# paper.pdf ## Metadata - PDFFormatVersion=1.4 - Language=EN - IsLinearized=false - IsAcroFormPresent=false - IsXFAPresent=false - IsCollectionPresent=false - IsSignaturesPresent=false - Author=Riley Bove - CreationDate=D:20260629153537+05'30' - Creator=Springer - Custom.CrossMarkDomains[1]=springer.com - Custom.CrossMarkDomains[2]=springerlink.com - Custom.CrossmarkDomainExclusive=true - Custom.CrossmarkMajorVersionDate=2010-04-23 - Custom.doi=10.1007/s00415-026-13960-5 - Custom.robots=noindex - Keywords=Relapsing Multiple Sclerosis (RMS); Ofatumumab; Treatment Switch; Disease-Modifying Therapies (DMTs); Fingolimod; Fumarates - ModDate=D:20260629161928+02'00' - Producer=Acrobat Distiller 10.1.8 (Windows); modified using iText® 5.5.13.4 ©2000-2024 iText Group NV (SPRINGER SBM; licensed version) - Subject=Journal of Neurology, https://doi.org/10.1007/s00415-026-13960-5 - Title=Efficacy and safety of ofatumumab in participants with relapsing multiple sclerosis and breakthrough disease on oral fingolimod or fumarates: results from the ARTIOS study - Trapped=False - dc:publisher=Springer Berlin Heidelberg - dc:description=Journal of Neurology, https://doi.org/10.1007/s00415-026-13960-5 - dc:subject=Relapsing Multiple Sclerosis (RMS),Ofatumumab,Treatment Switch,Disease-Modifying Therapies (DMTs),Fingolimod,Fumarates - dc:title=Efficacy and safety of ofatumumab in participants with relapsing multiple sclerosis and breakthrough disease on oral fingolimod or fumarates: results from the ARTIOS study - dc:creator=Riley Bove,Dawn Langdon,Maciej Maciejowski,Elżbieta Jasińska,Michal Dufek,Anil Abeyewickreme,Anamaria Rauh,Haoyi Fu,Imran Ali Khan,Matthias Böhringer,Sara Madueno Eichau,Tobias Derfuss - crossmark:crossmarkdomains=springer.comspringerlink.com - pdfx:crossmarkdomains=springer.comspringerlink.com ## Contents ### Page 1 Vol.:(0123456789)Journal of Neurology (2026) 273:434 https://doi.org/10.1007/s00415-026-13960-5ORIGINAL COMMUNICATIONEfficacy and safety of ofatumumab in participants with relapsing multiple sclerosis and breakthrough disease on oral fingolimod or fumarates: results from the ARTIOS studyRiley Bove1 · Dawn Langdon2 · Maciej Maciejowski3 · Elżbieta Jasińska4 · Michal Dufek5 · Anil Abeyewickreme6 · Anamaria Rauh7 · Haoyi Fu8 · Imran Ali Khan9 · Matthias Böhringer10 · Sara Madueno Eichau11 · Tobias Derfuss12Received: 30 March 2026 / Revised: 12 June 2026 / Accepted: 13 June 2026 © The Author(s) 2026AbstractBackground Initiating high-efficacy disease-modifying therapies (DMTs) early in relapsing multiple sclerosis (RMS) can reduce inflammation and limit disability progression; however, moderate-efficacy oral DMTs remain common first-line treatments. Ofatumumab demonstrated superior efficacy and tolerable safety in the phase 3 ASCLEPIOS trials, although few participants (≤ 5%) transitioned from oral DMTs. ARTIOS evaluated the efficacy and safety of ofatumumab in adults with RMS switching from fingolimod or fumarates following breakthrough disease.Methods ARTIOS was a phase 3b, open-label, single-arm, multicenter, noncomparative study. Primary endpoint was annu- alized relapse rate (ARR); secondary endpoint was safety.Results 562 adults on fingolimod (n = 181) or fumarates (n = 381) with breakthrough disease, defined as ≥ 1 relapse in prior year or ≥ 2 relapses in prior 2 years and/or magnetic resonance imaging (MRI) evidence of disease activity in prior year, were enrolled. The primary endpoint was met, with a low ARR overall (0.06; 95% CI: 0.05–0.08; p < 0.0001) and by prior DMT (fingolimod: 0.09; 95% CI: 0.06–0.1; fumarates: 0.06; 95% CI: 0.04–0.08), despite greater baseline disease severity with fingolimod. Ofatumumab resulted in near-complete suppression of MRI lesions, and 90.9% of participants achieved no evidence of disease activity, regardless of prior DMT. Six-month confirmed disability worsening occurred in few participants (7.3%). Safety outcomes were consistent with those of prior studies; most treatment-emergent adverse events (TEAEs) were mild to moderate, serious TEAEs were uncommon (5.9%), and rates of treatment discontinuations and interruptions were low.Conclusions ARTIOS complements the ASCLEPIOS studies and supports ofatumumab following switch from oral DMTs.Trial registration ClinicalTrials.gov, NCT04353492; April 20, 2020.Keywords Relapsing Multiple Sclerosis (RMS) · Ofatumumab · Treatment Switch · Disease-Modifying Therapies (DMTs) · Fingolimod · Fumarates* Tobias DerfussTobias.Derfuss@usb.ch 1 University of California San Francisco, San Francisco, CA, USA 2 Royal Holloway, University of London, London, UK 3 MA-LEK, MS Center, Katowice, Poland 4 Collegium Medicum, Jan Kochanowski University, Kielce, Poland 5 First Department of Neurology, St. Anne’s University Hospital, Masaryk University, Brno, Czechia 6 Novartis Pharmaceuticals UK, London, UK 7 Novartis Pharma AG, Basel, Switzerland 8 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA 9 Novartis Healthcare Private Limited, Hyderabad, India 10 Neurozentrum Bielefeld, Bielefeld, Germany 11 Department of Neurology, Hospital Universitario Virgen Macarena, Seville, Spain 12 Neurology Clinic and Policlinic and Research Center for Clinical Neuroimmunology and Neuroscience, Departments of Medicine and Biomedicine, University Hospital and University of Basel, Basel, Switzerland ### Page 2 Journal of Neurology (2026) 273:434434 Page 2 of 13IntroductionMultiple sclerosis (MS) specialists have shifted toward ini- tiating high-efficacy therapies (HETs) early in disease to optimize patient outcomes, including reduced inflammatory activity, neuronal injury, and disability [1–5]. Across pro- spective and retrospective studies, interventional trials and observational real-world studies in MS, early initiation of HETs, such as anti-CD20 monoclonal antibodies, improves long-term outcomes by reducing inflammatory activity and slowing disability progression [6–11]. Despite these find- ings, moderate-efficacy oral therapies, such as fingolimod or fumarates, are still often used as first-line treatments, due to being perceived as safer [1, 4]. If disease is not well controlled on such treatments, early switch to HETs can help avoid further central nervous system damage and may be preferable to cycling between lower-efficacy therapies, which remains common but can increase risk of disability worsening and progression [1, 5]. Ofatumumab, a fully human anti-CD20 monoclonal