Comparison Between Dimethyl Fumarate, Fingolimod, and Ocrelizumab After Natalizumab Cessation

Abstract

ImportanceNatalizumab cessation is associated with a risk of rebound disease activity. It is important to identify the optimal switch disease-modifying therapy strategy after natalizumab to limit the risk of severe relapses.ObjectivesTo compare the effectiveness and persistence of dimethyl fumarate, fingolimod, and ocrelizumab among patients with relapsing-remitting multiple sclerosis (RRMS) who discontinued natalizumab.Design, Setting, and ParticipantsIn this observational cohort study, patient data were collected from the MSBase registry between June 15, 2010, and July 6, 2021. The median follow-up was 2.7 years. This was a multicenter study that included patients with RRMS who had used natalizumab for 6 months or longer and then were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months after natalizumab discontinuation. Patients without baseline data were excluded from the analysis. Data were analyzed from May 24, 2022, to January 9, 2023.ExposuresDimethyl fumarate, fingolimod, and ocrelizumab.Main Outcomes and MeasuresPrimary outcomes were annualized relapse rate (ARR) and time to first relapse. Secondary outcomes were confirmed disability accumulation, disability improvement, and subsequent treatment discontinuation, with the comparisons for the first 2 limited to fingolimod and ocrelizumab due to the small number of patients taking dimethyl fumarate. The associations were analyzed after balancing covariates using an inverse probability of treatment weighting method.ResultsAmong 66 840 patients with RRMS, 1744 had used natalizumab for 6 months or longer and were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months of natalizumab discontinuation. After excluding 358 patients without baseline data, a total of 1386 patients (mean [SD] age, 41.3 [10.6] years; 990 female [71%]) switched to dimethyl fumarate (138 [9.9%]), fingolimod (823 [59.4%]), or ocrelizumab (425 [30.7%]) after natalizumab. The ARR for each medication was as follows: ocrelizumab, 0.06 (95% CI, 0.04-0.08); fingolimod, 0.26 (95% CI, 0.12-0.48); and dimethyl fumarate, 0.27 (95% CI, 0.12-0.56). The ARR ratio of fingolimod to ocrelizumab was 4.33 (95% CI, 3.12-6.01) and of dimethyl fumarate to ocrelizumab was 4.50 (95% CI, 2.89-7.03). Compared with ocrelizumab, the hazard ratio (HR) of time to first relapse was 4.02 (95% CI, 2.83-5.70) for fingolimod and 3.70 (95% CI, 2.35-5.84) for dimethyl fumarate. The HR of treatment discontinuation was 2.57 (95% CI, 1.74-3.80) for fingolimod and 4.26 (95% CI, 2.65-6.84) for dimethyl fumarate. Fingolimod use was associated with a 49% higher risk for disability accumulation compared with ocrelizumab. There was no significant difference in disability improvement rates between fingolimod and ocrelizumab.Conclusion and RelevanceStudy results show that among patients with RRMS who switched from natalizumab to dimethyl fumarate, fingolimod, or ocrelizumab, ocrelizumab use was associated with the lowest ARR and discontinuation rates, and the longest time to first relapse.

Safety and effectiveness of disease-modifying therapies after switching from natalizumab

“…24 Our study showed similar results when comparing RTX/OCR with fingolimod over a longer follow-up period (2.4–4.3 years). 25 Similar outcomes were reported in a large retrospective observational MSBase registry study 25 comparing the effectiveness and treatment discontinuation rates in patients switching from NTZ to dimethyl fumarate, fingolimod, or OCR. Patients on fingolimod had higher ARRs (OR = 4.33; 95% CI = 3.12–6.01), increased risk of disability progression (49%), and higher treatment discontinuation rates (OR = 2.57; 95% CI = 1.74–3.80) compared with OCR.…”

High-Efficacy Therapy Discontinuation vs Continuation in Patients 50 Years and Older With Nonactive MS

“…Our study suggests that in patients 50 years and older with nonactive MS, discontinuation of fingolimod and natalizumab significantly increased risk of relapse compared with continuing these treatments. Further studies are needed to identify the best therapeutic strategy: switching to an anti-CD20 therapy as in younger patients or deescalation to an MET. On the contrary, we did not find a higher risk of relapse in the anti-CD20 therapy discontinuation group.…”

Successful switch to ofatumumab after liver injury associated with ocrelizumab treatment in multiple sclerosis: a case report

“…In our patient, serological markers of HBV infection were repeatedly negative, as it was HBV DNA, thus allowing us to rule out that the latest episode of DILI was associated with HBV reactivation. As low-dose IVMP (100 mg) is administered as an ancillary drug before ocrelizumab infusion, we cannot exclude that this might have contributed to the DILI event associated with ocrelizumab, also considering the previous history of IVMP-associated DILI (mostly observed in association with other treatments) ( 18 ).…”

“…PML risk (index 3.54 plus previous exposure to immunosuppressive treatment) and patient’s convenience (she needs to travel for almost 3 h to get to the hospital) led to the exclusion of natalizumab, as it was deemed to have a detrimental impact on her quality of life, even if adopting an extended interval dosing. Sphingosine 1-phosphate modulators were also discussed, but their efficacy/safety profile was considered less favorable compared to that of CD20-depleting mAbs ( 18–20 ).…”