Background <p>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.</p> Methods <p>ARTIOS was a phase 3b, open-label, single-arm, multicenter, noncomparative study. Primary endpoint was annualized relapse rate (ARR); secondary endpoint was safety.</p> Results <p>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&#xa0;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 &lt; 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.</p> Conclusions <p>ARTIOS complements the ASCLEPIOS studies and supports ofatumumab following switch from oral DMTs.</p> Trial registration <p>ClinicalTrials.gov, NCT04353492; April 20, 2020.</p>