Efficacy and safety of ofatumumab in participants with relapsing multiple sclerosis and breakthrough disease on oral fingolimod or fumarates: results from the ARTIOS study

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

doi:10.1007/s00415-026-13960-5

. 2026 Jun 29;273(7):434. doi: 10.1007/s00415-026-13960-5

Efficacy and safety of ofatumumab in participants with relapsing multiple sclerosis and breakthrough disease on oral fingolimod or fumarates: results from the ARTIOS study

Riley Bove ¹, Dawn Langdon ², Maciej Maciejowski ³, Elżbieta Jasińska ⁴, Michal Dufek ⁵, Anil Abeyewickreme ⁶, Anamaria Rauh ⁷, Haoyi Fu ⁸, Imran Ali Khan ⁹, Matthias Böhringer ¹⁰, Sara Madueno Eichau ¹¹, Tobias Derfuss ^12,^✉

PMCID: PMC13315151 PMID: 42371147

Abstract

Background

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 annualized 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.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00415-026-13960-5.

Keywords: Relapsing Multiple Sclerosis (RMS), Ofatumumab, Treatment Switch, Disease-Modifying Therapies (DMTs), Fingolimod, Fumarates

Introduction

Multiple sclerosis (MS) specialists have shifted toward initiating high-efficacy therapies (HETs) early in disease to optimize patient outcomes, including reduced inflammatory activity, neuronal injury, and disability [1–5]. Across prospective 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 findings, 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 antibody 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 ofatumumab versus teriflunomide in RMS [12–15]. However, in these pivotal studies, ≤ 5% of participants had been previously 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.

Methods

Study design

ARTIOS was a phase 3b, open-label, single-arm, multicenter, non-comparative, 96-week study of ofatumumab 20 mg administered subcutaneously every 4 weeks in participants 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 flexibility 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 screening 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. During 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. During 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 participants who completed the treatment period without continuing 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 Committee 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.

Participants

All 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. Participants 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-enhancing (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 assessments

The 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 (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 confirmed 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 proportion 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 analysis

The 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 prematurely 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 (fingolimod 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 event type, 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.

Results

Patient disposition, baseline demographics, and clinical characteristics

A 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 ofatumumab exposure was 91.8 weeks.

Participants switching from fingolimod had more advanced MS at baseline compared with participants switching 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).

Table 1.

Baseline demographics and clinical characteristics (FAS): overall and by prior DMT

Characteristic	Overall population (N = 562)	By last prior DMT
Characteristic	Overall population (N = 562)	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 seconds^a	52.8 ± 13.87^b	51.1 ± 14.40^a	53.6 ± 13.56^a,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 ± 4.96^d	1.9 ± 5.39^e	1.0 ± 4.72^f
Total volume of T2 lesions, cm³	10.56 ± 11.68^g	12.47 ± 12.30^a	9.65 ± 11.28^a,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 0^a
Duration of MS since diagnosis, years^a	5.42 ± 2.81	6.06 ± 2.72^a	5.11 ± 2.81^a
Number of relapses in the last 12–24 months prior to screening	0.8 ± 1.04	1.1 ± 1.29^a	0.8 ± 0.89^a
IgG, g/L^a	9.97 ± 2.05^g	9.10 ± 1.95^a	10.38 ± 1.97^a,h
IgM, g/L^a	1.16 ± 0.64^g	0.99 ± 0.57^a	1.24 ± 0.66^a,h
Lymphocytes (10⁹/L)^a	1.36 ± 0.55^g	1.12 ± 0.48^a,i	1.48 ± 0.54^a
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

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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 = 180

DMT disease-modifying therapy; EDSS Expanded Disability Status Scale; FAS full analysis set; Gd + gadolinium enhancing; Ig immunoglobulin; MS multiple sclerosis; SF safety set; SD standard deviation; SDMT symbol digit modalities test; SF safety set

Efficacy

Annualized 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), meeting the 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 transitioning 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 endpoints

Ofatumumab 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 suppressed 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); representing 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).

