ARTIOS
Efficacy and safety of ofatumumab in participants with relapsing multiple sclerosis and breakthrough disease on oral fingolimod or fumarates: results from the ARTIOS study
Study Overview
Objective
To evaluate the efficacy and safety of subcutaneous ofatumumab in adults with relapsing multiple sclerosis who switched from oral fingolimod or fumarates because of breakthrough disease activity.
Study Summary
- Adjusted annualized relapse rate was 0.06 (95% CI 0.05-0.08; p<0.0001) over 96 weeks, meeting the primary endpoint
- NEDA-3 was achieved by 90.9% of participants in Year 2 (88.0% fingolimod; 92.2% fumarates)
- Gd+ T1 lesions were reduced 93.7%, 97.3%, and 98.1% at Weeks 24, 48, and 96; neT2 lesions were nearly completely suppressed
- 6-month confirmed disability worsening occurred in only 7.3% of participants
- Safety profile consistent with prior ofatumumab trials: TEAEs 90.6% (mostly mild-moderate), serious TEAEs 5.9%, discontinuations 0.9%, no deaths
Intervention
Ofatumumab 20 mg subcutaneously (autoinjector) — induction doses on Days 1, 7, and 14, then 20 mg every 4 weeks
Patients per Arm
562 total — 181 prior fingolimod (32.2%), 381 prior fumarates (67.8%)
Bottom Line
In 562 adults with RMS and breakthrough disease on fingolimod or fumarates, switching to subcutaneous ofatumumab produced a low annualized relapse rate (0.06), near-complete suppression of MRI activity, high NEDA-3 rates (90.9% in Year 2), and few disability worsening events (7.3%), with a safety profile consistent with prior ofatumumab studies.
Major Points
- Primary endpoint met: adjusted ARR 0.06 over 96 weeks (95% CI 0.05-0.08; p<0.0001), with Year 1 ARR 0.10 falling to 0.02 in Year 2
- NEDA-3 achieved by 90.9% of participants in Year 2 despite the fingolimod subgroup having more advanced baseline disease
- Gd+ T1 lesions reduced by 98.1% at Week 96; neT2 lesions dropped from 1.95 (Week 24) to 0.07 (Week 96)
- Only 7.3% experienced 6-month confirmed disability worsening
- TEAEs 90.6% (mostly mild-moderate), serious TEAEs 5.9%, treatment discontinuation for TEAE 0.9%, no deaths
- Systemic IRRs common (53.4%) but concentrated after the first injection (45.6%) and none led to discontinuation
- Mean IgG remained stable above LLN through Week 96; IgM decreased but stayed above LLN, with no severe infections attributed to low Ig
- Post hoc analyses showed no clinically meaningful differences by washout duration; short (<30-day) washout may reduce rebound risk in fingolimod switchers
Design
Study Type: Phase 3b, open-label, single-arm, multicenter, noncomparative clinical trial
Randomization:
Blinding: Open-label
Enrollment Period: Registered April 20, 2020 (NCT04353492); initiated during first year of COVID-19 pandemic
Follow-up Duration: 96 weeks of treatment plus safety follow-up up to 6 months
Countries: Multinational — sites in USA, UK, Poland, Czechia, Germany, Spain, Switzerland (per author affiliations)
Sample Size: 562
Analysis: Full analysis set (all who received ≥1 dose) for efficacy; modified FAS for NEDA-3; Safety Set for AEs; ARR analyzed by negative binomial regression adjusted for prior DMT, prior-year relapses, baseline EDSS, T1 Gd+ lesions, and age
Inclusion Criteria
- Adults aged 18-60 years
- Relapsing MS (including active secondary progressive MS), diagnosed per 2017 revised McDonald criteria
- EDSS score 0-4 at screening
- Prior treatment with a maximum of 3 DMTs
- Transitioning from fingolimod or fumarates administered for ≥6 months as last prior DMT
- Breakthrough disease activity: ≥1 documented relapse in the past year, or ≥2 relapses in the past 2 years, or ≥1 Gd+ MRI lesion within the past year, or new/enlarging T2 lesions within the past year
- Written informed consent
Exclusion Criteria
- Age <18 or >60 years
- EDSS >4 at screening
- >3 prior DMTs
- Last prior DMT other than fingolimod or fumarates
- <6 months of prior fingolimod or fumarate therapy
- Concurrent use of another DMT during the transition/screening period
Arms
| Field | Ofatumumab (single arm) |
|---|---|
| Intervention | Ofatumumab 20 mg subcutaneous via autoinjector — induction on Days 1, 7, and 14, then 20 mg every 4 weeks |
| Duration | 96 weeks |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Annualized relapse rate (ARR) over 96 weeks | Primary | <0.0001 | |||
| Adjusted rate of Gd+ T1 lesions per scan at baseline | Secondary | Value: 0.85 (95% CI 0.59-1.21) | |||
| Adjusted rate of Gd+ T1 lesions Week 24 | Secondary | <0.0001 | |||
| Adjusted rate of Gd+ T1 lesions Week 48 | Secondary | <0.0001 | |||
| Adjusted rate of Gd+ T1 lesions Week 96 | Secondary | <0.0001 | |||
| Adjusted number of neT2 lesions Week 24 | Secondary | Value: 1.95 (95% CI 1.61-2.37) | |||
| Adjusted number of neT2 lesions Week 48 | Secondary | Value: 0.16 (95% CI 0.11-0.23) | |||