anti- body with a 20 mg subcutaneous monthly dosage regimen, is the only self-administered anti-CD20 therapy approved for the treatment of adults with relapsing MS (RMS). Approval was based on results of the ASCLEPIOS phase 3 trials, which established the favorable benefit-risk profile of ofa- tumumab versus teriflunomide in RMS [12–15]. However, in these pivotal studies, ≤ 5% of participants had been previ- ously treated with oral therapies. Therefore, it was important to better understand outcomes in participants switching to ofatumumab after oral therapy [16, 17]. This article reports findings from ARTIOS (NCT04353492), a phase 3b study to assess the efficacy and safety of ofatumumab in participants with RMS transitioning from fingolimod or fumarates due to breakthrough disease activity.MethodsStudy designARTIOS was a phase 3b, open-label, single-arm, multi- center, non-comparative, 96-week study of ofatumumab 20 mg administered subcutaneously every 4 weeks in par- ticipants with RMS who experienced breakthrough disease (defined in “Participants” section) while being treated with fingolimod or fumarates. The study was designed to allow alignment with locally approved ofatumumab labels and standard medical practice, providing investigators flex- ibility in assessments such as prior disease-modifying therapy (DMT) washout duration, symptoms assessment, and observation time at the site. The study consisted of three periods (Fig. 1). The screen- ing period (Part 1) lasted up to 60 days and included the transition phase, during which the exact timing between discontinuation of prior DMT and initiation of ofatumumab was determined by investigator’s clinical judgement. Dur- ing this period, participants were not permitted to receive any other DMTs. The treatment period (Part 2) consisted of induction and maintenance phases over 96 weeks. Dur- ing the induction phase (Weeks 1–4), participants received subcutaneous ofatumumab 20 mg via autoinjector on Days 1, 7, and 14. Induction was followed by a maintenance phase in which participants received subcutaneous ofatumumab 20 mg every 4 weeks, starting at Week 4. The safety follow- up period (Part 3) lasted ≤ 6 months and applied to par- ticipants who completed the treatment period without con- tinuing ofatumumab post-trial and those who prematurely discontinued treatment during the study. The ARTIOS protocol was reviewed and approved by an Institutional Review Board/Independent Ethics Com- mittee at each participating site (Online Resource Table 1). ARTIOS was conducted in accordance with the Declaration of Helsinki and Council for International Organizations of Medical Sciences international ethical guidelines, applicable ICH Good Clinical Practice guidelines, and all applicable laws and regulations.ParticipantsAll participants provided written informed consent. Enrolled participants included adults (aged 18–60 years) with RMS, including active secondary progressive MS [18], diagnosed according to the 2017 revised McDonald criteria [19]; an Expanded Disability Status Scale (EDSS) score of 0 to 4 at screening; prior treatment with a maximum of 3 DMTs; and transitioning from either fingolimod or fumarates administered for ≥ 6 months as their last prior DMT. Par- ticipants had to have breakthrough disease activity while receiving adequate treatment with fingolimod or fumarates for ≥ 6 months prior to transitioning. Breakthrough disease was defined as ≥ 1 documented relapse in the previous year or ≥ 2 relapses in previous 2 years; ≥ 1 gadolinium-enhanc- ing (Gd +) magnetic resonance imaging (MRI) lesion within the last year; or new or enlarging T2 lesions (neT2) within the last year. Full inclusion and exclusion criteria are listed in the Supplementary Information.Endpoints and assessmentsThe primary endpoint was the annualized relapse rate (ARR), defined as the number of confirmed MS relapses measured over 96 weeks. The secondary endpoint was safety, including assessment of treatment-emergent adverse events (TEAEs), injection-related reactions ### Page 3 Journal of Neurology (2026) 273:434 Page 3 of 13 434(IRRs), and clinical laboratory evaluations, including mean immunoglobulin (Ig) G and IgM levels, and the proportion of participants discontinuing treatment due to insufficient effectiveness or for tolerability or safety reasons. Exploratory efficacy assessments included time to 6-month confirmed disability worsening (6mCDW), defined as an increase from baseline in EDSS score sustained for 6 months; number of T1 Gd + lesions per scan, number of neT2 lesions per year, and proportion of participants with no evidence of disease activity (NEDA-3) during the 96-week period, a composite endpoint defined as no con- firmed relapses, no neT2 lesions compared with baseline, no T1 Gd + lesions, and no 6mCDW. Additional exploratory endpoints included timed 25-foot walk (T25FW), nine-hole peg test (9HPT), symbol digit modalities test (SDMT), low- contrast visual acuity (LCVA), time to 6-month confirmed cognitive decline (6mCCD), serum biomarker neurofilament light chain (NfL) values, T2 lesion volume, and propor- tion of participants without MRI activity. Patient-reported outcome (PRO) assessments of the impact of MS disease included change from baseline in the Multiple Sclerosis Impact Scale 29 (MSIS-29), change from baseline on the Fatigue Scale for Motor and Cognitive Functions (FSMC), and change from baseline on the Treatment Satisfaction Questionnaire for Medication (TSQM 1.4).Statistical analysisThe full analysis set (FAS) included all study participants who were assigned and received ≥ 1 dose of the study drug. The FAS was used for all efficacy analyses except NEDA- 3, which used a modified FAS excluding participants who achieved NEDA-3 but then discontinued treatment prema- turely for reasons other than lack of efficacy or death. ARR was analyzed using a negative binomial regression model with log-link and adjusted for prior MS therapies (fingoli- mod or fumarates), number of relapses in previous year, and participant’s baseline EDSS, number of T1 Gd + lesions, and age as covariates. The natural log of the time-in-study (in years) was used as offset. Safety analyses included the Safety Set, which included all participants who received ≥ 1 dose of study drug, and used data collected through 100 days after the last study drug administration or permanent treatment discontinuation. TEAEs (new or worsening from baseline) are summarized by system organ class and/or preferred term, severity (based on the most current Common Terminology Criteria for Adverse Events grading system), adverse eventFig. 