6 mouse | MOG35–55-induced T-cell-dependent EAE | T-cell-dominant |
SJL mouse | PLP-induced relapsing-remitting EAE | Relapsing-remitting course |
NOD mouse | MOG-induced EAE with a secondary progressive course | Progressive disease-course features |
Lewis rat | MBP-induced EAE | T-cell-dominant |
MOG, myelin oligodendrocyte glycoprotein; PLP, proteolipid protein; MBP, myelin basic protein. Model selection should reflect the therapeutic mechanism, species pharmacology, disease course and endpoints relevant to the development question. Different EAE models provide complementary information about human MS.
Author: Irene | Scientific review: Ding Ying | Editor: Jing Yan
HKeyBio is a preclinical contract research organization specializing in in vivo efficacy services for autoimmune disease. Its core technical team brings more than 20 years of experience in autoimmune drug development. The company is ISO 9001 certified, with molecular, cellular, pathology, small-animal and analytical testing facilities in Suzhou Industrial Park, and nonhuman primate research facilities in Guangxi and Suzhou.
HKeyBio has approximately 60 employees, with project leaders holding master’s or doctoral degrees. The team has experience supporting more than 300 investigational new drug (IND) applications and helps partners address complex questions throughout autoimmune drug development and regulatory submission.
· More than 30 nonhuman primate models of autoimmune disease.
· More than 300 animal models of autoimmune disease.
· Experience supporting more than 300 autoimmune disease IND applications.
[1] Lublin FD et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology. 2014. Source
[2] Rebaseline no evidence of disease activity (NEDA-3) as a predictor of long-term disease course in a Norwegian multiple sclerosis population. Source
[3] Novartis. FDA approves Kesimpta (ofatumumab) for relapsing multiple sclerosis. August 20, 2020. Source
[4] Stanford. IDP-023 g-NK cells plus ocrelizumab in progressive multiple sclerosis. NCT06677710. Source
[5] Zenas BioPharma. Phase 2 MoonStone results in relapsing multiple sclerosis. October 27, 2025. Source
[6] Merck KGaA. Update on phase III results for evobrutinib in relapsing multiple sclerosis. December 5, 2023. Source
[7] Randomized studies of elezanumab added to standard of care in relapsing and progressive multiple sclerosis. Ann Neurol. 2025;98:590–602. Source