Fig. 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 binomial 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 baseline 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

Participants’ neT2 lesions were almost completely suppressed between Weeks 24 and 96 in the overall population and by prior DMT subgroup. At Week 24, the adjusted number of neT2 lesions was 1.95 (95% CI: 1.61–2.37), decreasing 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-3

In 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).

6mCDW

During the 96-week treatment period, 40 participants experienced 6mCDW (7.3%; 95% CI: 5.4–9.9) (Fig. 4), including 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 PROs

No deterioration in function was identified across exploratory 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 cumulative event rates were 11.4% and 11.9% at Year 1 and Year 2, respectively (Online Resource Table 3). NfL concentrations 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).

Safety

TEAEs 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.

Table 2.

Safety profile in participants receiving ofatumumab: overall and by prior DMT

All grades, n (%)	Overall population (N = 562)	By last prior DMT
All grades, n (%)	Overall population (N = 562)	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)

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^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 AE

AE adverse event; DMT disease-modifying therapy; MRI magnetic resonance imaging; SAE serious adverse event; UTI urinary tract infection

TEAEs by preferred term that occurred in ≥ 10% of participants 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. Serious 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 leiomyoma, 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 assessment 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 leukoencephalopathy, later confirmed as new MS lesions, that led to study discontinuation based on investigator judgment; n = 1), and cancer (n = 3). Cancer cases included adenocarcinoma (n = 1), bladder cancer (n = 1), and medullary carcinoma of breast (n = 1).

Injection-related reactions

A 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 participants (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% following 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 serious IRR events were reported. The most common symptom associated with systemic IRRs was fever, followed by chills and headache. No IRRs led to treatment interruption or discontinuation.

IgG/IgM levels

Mean 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 subgroups decreased from baseline to Week 96 but remained above the LLN (0.4 g/L) at all time points. A low number 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.

Post hoc efficacy and safety analyses

Post hoc efficacy analysis revealed no clinically meaningful 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 outcomes were generally consistent across washout durations, with types of TEAEs occurring in ≥ 10% of participants being comparable across subgroups (Online Resource Table 12).

Discussion

ARTIOS 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 comparable 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). Overall, 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. Ofatumumab 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 support 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%) experiencing 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 disease, decreased from Week 24 following the switch to ofatumumab and then remained stable through 96 weeks [23–25]. The reduction and stabilization of serum NfL levels observed following the switch to ofatumumab are consistent with improved MS disease control and with observed ARR and MRI improvements seen in the current 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. Overall, 11.4% and 11.9% of participants experienced 6mCCD in Years 1 and 2, respectively, supporting an apparent stabilization 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, effectiveness, 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 participants 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 switching 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 efficacy 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 preliminary 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 interruptions. 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. Excluding 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 ofatumumab, 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 remaining 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 subgroup, 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 participants were enrolled during periods of breakthrough disease 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 population 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 assessment to more closely reflect a real-world environment.

Conclusions

Data from the ARTIOS study supports ofatumumab as a HET with a favorable safety profile in participants with breakthrough disease on oral fingolimod or fumarates. Switching to ofatumumab resulted in strong disease control, with consistent efficacy outcomes across prior DMT subgroups, including in participants who switched from fingolimod, despite these participants having more advanced disease at baseline. No new safety concerns were observed, and safety findings were similar across prior DMT subgroups 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

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 718 KB)^{(712.2KB, docx)}

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 submission. 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 external researchers, access to patient-level data and supporting clinical documents 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.

Declarations

Conflict 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 participation 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 compensation for lectures and/or advisory board participation from Roche, Biogen, 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 committees of Novartis and Biogen. Sara Madueno Eichau has received speaker honoraria and consultant fees from Biogen, Merck, Neuraxpharm, 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 Institutional Review Board/Independent Ethics Committee at each participating site 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. The study was registered on ClinicalTrials.gov (NCT04353492).

Consent to participate

All participants provided written informed consent prior to study participation.