1 ARTIOS study design. a Ofatumumab 20 mg was adminis- tered subcutaneously every 4 weeks following an initial loading regimen of three 20 mg subcutaneous doses over the first 14 days (administered on Days 1, 7, and 14). b Additional follow-up vis- its occurred every 3 months (± 14 days) after the second safety follow-up visit (SF2). Participants who prematurely discontin- ued during the treatment period, as well as those who completed the study but did not continue ofatumumab treatment, entered the safety follow-up period. BL baseline; D day; EDSS Expanded Disability Status Scale; MRI magnetic resonance imaging; PROpatient-reported outcome; S screening; SF safety follow-up visit;W week ### Page 4 Journal of Neurology (2026) 273:434434 Page 4 of 13type, and relation to study drug. For exploratory endpoints, the number of T1 Gd + lesions per scan and the number of neT2 lesions per year were analyzed using a negative binomial regression model, while participants meeting NEDA-3 and 6mCDW were reported descriptively and via Kaplan–Meier estimate, respectively. Statistical hypotheses were tested at the 5% significance level, and p values less than 0.05 were considered statistically significant for the primary endpoint.ResultsPatient disposition, baseline demographics, and clinical characteristicsA total of 562 participants who had breakthrough disease on fingolimod (n = 181; 32.2%) or fumarates (n = 381; 67.8%) were enrolled. Of these, 39 participants (6.9%) discontinued the study, primarily due to participant decision (n = 24); 523 participants (93.1%) completed the 96 weeks of treatment with ofatumumab (Online Resource Fig. 1). Mean ofatu- mumab exposure was 91.8 weeks. Participants switching from fingolimod had more advanced MS at baseline compared with participants switch- ing from fumarates (Table 1). This was evidenced by longer MS disease duration since diagnosis, a greater number of relapses in the last 12–24 months prior to screening, a lower proportion of participants free of Gd + T1 lesions, higher T2 lesion volume, lower SDMT scores, and treatment with a higher number of prior DMTs in the fingolimod group compared with participants switching from fumarates (all p < 0.05; Table 1).EfficacyAnnualized relapse rate (primary endpoint)Over 96 weeks, the adjusted ARR in the overall population was low at 0.06 (95% CI: 0.05–0.08; p < 0.0001), meetingTable 1 Baseline demographics and clinical characteristics (FAS): overall and by prior DMT Unless specified otherwise, values are represented as mean ± SD. One participant with a history of 4 prior DMTs was included in both the FAS and SF; this was documented as a protocol deviation a p < 0.05 between the fingolimod and fumarate subgroups Number of participants with available data at baseline: b n = 560. c n = 379. d n = 556. e n = 178. f n = 378. g n = 561. h n = 380. i n = 180DMT disease-modifying therapy; EDSS Expanded Disability Status Scale; FAS full analysis set; Gd + gadolinium enhancing; Ig immunoglobu- lin; MS multiple sclerosis; SF safety set; SD standard deviation; SDMT symbol digit modalities test; SF safety set Characteristic Overall population (N = 562) By last prior DMT Fingolimod (n = 181) Fumarates (n = 381) Age, years 36.3 ± 9.65 36.1 ± 9.71 36.4 ± 9.63 Female, n (%) 369 (65.7) 121 (66.9) 248 (65.1) Male, n (%) 193 (34.3) 60 (33.1) 133 (34.9) EDSS 2.32 ± 1.143 2.40 ± 1.154 2.29 ± 1.137 SDMT, number of correct answers in 90 secondsa 52.8 ± 13.87b 51.1 ± 14.40a 53.6 ± 13.56a,c Proportion of participants free of Gd + T1 lesions, n (%)a 401 (71.4) 113 (62.4)a 288 (75.6)a Number of Gd + T1 lesions 1.3 ± 4.96d 1.9 ± 5.39e 1.0 ± 4.72f Total volume of T2 lesions, cm3 10.56 ± 11.68 g 12.47 ± 12.30a 9.65 ± 11.28a,h Number of prior DMTs, n (%)a 1 2 3 4 269 (47.9) 207 (36.8) 85 (15.1) 1 (0.2) 61 (33.7)a 82 (45.3)a 37 (20.4)a 1 (0.6)a 208 (54.6)a 125 (32.8)a 48 (12.6)a 0a Duration of MS since diagnosis, yearsa 5.42 ± 2.81 6.06 ± 2.72a 5.11 ± 2.81a Number of relapses in the last 12–24 months prior to screening 0.8 ± 1.04 1.1 ± 1.29a 0.8 ± 0.89a IgG, g/La 9.97 ± 2.05 g 9.10 ± 1.95a 10.38 ± 1.97a,h IgM, g/La 1.16 ± 0.64 g 0.99 ± 0.57a 1.24 ± 0.66a,h Lymphocytes (109/L)a 1.36 ± 0.55 g 1.12 ± 0.48a,i 1.48 ± 0.54a Duration of washout, days, n (%)a< 30 days≥ 30 days 251 (44.7) 311 (55.3) 47 (26.0)a 134 (74.0)a 204 (53.5)a 177 (46.5)a ### Page 5 Journal of Neurology (2026) 273:434 Page 5 of 13 434the threshold for significance. The adjusted ARR was 0.09 for participants transitioning from fingolimod (95% CI: 0.06–0.13) and 0.06 (95% CI: 0.04–0.08) for those transi- tioning from fumarates. There was a notable decrease in the adjusted ARR from Year 1 (0.10; 95% CI: 0.07–0.13) to Year 2 (0.02; 95% CI: 0.01–0.04).MRI‑associated endpointsOfatumumab treatment significantly reduced the adjusted rate of Gd + T1 lesions per scan at Week 24 (0.05; 95% CI: 0.02–0.13; p < 0.0001) compared with baseline (0.85; 95% CI: 0.59–1.21). Gd + T1 lesions were almost completely sup- pressed at Weeks 48 (0.02; 95% CI: 0.01–0.07; p < 0.0001) and 96 (0.02; 95% CI: 0.01–0.04; p < 0.0001); represent- ing reductions in detected Gd + T1 lesions of 93.7%, 97.3%, and 98.1% at Weeks 24, 48, and 96, respectively (Fig. 2a). At baseline, the proportion of participants in the fumarate subgroup with no Gd + T1 lesions was higher than in the fingolimod subgroup (76.2% versus 64.0%); however, the proportion of participants free of Gd + T1 became similar in both subgroups by Week 24 and beyond following the switch to ofatumumab, despite initial differences at baseline (Online Resource Table 2). Participants’ neT2 lesions were almost completely sup- pressed between Weeks 24 and 96 in the overall population and by prior DMT subgroup. At Week 24, the adjusted num- ber of neT2 lesions was 1.95 (95% CI: 1.61–2.37), decreas- ing to 0.16 (95% CI: 0.11–0.23) at Week 48, and 0.07 (95% CI: 0.05–0.10) at Week 96 (Fig. 2b). The decreases in the annualized neT2 lesion rate were accompanied by decreases in lesion load, as shown by decreases from baseline in T2 lesion volume (Online Resource Fig. 2).NEDA‑3In the overall population, NEDA-3 was achieved by 51.8% of participants in Year 1 (95% CI: 47.6–56.0) and 90.9% in Year 2 (95% CI: 