Yesterday we had CD20-depleting antibodies switch after alemtuzumab works well and today it is a switch from fingolimod. Fingolimod is a strange drug because it hangs around a long time and when the drug wears of there is the potential for relapse = rebound
Now it have been suggested that relapse occurs more frequently in people treated with alemtuzumab, if pretreated with fingolimod. This may be because fingolimod traps the cells in the lymph glands. Alemtuzumab disappears as it goes through its half-lives (half of the drug is lost during a half-life) and is injected at low dose, so by the time fingolimod wears off and the white cells enter the blood the alemtuzumab has gone.
So what happens with CD20-depleters?
Ocrelizumab is given as a large dose e.g. 600mg verses 21-60mg (alemtuzumab) and so hangs around a long time but if the targets hang around, out-of-sight for a long time something similar to alemtuzumab could happen. Ofatumumab is given as a low dose and is given often so if fingolimod wore off, cells leaving lymph glands but they would be targeted with a maximum dose pretty quickly. So what happens? In real life. It seems if people get ocrelizumab it works less well (about 80% less well) than if they had ofatumumab.
Abbadessa G, Marastoni D, Bile F, Signoriello E, Zanghì A, Cellerino M, Cerqua R, Evangelista L, Tomassini V, Sensi S, Romano G, Risi M, Lagonigro E, Mazzone A, Gelibter S, Rispoli M, Vercellino M, Schirò G, Ragonese P, Sartori A, Malagù S, Ganino C, Mancinelli L, Lugaresi A, Lus G, Rosso F, Comar M, Merlino G, Valente M, Montepietra S, Marti A, Piscaglia MG, Surcinelli A, Tsantes E, Curti E, Fiore A, Ferraro D, Fantozzi R, Lavorgna L, D’Amico E, Gallo A, Cavalla P, Calabrese M, Inglese M, Bonavita S, Foschi M.CNS Drugs. 2026. doi: 10.1007/s40263-025-01267-4
Background and aims: Evidence directly comparing ocrelizumab (OCR) and ofatumumab (OFA) after sphingosine-1-phosphate receptor modulators (S1PRMs) withdrawal is limited, even though this transition period carries an increased risk of disease reactivation and the two anti-CD20 agents differ in molecular properties that may influence post-S1PRM outcomes. We compared effectiveness, safety, and tolerability of OFA versus OCR in relapsing-remitting multiple sclerosis (RRMS) after S1PRM therapy.
Methods: We retrospectively analyzed adult (> 18 years) patients with RRMS from 23 Italian centers who switched from S1PRMs to OCR or OFA (October 2016 to July 2024). Clinical outcomes included annualized relapse rate (ARR), cumulative relapse incidence, confirmed disability progression (CDP), progression independent of relapse activity (PIRA), confirmed disability improvement (CDI), and variation in the expanded disability status scale score (ΔEDSS) from baseline to last follow-up. Magnetic resonance imaging (MRI) outcomes included time to overall MRI activity, new/enlarging T2 lesions, and new T1 Gd-enhancing lesions. Persistence on anti-CD20 and safety were also assessed.
Results: We included 225 subjects (mean age 43.3 ± 10.6 years; OCR = 131, OFA = 94), with a median follow-up of 33 months. After IPTW, groups were well balanced. Compared with OCR, OFA was associated with lower ARR (adjusted relative risk [aRR] 0.22, 95% CI 0.06-0.86, p = 0.030) and relapse hazard (adjusted hazard ratio [aHR] 0.21, 95% CI 0.05-0.83, p = 0.026). When restricting washout to ≤ 10 weeks and applying spline-based Andersen-Gill models, results remained consistent, with OFA showing a lower relapse risk than OCR across short-to-intermediate washout intervals. CDP hazard was lower (aHR 0.38, 95% CI 0.15-0.94, p = 0.038), while PIRA and CDI did not differ. ΔEDSS favored OFA (adjusted mean difference [aMD] – 0.26, 95% CI – 0.51 to – 0.02, p = 0.046). OFA showed a lower hazard of overall MRI activity (aHR 0.41, 95% CI 0.19-0.92, p = 0.030), with similar risk for new T1 Gd+ lesions. A sensitivity analysis restricted to patients who switched to OFA or OCR during the same availability window yielded results consistent with the primary analysis. Treatment persistence was shorter on OFA, but absolute discontinuation rates were low in both groups. Severe AEs were rare and did not differ.
Conclusions: In S1PRM-exposed RRMS, OFA was associated with reduced relapse risk, disability accumulation, EDSS worsening, and MRI activity compared with OCR, with overall good tolerability and safety.
So this suggests that ofatumumab is a more obvious switch to option
Source: multiple-sclerosis-research.org