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary file1 (DOCX 718 KB)^{(712.2KB, docx)}

Data Availability Statement

[CR1] 1.Singer BA, Feng J, Chiong-Rivero H (2024) Early use of high-efficacy therapies in multiple sclerosis in the United States: benefits, barriers, and strategies for encouraging adoption. J Neurol 271(6):3116–3130. 10.1007/s00415-024-12305-4 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR2] 2.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. 10.1007/s00415-022-11193-w [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR3] 3.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. 10.1007/s00415-023-12021-5 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR4] 4.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. 10.1016/j.msard.2016.07.003 [DOI] [PubMed] [Google Scholar]

[CR5] 5.Selmaj K, Cree BAC, Barnett M et al (2024) Multiple sclerosis: time for early treatment with high-efficacy drugs. J Neurol 271(1):105–115. 10.1007/s00415-023-11969-8 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR6] 6.Labiano-Fontcuberta A, Costa-Frossard L, Sainz de la Maza S et al (2022) The effect of timing of high-efficacy therapy on processing speed performance in multiple sclerosis. Multi Scler Relat Disord 64:103959. 10.1016/j.msard.2022.103959 [DOI] [PubMed] [Google Scholar]

[CR7] 7.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. 10.1016/s1474-4422(20)30067-3 [DOI] [PubMed] [Google Scholar]

[CR8] 8.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 population-based registry. Front Neurol 12:693017. 10.3389/fneur.2021.693017 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR9] 9.Iaffaldano P, Lucisano G, Caputo F et al (2021) Long-term disability trajectories in relapsing multiple sclerosis patients treated with early intensive or escalation treatment strategies. Ther Adv Neurol Disord 14:17562864211019574. 10.1177/17562864211019574 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR10] 10.Rojas JI, Patrucco L, Alonso R et al (2022) Effectiveness and safety of early high-efficacy versus escalation therapy in relapsing-remitting multiple sclerosis in Argentina. Clin Neuropharmacol 45(3):45–51. 10.1097/wnf.0000000000000503 [DOI] [PubMed] [Google Scholar]

[CR11] 11.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. 10.1016/j.autrev.2017.04.010 [DOI] [PubMed] [Google Scholar]

[CR12] 12.Kesimpta (ofatumumab). Prescribing information. Novartis Pharmaceuticals Corporation; 2025. Accessed January 22, 2026. https://www.novartis.com/us-en/sites/novartis_us/files/kesimpta.pdf

[CR13] 13.Kesimpta (ofatumumab). Summary of product characteristics. Novartis Pharmaceuticals UK. Accessed January 22, 2026. https://www.ema.europa.eu/en/documents/product-information/kesimpta-epar-product-information_en.pdf

[CR14] 14.Hauser SL, Bar-Or A, Cohen JA et al (2020) Ofatumumab versus teriflunomide in multiple sclerosis. N Engl J Med 383(6):546–557. 10.1056/NEJMoa1917246 [DOI] [PubMed] [Google Scholar]

[CR15] 15.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-novartis-kesimpta-ofatumumab-first-and-only-self-administered-targeted-b-cell-therapy-patients-relapsing-multiple-sclerosis

[CR16] 16.Cerdá-Fuertes N, Nagy S, Schaedelin S et al (2023) Evaluation of frequency, severity, and independent risk factors for recurrence of disease activity after fingolimod discontinuation in a large real-world cohort of patients with multiple sclerosis. Ther Adv Neurol Disord 16:17562864221150312. 10.1177/17562864221150312 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR17] 17.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. 10.1212/nxi.0000000000001183 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR18] 18.Lublin FD, Reingold SC, Cohen JA et al (2014) Defining the clinical course of multiple sclerosis. Neurology 83(3):278–286. 10.1212/wnl.0000000000000560 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR19] 19.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. 10.1016/s1474-4422(17)30470-2 [DOI] [PubMed] [Google Scholar]

[CR20] 20.de Sèze J, Maillart E, Gueguen A et al (2023) Anti-CD20 therapies in multiple sclerosis: from pathology to the clinic. Front Immunol 14:1004795. 10.3389/fimmu.2023.1004795 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR21] 21.Alonso R, Casas M, Lazaro L et al (2023) Achieving no evidence 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. 10.1177/20552173231154712 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR22] 22.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. 10.1001/jamaneurol.2014.3537 [DOI] [PubMed] [Google Scholar]

[CR23] 23.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. 10.1136/jnnp-2018-320106 [DOI] [PubMed] [Google Scholar]