88.4–93.3) (Fig. 3a). When stratified by prior DMT (Fig. 3b), in the fingolimod subgroup, 35.2% achieved NEDA-3 in Year 1 (95% CI: 28.2–42.2) and 88.0% in Year 2 (95% CI: 83.1–92.9). In the fumarate subgroup, 59.8% achieved NEDA-3 in Year 1 (95% CI: 54.8–64.8) and 92.2% in Year 2 (95% CI: 89.4–95.0).6mCDWDuring the 96-week treatment period, 40 participants expe- rienced 6mCDW (7.3%; 95% CI: 5.4–9.9) (Fig. 4), includ- ing 15 who switched from fingolimod (8.5%; 95% CI: 5.2–13.8) and 25 who switched from fumarates (6.8%; 95% CI: 4.6–9.9).Additional exploratory endpoints and PROsNo deterioration in function was identified across explora- tory endpoints and PROs. Scores for the T25FW, 9HPT, SDMT, and LCVA remained stable, with changes from baseline not reaching clinically meaningful thresholds (Online Resource Figs. 3–6). For the 6mCCD, the cumula- tive event rates were 11.4% and 11.9% at Year 1 and Year 2, respectively (Online Resource Table 3). NfL concentra- tions decreased from Week 24 and remained stable through 96 weeks (Online Resource Fig. 7). Among the PROs assessed, TSQM scores exhibited gradual improvements over the course of the study, as illustrated by higher overall patient satisfaction, treatment effectiveness, and treatment convenience (Online Resource Fig. 8). MSIS-29 physical and psychological domain scores remained stable, with no indication of functional decline (Online Resource Fig. 9). Similarly, changes versus baseline in fatigue scores per the FSMC did not show deterioration, with no clinically meaningful changes observed through the treatment period (Online Resource Table 4).SafetyTEAEs and TEAEs stratified by last prior DMT are shown in Table 2. Overall, 509 participants (90.6%) reported a TEAE, with similar percentages between those switching from fingolimod (90.1%) or fumarates (90.8%). Most TEAEs (90.6%) were mild or moderate (grade 1 or 2) in severity. Infections and infestations were the most frequently reported system organ class (SOC), with TEAEs reported in 69.8% of participants. TEAEs by preferred term that occurred in ≥ 10% of par- ticipants are listed in Online Resource Table 5. The most common TEAEs were systemic IRRs (53.4%), followed by COVID-19 (37.0%), nasopharyngitis (17.1%) and headache (16.4%). COVID-19 cases were predominantly mild or moderate (99.5%), with 1 case classified as grade 3. Seri- ous TEAEs were reported in 33 participants (5.9%), with 13 (7.2%) switching from fingolimod and 20 (5.2%) switching from fumarates (Online Resource Table 6). Three serious TEAEs were reported by > 1 participant: uterine leiomy- oma, suicidal ideation, and intervertebral disc protrusion were reported in 2 participants (0.4%) each. No deaths were reported during the study or the subsequent safety assess- ment period. TEAEs resulting in treatment interruption were reported in 33 participants (5.9%) (Online Resource Table 7), largely arising from COVID-19 (23 [4.1%]). Five participants (0.9%) discontinued ofatumumab treatment due to TEAEs, including COVID-19 (n = 1), abnormal MRI (consisting of a lesion initially suspicious for progressive multifocal leu- koencephalopathy, later confirmed as new MS lesions, that ### Page 6 Journal of Neurology (2026) 273:434434 Page 6 of 13led to study discontinuation based on investigator judgment; n = 1), and cancer (n = 3). Cancer cases included adenocar- cinoma (n = 1), bladder cancer (n = 1), and medullary carci- noma of breast (n = 1).Injection‑related reactionsA breakdown of systemic IRRs is detailed in Fig. 5. Local- site IRRs were reported in 62 participants (11.0%). Nearly all systemic IRRs (296 of 299) were mild to moderate in severity, with grade 1 systemic IRRs reported in 200 partici- pants (35.6%), grade 2 in 96 participants (17.1%), and grade 3 in 3 participants (0.5%). The incidence of systemic IRRs decreased substantially after the first injection (45.6% fol- lowing the first injection versus a cumulative 7.6% across all subsequent injections; Fig. 5). All local-site IRRs were mild to moderate in severity (grade 1 or 2). No grade 4 or seri- ous IRR events were reported. The most common symptomFig. 2 MRI activity in the overall population over 96 weeks following the switch from fingolimod or fumarates to ofatumumab. a Adjusted rate of Gd + T1 lesions per scan, estimated using a negative bino- mial regression model with a log link, adjusted for prior MS therapy (fingolimod or fumarates) and visit as factors, and for number of relapses in the previous year, baseline EDSS score, and age at base- line as covariates. The natural log of the number of scans was used as an offset for Gd + lesions; b Annualized rate of new or enlarging T2 lesions, estimated using a negative binomial regression model with a log link, adjusted for prior MS therapy and visit as factors, and for number of relapses in the previous year, baseline EDSS score, age at baseline, and baseline T2 lesion volume as covariates. The natural log of time since the previous MRI scan (in years) was used as an offset.EDSS Expanded Disability Status Scale; Gd+ gadolinium-enhancing;MRI magnetic resonance imaging; MS multiple sclerosis; neT2 new or enlarging T2 ### Page 7 Journal of Neurology (2026) 273:434 Page 7 of 13 434associated with systemic IRRs was fever, followed by chills and headache. No IRRs led to treatment interruption or discontinuation.IgG/IgM levelsMean serum IgG levels remained stable and above the lower limit of normal (LLN; 5.65 g/mL) through Week 96 for the overall study population and in both prior DMT subgroups (Online Resource Fig. 10). Mean serum IgM levels in the overall study population and prior DMT sub- groups decreased from baseline to Week 96 but remained above the LLN (0.4 g/L) at all time points. A low num- ber of participants had ≥ 1 Ig level below LLN post baseline (2.1% for IgG and 22.8% for IgM); these events were not associated with severe infections or treatment discontinuations.Fig. 3 Proportion of participants achieving NEDA-3 in Years 1 and 2 following switch to ofatumumab treatment, measured overall and by prior DMT. a NEDA-3 by year in the overall population; and b NEDA-3 by prior DMT subgroup by year, where NEDA-3 was defined as no 6mCDW, no confirmed MS relapse, no new or enlarging T2 lesions compared with baseline, and no gadolinium- enhancing (Gd +) T1 lesions. The modified FAS for NEDA-3 included all participants in the FAS, but participants who dis- continued from the study treatment prematurely for reasons other than lack of efficacy or death and achieved NEDA-3 before treat- ment discontinuations were excluded. 