| Adjusted number of neT2 lesions Week 96 | Secondary | Value: 0.07 (95% CI 0.05-0.10) | |||
| NEDA-3 Year 1 (overall) | Secondary | Value: 51.8% (95% CI 47.6-56.0) | |||
| NEDA-3 Year 2 (overall) | Secondary | Value: 90.9% (95% CI 88.4-93.3) | |||
| NEDA-3 Year 1 (fingolimod) | Secondary | Value: 35.2% (95% CI 28.2-42.2) | |||
| NEDA-3 Year 2 (fingolimod) | Secondary | Value: 88.0% (95% CI 83.1-92.9) | |||
| NEDA-3 Year 1 (fumarates) | Secondary | Value: 59.8% (95% CI 54.8-64.8) | |||
| NEDA-3 Year 2 (fumarates) | Secondary | Value: 92.2% (95% CI 89.4-95.0) | |||
| 6-month confirmed disability worsening (overall) | Secondary | Value: 40/562 (7.3%; 95% CI 5.4-9.9) | |||
| 6mCDW fingolimod | Secondary | Value: 15/181 (8.5%; 95% CI 5.2-13.8) | |||
| 6mCDW fumarates | Secondary | Value: 25/381 (6.8%; 95% CI 4.6-9.9) | |||
| 6-month confirmed cognitive decline Year 1 | Secondary | Value: 11.4% | |||
| 6mCCD Year 2 | Secondary | Value: 11.9% | |||
| T25FW, 9HPT, SDMT, LCVA | Secondary | Value: Stable; changes did not reach clinically meaningful thresholds | |||
| MSIS-29 physical and psychological | Secondary | Value: Stable — no functional decline | |||
| FSMC fatigue | Secondary | Value: No clinically meaningful change | |||
| TSQM (satisfaction, effectiveness, convenience) | Secondary | Value: Gradual improvement over the study | |||
| Serum NfL | Secondary | Value: Decreased from Week 24 and remained stable through Week 96 | |||
| T2 lesion volume | Secondary | Value: Decreased from baseline | |||
| Any TEAE | Adverse | 509/562 (90.6%) — 90.1% fingolimod vs 90.8% fumarates | |||
| Severity (mild or moderate, Grade 1-2) | Adverse | 90.6% of TEAEs | |||
| Most common SOC (infections and infestations) | Adverse | 69.8% | |||
| Systemic injection-related reactions (any) | Adverse | 53.4% (grade 1: 35.6%; grade 2: 17.1%; grade 3: 0.5%; no grade 4 or serious IRRs) | |||
| Systemic IRRs after 1st injection | Adverse | 45.6% | |||
| Cumulative systemic IRRs across subsequent injections | Adverse | 7.6% | |||
| Local-site IRRs | Adverse | 11.0% (all mild-moderate) | |||
| COVID-19 | Adverse | 37.0% (99.5% mild/moderate; 1 grade 3) | |||
| Nasopharyngitis | Adverse | 17.1% | |||
| Headache | Adverse | 16.4% | |||
| Serious TEAEs | Adverse | 33/562 (5.9%) — 7.2% fingolimod, 5.2% fumarates | |||
| Recurring serious TEAEs (>1 participant, 0.4% each) | Adverse | Uterine leiomyoma, suicidal ideation, intervertebral disc protrusion | |||
| TEAEs leading to treatment interruption | Adverse | 33 (5.9%) — largely COVID-19 (23; 4.1%) | |||
| Discontinuations due to TEAE | Adverse | 5 (0.9%) — COVID-19 (1), MRI lesion initially suspected PML later confirmed as new MS lesion (1), cancers (3: adenocarcinoma, bladder cancer, medullary breast carcinoma) | |||
| Deaths | Adverse | 0 | |||
| Mean IgG through Week 96 | Adverse | Stable, above lower limit of normal (5.65 g/L) | |||
| Mean IgM through Week 96 | Adverse | Decreased from baseline but remained above LLN (0.4 g/L) | |||
| IgG <LLN post-baseline | Adverse | 2.1% of participants | |||
| IgM <LLN post-baseline | Adverse | 22.8% of participants (not associated with severe infection or discontinuation) | |||
Subgroup Analysis
Efficacy consistent across prior fingolimod vs fumarates subgroups despite baseline severity differences. Post hoc analyses by washout duration showed no clinically meaningful differences; however, fingolimod switchers with a 30-60 day washout had a small, non-significant increase in Gd+ T1 and neT2 lesions vs those with <30-day washout, suggesting a shorter washout may reduce rebound risk. Safety consistent across washout durations.
Criticisms
- Single-arm, open-label design without an active comparator limits definitive efficacy conclusions and cross-HET comparisons
- Relatively short 96-week follow-up given the chronicity of MS
- Regression to the mean is possible because enrollment was triggered by recent breakthrough disease activity
- Few participants aged >55 years limits interpretation of NfL data by age
- Study initiated during the first year of the COVID-19 pandemic, likely inflating infection-related TEAE rates
- Lower premedication use than in ASCLEPIOS may have contributed to the higher rate of systemic IRRs
- Investigator-flexible design (washout, symptom assessment timing) improves real-world relevance but introduces heterogeneity
Funding
Novartis (multiple author affiliations with Novartis Pharma AG (Basel), Novartis Pharmaceuticals UK (London), Novartis Pharmaceuticals Corporation (East Hanover, NJ), and Novartis Healthcare Private Limited (Hyderabad))
Based on: ARTIOS (Journal of Neurology, 2026)
Authors: Bove R, Langdon D, Maciejowski M, ..., Derfuss T
Citation: J Neurol 2026;273(7). DOI: 10.1007/s00415-026-13960-5 (PMID: 42371147; PMCID: PMC13315151; NCT04353492)
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