[CR24] 24.Khalil M, Teunissen CE, Lehmann S et al (2024) Neurofilaments as biomarkers in neurological disorders - towards clinical application. Nat Rev Neurol 20(5):269–287. 10.1038/s41582-024-00955-x [DOI] [PubMed] [Google Scholar]

[CR25] 25.Siller N, Kuhle J, Muthuraman M et al (2019) Serum neurofilament light chain is a biomarker of acute and chronic neuronal damage in early multiple sclerosis. Mult Scler 25(5):678–686. 10.1177/1352458518765666 [DOI] [PubMed] [Google Scholar]

[CR26] 26.Ross AP, Nicholas J, Tai MH et al (2025) Real-world satisfaction and experience with injection and autoinjector device for ofatumumab indicated for multiple sclerosis. BMC Neurol 25(1):28. 10.1186/s12883-024-04007-1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR27] 27.Singer BA, Morgan D, Stamm JA et al (2024) Patient and physician perspectives of treatment burden in multiple sclerosis. Neurol Ther 13(6):1507–1525. 10.1007/s40120-024-00654-1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR28] 28.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. 10.2147/dddt.S315174 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR29] 29.Hauser SL, Cohen JA, de Sèze J et al (2025) Five-year safety and efficacy outcomes with ofatumumab in patients with relapsing multiple sclerosis. Neurol Ther 14(5):1975–1992. 10.1007/s40120-025-00784-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR30] 30.Pardo G, Bar-Or A, Montalban X et al (2025) Continuous ofatumumab treatment up to 7 years shows a consistent safety profile and delays disability progression in people with relapsing multiple sclerosis (P7-1.016). Neurology 104(suppl 7):2630. 10.1212/WNL.0000000000210474 [Google Scholar]

[CR31] 31.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. 10.1002/ana.26028 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR32] 32.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. 10.1001/jamanetworkopen.2023.19766 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR33] 33.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 multiple sclerosis. Mult Scler Relat Disord 105:106886. 10.1016/j.msard.2025.106886 [DOI] [PubMed] [Google Scholar]

[CR34] 34.van Munster CE, Uitdehaag BM (2017) Outcome measures in clinical trials for multiple sclerosis. CNS Drugs 31(3):217–236. 10.1007/s40263-017-0412-5 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR35] 35.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. 10.1016/j.msard.2024.105731 [DOI] [PubMed] [Google Scholar]

[CR36] 36.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. 10.1177/1352458506070768 [DOI] [PubMed] [Google Scholar]

[CR37] 37.Benedict RH, DeLuca J, Phillips G et al (2017) Validity of the Symbol Digit Modalities Test as a cognition performance outcome measure for multiple sclerosis. Mult Scler 23(5):721–733. 10.1177/1352458517690821 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR38] 38.Balcer LJ, Baier ML, Cohen JA et al (2003) Contrast letter acuity as a visual component for the multiple sclerosis functional composite. Neurology 61(10):1367–1373. 10.1212/01.wnl.0000094315.19931.90 [DOI] [PubMed] [Google Scholar]

[CR39] 39.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. 10.1016/j.apmr.2013.07.008 [DOI] [PubMed] [Google Scholar]

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PERMALINK

Efficacy and safety of ofatumumab in participants with relapsing multiple sclerosis and breakthrough disease on oral fingolimod or fumarates: results from the ARTIOS study

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

Abstract

Background

Methods

Results

Conclusions

Trial registration

Supplementary Information

Introduction

Methods

Study design

Fig. 1.

Participants

Endpoints and assessments

Statistical analysis

Results

Patient disposition, baseline demographics, and clinical characteristics

Table 1.

Efficacy

Annualized relapse rate (primary endpoint)

MRI-associated endpoints

Fig. 2.

NEDA-3

Fig. 3.

6mCDW

Fig. 4.

Additional exploratory endpoints and PROs

Safety

Table 2.

Injection-related reactions

Fig. 5.

IgG/IgM levels

Post hoc efficacy and safety analyses

Discussion

Conclusions

Supplementary Information

Acknowledgements

Author contributions

Funding

Data availability

Declarations

Conflict of interest

Ethical approval

Consent to participate

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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