6mCDW 6-month confirmed disability worsening; DMT disease-modifying therapy; FAS full analysis set; M total number of participants in the treatment group with response variable defined; n number of participants achieving NEDA-3; NEDA no evidence of disease activity ### Page 8 Journal of Neurology (2026) 273:434434 Page 8 of 13Post hoc efficacy and safety analysesPost hoc efficacy analysis revealed no clinically meaning- ful differences in efficacy endpoints when analyzed by washout duration before switching to ofatumumab (Online Resource Figs. 11–15). Rebaselining efficacy endpoints at Month 6 resulted in outcomes similar to those in the original dataset (Online Resource Tables 8–11), although the proportion of participants experiencing 6mCDW decreased following rebaselining (Fig. 4). Safety out- comes were generally consistent across washout dura- tions, with types of TEAEs occurring in ≥ 10% of par- ticipants being comparable across subgroups (Online Resource Table 12).Fig. 4 Number of 6mCDW events over the 96-week treatment period in the overall population. 6mCDW 6-month confirmed disability worsen- ing; KM Kaplan–Meier; OMB ofatumumabTable 2 Safety profile in participants receiving ofatumumab: overall and by prior DMT a A total of 41 (7.3%) participants had grade 3 or 4 AEs b Reasons for treatment discontinuation include COVID-19 (n = 1), abnormal MRI (consisting of a lesion initially suspicious for progressive multifocal leukoencephalopathy, later confirmed as new MS lesions, that led to study discontinuation based on investigator judgment; n = 1), and neoplasms (benign, malignant, and unspecified [including cysts and polyps]) (n = 3) c Drug interruptions were caused by gastrointestinal disorders (n = 3), infections and infestations (n = 32; COVID-19 [n = 23]), UTI [n = 2], other infections and infestations [n = 9]), migraine (n = 1) and suicidal ideation (n = 1). Participants could have discontinued or interrupted drug for ≥ 1 AEAE adverse event; DMT disease-modifying therapy; MRI magnetic resonance imaging; SAE serious adverse event; UTI urinary tract infection All grades, n (%) Overall population (N = 562) By last prior DMT Fingolimod (n = 181) Fumarates (n = 381) Participants with ≥ 1 AE 509 (90.6)a 163 (90.1) 346 (90.8) Participants with ≥ 1 SAE 33 (5.9) 13 (7.2) 20 (5.2) Participants with drug-related AE(s) 374 (66.5) 115 (63.5) 259 (68.0) Participants with AE(s) causing study drug discontinuations 5 (0.9)b 3 (1.7) 2 (0.5) Participants with AE(s) causing study drug interruptions 33 (5.9)c 11 (6.1) 22 (5.8) ### Page 9 Journal of Neurology (2026) 273:434 Page 9 of 13 434DiscussionARTIOS demonstrated that people with RMS switching to ofatumumab after breakthrough disease on fingolimod or fumarates had a substantial reduction in relapses and MRI activity, and few 6mCDW events. Initial baseline characteristics indicated more advanced disease among participants switching from fingolimod than in those switching from fumarates. Despite these differences, ofatumumab treatment demonstrated consistent and com- parable efficacy levels across both prior DMT subgroups. Ofatumumab treatment resulted in a low ARR (0.06) over 96 weeks in the overall population, and in each prior DMT subgroup (fingolimod, 0.09; fumarates, 0.06). Over- all, the low ARRs observed with ofatumumab in ARTIOS are consistent with those seen in participants treated with ofatumumab in the ASCLEPIOS trials [14]. The switch to ofatumumab also resulted in a substantial reduction of MRI activity in the overall population and by prior DMT. Ofatu- mumab treatment significantly reduced the rate of Gd + T1 lesions at Week 24 versus baseline, and Gd + T1 lesions were almost completely suppressed at Weeks 48 and 96. Similarly, ofatumumab almost completely suppressed neT2 lesions at Week 48 and 96 compared with Week 24, and reductions in MRI lesion load versus baseline were seen at Weeks 48 and 96. Overall, the ARR and MRI results sup- port the strong anti-inflammatory effects of ofatumumab in participants with RMS and, particularly, in participants with breakthrough disease despite treatment with oral fingolimod or fumarates. The low percentage (7.3%) of participants with 6mCDW events over the 2-year study duration further supports the clinical impact of ofatumumab treatment, consistent with confirmed disability worsening event rates seen with other anti-CD20 agents [20]. The low rates of ARR, near-complete suppression of MRI activity, and few 6mCDW events led to high NEDA-3 rates, with > 9 of every 10 participants (90.9%) experienc- ing NEDA-3 in Year 2, with similar outcomes observed in both prior DMT subgroups despite the initial difference in baseline disease activity. Achieving NEDA-3 during the first 2 years of treatment has been associated with a lower risk of long-term disability [21, 22], further supporting the switch to HETs among participants experiencing suboptimal responses to fingolimod or fumarates. Concentrations of NfL, a neuron-specific protein that is a marker of neuro-axonal damage in neurological dis- ease, decreased from Week 24 following the switch to ofatumumab and then remained stable through 96 weeks [23–25]. The reduction and stabilization of serum NfLFig. 5 Overall incidence of systemic injection-related reactions by injection number and severity. The injection number reflects the sequential number of actual injections received. M is the number of participants with the specified injections (% = n/M × 100). A partici- pant with multiple events of the same symptom is counted only once per injection. IRR injection-related reaction; M total number of par- ticipants with the specified injections; n number of participants with any symptom ### Page 10 Journal of Neurology (2026) 273:434434 Page 10 of 13levels observed following the switch to ofatumumab are consistent with improved MS disease control and with observed ARR and MRI improvements seen in the cur- rent study. Additional exploratory efficacy assessments, including assessments for ambulation (T25FW), upper limb function (9HPT), cognitive processing speed (SDMT), and visual acuity (LCVA) indicated stability in disease measures over time, with all endpoints remaining functionally stable. Over- all, 11.4% and 11.9% of participants experienced 6mCCD in Years 1 and 2, respectively, supporting an apparent stabiliza- tion of cognitive decline in Year 2 of ofatumumab treatment. Regarding PRO assessments, MSIS-29 and FSMC scores remained stable over the course of study, while TSQM scores improved, indicating higher patient satisfaction, effec- tiveness, and convenience after switching to ofatumumab [26]. This result may be a positive indication for strong future adherence [27]. Recurring disease activity is a known risk factor for par- ticipants discontinuing fingolimod therapy [16, 17]. While no notable evidence of rebound was observed in this study (as demonstrated by the similarity in efficacy endpoints when analyzed by washout duration), participants switch- ing from fingolimod after a 30-to-60–day washout showed a small, nonsignificant increase in Gd + T1 lesions and neT2 lesions compared with those who had a washout duration of < 30 days. Increases of a similar extent were not observed in participants with washout durations ≥ 60 days (possibly due to rebound activity occurring prior to the screening period), and clinically meaningful improvements in effi- cacy outcomes (ARR, MRI lesions, and NEDA-3) were not observed in the Month 6 rebaselined analyses. While further data is needed for more definitive conclusions, these pre- liminary findings may help inform clinicians of the potential advantages of a shorter (< 30-day) washout in preventing rebound potential. Additionally, no safety concerns were identified that would preclude a shorter washout duration. The overall safety profile of ofatumumab in the ARTIOS study was consistent with previous findings [28–30]. Most TEAEs (90.6%) were mild to moderate, with low rates of serious TEAEs and treatment discontinuations or inter- ruptions. Overall rates of TEAEs and serious TEAEs in ARTIOS were similar to those reported in the pivotal ASCLEPIOS trials [14]. In ARTIOS, the most frequent TEAEs by SOC were infections and infestations; however, the study was initiated during the first year of the COVID-19 pandemic, which may have impacted this finding. Exclud- ing COVID-19 cases, the infection rates were lower than in the ASCLEPIOS trials [14]. In ARTIOS, most COVID-19 cases were mild or moderate, with only 1 case classified as grade 3. These findings are noteworthy and highlight a safety profile of ofatumumab differentiated from that of other anti- CD20 agents, as prior studies reported an increased risk of severe COVID-19 outcomes among people with MS treated with certain anti-CD20 therapies [31, 32]. While a higher rate of IRRs was observed in ARTIOS compared with ASCLEPIOS [14], most IRRs were mild to moderate, with few Grade 3 IRRs reported. Most IRRs occurred after the first injection, and none led to treatment discontinuation or interruption. Notably, premedication use was lower in ARTIOS compared with ASCLEPIOS, which may have contributed to the higher incidence of IRRs reported in ARTIOS [14]. Mean IgG and IgM levels were also consistent with previously reported findings for ofatu- mumab, with mean serum IgG levels remaining stable and above the LLN (5.65 g/L) for ≤ 2 years, and mean serum IgM levels decreasing from baseline to Week 96 but remain- ing above the LLN (0.4 g/L). Of note, long-term data from the ALITHIOS open-label extension study demonstrated that mean IgG levels remained stable and above the LLN with continued ofatumumab treatment [29, 33]. Sustained Ig levels may differentiate ofatumumab from other anti-CD20 therapies and could be relevant to the favorable COVID-19 outcomes observed in participants treated with ofatumumab [14]. Although IgG and IgM levels were lower at baseline in the fingolimod subgroup compared with the fumarate sub- group, no differences in IgG or IgM levels were observed following the switch to ofatumumab, in line with prior long- term data [29]. Limitations of the study include the single-arm design, which limits the ability to draw definitive conclusions regarding efficacy or to compare outcomes in patients switching from fingolimod or fumarates to a different HET, as well as the short follow-up period. In addition, as par- ticipants were enrolled during periods of breakthrough dis- ease activity, the potential for outcomes to be partly due to “regression to the mean” should be considered. Lastly, due to the low number of participants aged > 55 years and the short study duration, the ability to assess potential impact of older age on NfL levels may have been limited, which should be considered when interpreting results for this exploratory endpoint. Strengths include the assessment of a patient pop- ulation often encountered in clinical practice (participants with breakthrough disease despite receiving oral DMTs) who were underrepresented in the phase 3 ASCLEPIOS studies, the inclusion of several exploratory endpoints and PROs, and the study design, which allowed alignment with local labels and provided investigators flexibility in assess- ment to more closely reflect a real-world environment.ConclusionsData from the ARTIOS study supports ofatumumab as a HET with a favorable safety profile in participants with breakthrough disease on oral fingolimod or fumarates. ### Page 11 Journal of Neurology (2026) 273:434 Page 11 of 13 434Switching to ofatumumab resulted in strong disease con- trol, with consistent efficacy outcomes across prior DMT subgroups, including in participants who switched from fin- golimod, despite these participants having more advanced disease at baseline. No new safety concerns were observed, and safety findings were similar across prior DMT sub- groups and consistent with findings of previous ofatumumab trials [14]. Treatment satisfaction strengthened during the study. Overall, results from ARTIOS complement the pivotal phase 3 ASCLEPIOS studies and support the efficacy and safety of ofatumumab following switch from oral DMTs in people with RMS with suboptimal responses to fingolimod or fumarates.Supplementary Information The online version contains supplemen- tary material available at https://doi.org/10.1007/s00415-026-13960-5.Acknowledgements We thank the patients who participated in the trial and their families and caregivers, the members of the independent data monitoring committee, the members of the trial steering committee, and the staff members at each site who assisted with the study. Medical writing support was provided by Andrew Street, PhD, and Nicolette Moya, PhD, of Nucleus Global, an Inizio company, and was funded by Novartis AG Basel in accordance with Good Publication Practice guidelines.Author contributions All authors contributed to the writing and reviewing of the manuscript and approved the manuscript for submis- sion. All authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.Funding Open access funding provided by University of Basel. This study was sponsored and funded by Novartis Pharma AG, Basel.Data availability Novartis is committed to sharing with qualified exter- nal researchers, access to patient-level data and supporting clinical doc- uments from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. The trial data availability is according to the criteria and process described on http://www.clinicalstudydatarequest.com.DeclarationsConflict of interest Riley Bove has received research support from Biogen, Eli Lilly, Novartis, Roche Genentech, and TG Therapeutics; and received personal fees for consulting or advisory board participa- tion from Alexion, Cadenza, EMD Serono, Sanofi Genzyme, and TG Therapeutics. Dawn Langdon has participated in speakers bureaus for Almirall, Bayer, Biogen, Merck, Novartis, Roche, Sanofi, and Teva; has received consultancy fees from Bayer, Biogen, Merck, Novartis, and Teva; and has received research grants from Bayer, Biogen, Merck, and Novartis. Maciej Maciejowski has received compensa- tion for lectures and/or advisory board participation from Roche, Bio- gen, Novartis, Bristol Myers Squibb, and Amgen. Elżbieta Jasińska has participated in speakers bureaus for Novartis, Neuraxpharm, and Sanofi Genzyme; and served on advisory boards and/or steering com- mittees of Novartis and Biogen. Sara Madueno Eichau has received speaker honoraria and consultant fees from Biogen, Merck, Neurax- pharm, Novartis, Almirall, Roche, Sanofi, and Teva. Tobias Derfuss’s institution has received compensation from Actelion, Amgen, Alexion, Biogen, Celgene, GeNeuro, Janssen, Johnson & Johnson, Novartis, Roche, MedDay, Merck, Sanofi, and Polyneuron; and research grants from Alexion, Roche, and Biogen. An immediate family member of Tobias Derfuss has been an employee of Novartis and Roche. Anil Abeyewickreme, Anamaria Rauh, Haoyi Fu, and Imran Ali Khan are employees of Novartis. Michal Dufek and Matthias Böhringer have declared no conflicts of interest.Ethical approval The protocol was reviewed and approved by an Insti- tutional Review Board/Independent Ethics Committee at each partici- pating site in accordance with the Declaration of Helsinki and Coun- cil for International Organizations of Medical Sciences international ethical guidelines, applicable ICH Good Clinical Practice guidelines, and all applicable laws and regulations. The study was registered on ClinicalTrials.gov (NCT04353492).Consent to participate All participants provided written informed con- sent prior to study participation.Open Access This article is licensed under a Creative Commons Attri- bution 4.0 International License, which permits use, sharing, adapta- tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.References1. Singer BA, Feng J, Chiong-Rivero H (2024) Early use of high- efficacy therapies in multiple sclerosis in the United States: ben- efits, barriers, and strategies for encouraging adoption. J Neurol 271(6):3116–3130. https://doi.org/10.1007/s00415-024-12305-42. Filippi M, Amato MP, Centonze D et al (2022) Early use of high-efficacy disease-modifying therapies makes the difference in people with multiple sclerosis: an expert opinion. J Neurol 269(10):5382–5394. https://doi.org/10.1007/s00415-022-11193-w3. Ontaneda D, Chitnis T, Rammohan K et al (2024) Identification and management of subclinical disease activity in early multiple sclerosis: a review. J Neurol 271(4):1497–1514. https://doi.org/10.1007/s00415-023-12021-54. Giovannoni G, Butzkueven H, Dhib-Jalbut S et al (2016) Brain health: time matters in multiple sclerosis. Multi Scler Relat Disord 9(suppl 1):S5–S48. https://doi.org/10.1016/j.msard.2016.07.0035. Selmaj K, Cree BAC, Barnett M et al (2024) Multiple sclero- sis: time for early treatment with high-efficacy drugs. J Neurol 271(1):105–115. https://doi.org/10.1007/s00415-023-11969-86. Labiano-Fontcuberta A, Costa-Frossard L, Sainz de la Maza S et al (2022) The effect of timing of high-efficacy therapy on pro- cessing speed performance in multiple sclerosis. Multi Scler Relat Disord 64:103959. https://doi.org/10.1016/j.msard.2022.1039597. He A, Merkel B, Brown JWL et al (2020) Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study. Lancet Neurol 19(4):307–316. https:// doi. org/ 10. 1016/s1474-4422(20)30067-38. Simonsen CS, Flemmen H, Broch L et al (2021) Early high efficacy treatment in multiple sclerosis is the best predictor of future disease activity over 1 and 2 years in a Norwegian ### Page 12 Journal of Neurology (2026) 273:434434 Page 12 of 13population-based registry. Front Neurol 12:693017. https://doi.org/10.3389/fneur.2021.6930179. Iaffaldano P, Lucisano G, Caputo F et al (2021) Long-term dis- ability trajectories in relapsing multiple sclerosis patients treated with early intensive or escalation treatment strategies. Ther Adv Neurol Disord 14:17562864211019574. https://doi.org/10.1177/1756286421101957410. Rojas JI, Patrucco L, Alonso R et al (2022) Effectiveness and safety of early high-efficacy versus escalation therapy in relaps- ing-remitting multiple sclerosis in Argentina. Clin Neuropharma- col 45(3):45–51. https://doi.org/10.1097/wnf.000000000000050311. Merkel B, Butzkueven H, Traboulsee AL et al (2017) Timing of high-efficacy therapy in relapsing-remitting multiple sclerosis: a systematic review. Autoimmun Rev 16(6):658–665. https://doi.org/10.1016/j.autrev.2017.04.01012. Kesimpta (ofatumumab). Prescribing information. Novartis Pharmaceuticals Corporation; 2025. Accessed January 22, 2026. https:// www. novar tis. com/ us- en/ sites/ novar tis_ us/ files/kesimpta.pdf13. Kesimpta (ofatumumab). Summary of product characteristics. Novartis Pharmaceuticals UK. Accessed January 22, 2026. https://www.ema.europa.eu/en/documents/product-infor mation/kesimpta-epar-product-infor mation_en.pdf14. Hauser SL, Bar-Or A, Cohen JA et al (2020) Ofatumumab versus teriflunomide in multiple sclerosis. N Engl J Med 383(6):546–557. https://doi.org/10.1056/NEJMoa191724615. FDA approves Novartis Kesimpta® (ofatumumab), the first and only self-administered, targeted B-cell therapy for patients with relapsing multiple sclerosis. Novartis; 2020. Accessed March 3, 2026. https://www.novartis.com/news/media-releases/fda-approves- novar tis- kesimpta- ofatu mumab- first- and- only- self- administered-targeted-b-cell-therapy-patients-relapsing-multiple-sclerosis16. Cerdá-Fuertes N, Nagy S, Schaedelin S et al (2023) Evaluation of frequency, severity, and independent risk factors for recur- rence of disease activity after fingolimod discontinuation in a large real-world cohort of patients with multiple sclerosis. Ther Adv Neurol Disord 16:17562864221150312. https://doi.org/10.1177/1756286422115031217. Rowles WM, Hsu WY, McPolin K et al (2022) Transitioning from S1P receptor modulators to B cell-depleting therapies in multiple sclerosis: clinical, radiographic, and laboratory data. Neurol Neuroimmunol Neuroinflamm 9(4):e1183. https://doi.org/10.1212/nxi.000000000000118318. Lublin FD, Reingold SC, Cohen JA et al (2014) Defining the clinical course of multiple sclerosis. Neurology 83(3):278–286. https://doi.org/10.1212/wnl.000000000000056019. Thompson AJ, Banwell BL, Barkhof F et al (2018) Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 17(2):162–173. https://doi.org/10.1016/s1474-4422(17)30470-220. de Sèze J, Maillart E, Gueguen A et al (2023) Anti-CD20 thera- pies in multiple sclerosis: from pathology to the clinic. Front Immunol 14:1004795. https:// doi. org/ 10. 3389/ fimmu. 2023.100479521. Alonso R, Casas M, Lazaro L et al (2023) Achieving no evi- dence of disease activity-3 in highly active multiple sclerosis patients treated with cladribine and monoclonal antibodies. Mult Scler J Exp Transl Clin 9(1):20552173231154712. https://doi.org/10.1177/2055217323115471222. Rotstein DL, Healy BC, Malik MT et al (2015) Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. JAMA Neurol 72(2):152–158. https://doi.org/10.1001/jamaneurol.2014.353723. Gaetani L, Blennow K, Calabresi P et al (2019) Neurofilament light chain as a biomarker in neurological disorders. J Neurol Neurosurg Psychiatry 90(8):870–881. https://doi.org/10.1136/jnnp-2018-32010624. Khalil M, Teunissen CE, Lehmann S et al (2024) Neurofila- ments as biomarkers in neurological disorders - towards clinical application. Nat Rev Neurol 20(5):269–287. https://doi.org/10.1038/s41582-024-00955-x25. Siller N, Kuhle J, Muthuraman M et al (2019) Serum neurofila- ment light chain is a biomarker of acute and chronic neuronal damage in early multiple sclerosis. Mult Scler 25(5):678–686. https://doi.org/10.1177/135245851876566626. Ross AP, Nicholas J, Tai MH et al (2025) Real-world satis- faction and experience with injection and autoinjector device for ofatumumab indicated for multiple sclerosis. BMC Neurol 25(1):28. https://doi.org/10.1186/s12883-024-04007-127. Singer BA, Morgan D, Stamm JA et al (2024) Patient and physician perspectives of treatment burden in multiple scle- rosis. Neurol Ther 13(6):1507–1525. https:// doi. org/ 10. 1007/s40120-024-00654-128. Awada Z, Hameed N, Harel A (2024) Profile of ofatumumab in the treatment of multiple sclerosis: design, development and place in therapy. Drug Des Devel Ther 18:5985–5996. https://doi.org/10.2147/dddt.S31517429. Hauser SL, Cohen JA, de Sèze J et al (2025) Five-year safety and efficacy outcomes with ofatumumab in patients with relaps- ing multiple sclerosis. Neurol Ther 14(5):1975–1992. https://doi.org/10.1007/s40120-025-00784-030. Pardo G, Bar-Or A, Montalban X et al (2025) Continuous ofatu- mumab treatment up to 7 years shows a consistent safety profile and delays disability progression in people with relapsing multi- ple sclerosis (P7-1.016). Neurology 104(suppl 7):2630. https://doi.org/10.1212/WNL.000000000021047431. Sormani MP, De Rossi N, Schiavetti I et al (2021) Disease- modifying therapies and coronavirus disease 2019 severity in multiple sclerosis. Ann Neurol 89(4):780–789. https://doi.org/10.1002/ana.2602832. Januel E, Hajage D, Labauge P et al (2023) Association between anti-CD20 therapies and COVID-19 severity among patients with relapsing-remitting and progressive multiple sclerosis. JAMA Netw Open 6(6):e2319766. https:// doi. org/ 10. 1001/jamanetworkopen.2023.1976633. Hauser SL, Freedman MS, Nakahara J et al (2026) Six-year safety and efficacy outcomes with first-line ofatumumab in recently diagnosed treatment-naive patients with relapsing mul- tiple sclerosis. Mult Scler Relat Disord 105:106886. https://doi.org/10.1016/j.msard.2025.10688634. van Munster CE, Uitdehaag BM (2017) Outcome measures in clinical trials for multiple sclerosis. CNS Drugs 31(3):217–236. https://doi.org/10.1007/s40263-017-0412-535. Oosterveer DM, Wouda NC, Volker G et al (2024) Reliability parameters of the Timed 25-Foot-Walk (T25FW) in patients with multiple sclerosis: lower walking speed is associated with greater smallest detectable change. Multi Scler Relat Disord 88:105731. https://doi.org/10.1016/j.msard.2024.10573136. Kragt JJ, van der Linden FA, Nielsen JM et al (2006) Clinical impact of 20% worsening on Timed 25-foot Walk and 9-hole Peg Test in multiple sclerosis. Mult Scler 12(5):594–598. https://doi.org/10.1177/135245850607076837. Benedict RH, DeLuca J, Phillips G et al (2017) Validity of the Symbol Digit Modalities Test as a cognition performance out- come measure for multiple sclerosis. Mult Scler 23(5):721–733. https://doi.org/10.1177/135245851769082138. Balcer LJ, Baier ML, Cohen JA et al (2003) Contrast letter acu- ity as a visual component for the multiple sclerosis functional composite. Neurology 61(10):1367–1373. https:// doi. org/ 10.1212/01.wnl.0000094315.19931.90 ### Page 13 Journal of Neurology (2026) 273:434 Page 13 of 13 43439. Widener GL, Allen DD (2014) Measurement characteristics and clinical utility of the 29-item multiple sclerosis impact scale. Arch Phys Med Rehabil 95(3):593–594. https:// doi. org/ 10.1016/j.apmr.2013.07.00840. Atkinson MJ, Sinha A, Hass SL et al (2004) Validation of a general measure of treatment satisfaction, the treatment satis- faction questionnaire for medication (TSQM), using a national panel study of chronic disease. Health Qual Life Outcomes 2:12. https://doi.org/10.1186/1477-7525-2-1241. Penner IK, Raselli C, Stöcklin M et al (2009) The Fatigue Scale for Motor and Cognitive Functions (FSMC): validation of a new instrument to assess multiple sclerosis-related fatigue. Mult Scler 15(12):1509–1517. https://doi.org/10.1177/1352458509348519