Disease-Modifying Therapy After Natalizumab Discontinuation in Patients with Relapsing Multiple Sclerosis

By Jai S. Perumal, MD

Assistant Professor of Neurology, Weill Cornell Medical College; Assistant Attending Neurologist, New York-Presbyterian Hospital

SYNOPSIS: In this retrospective cohort study, the investigators found that, when compared to fingolimod and dimethyl fumarate, ocrelizumab use was associated with significantly lower annualized relapse rate and treatment discontinuation. There were no significant differences in outcomes between fingolimod and dimethyl fumarate use. Ocrelizumab use was associated with a lower rate of disability accumulation when compared to fingolimod.

SOURCE: Zhu C, Kalincik T, Horakova D, et al. for the MSBase Study Group. Comparison between dimethyl fumarate, fingolimod, and ocrelizumab after natalizumab cessation. JAMA Neurol 2023;80:739-748.

Natalizumab is an effective treatment for relapsing multiple sclerosis. Although it offers high efficacy and convenient dosing, its use is associated with a relatively high risk of progressive multifocal leukoencephalopathy in those who are seropositive for John Cunningham (JC) virus antibodies. Patients taking natalizumab who convert to seropositive from negative for JC virus usually are taken off the medication. Planned pregnancy also is a strong reason for discontinuation of this medication.

A major concern, when discontinuing natalizumab, is disease recurrence, which happens around three months after treatment cessation. One of the strategies to mitigate this risk is the initiation of a different disease-modifying treatment within three months of discontinuation of natalizumab. Another consideration at discontinuation is the selection of a treatment that does not compromise efficacy but also does not significantly increase the risk of potential adverse events. Treatments that often are used after stopping natalizumab are ocrelizumab, fingolimod, and dimethyl fumarate.

This retrospective cohort study of patients in the MSBase registry analyzed outcomes following natalizumab cessation in 1,386 patients who subsequently were switched to ocrelizumab, fingolimod, or dimethyl fumarate. In this study, the authors reviewed the data of patients who switched from natalizumab to ocrelizumab, fingolimod, or dimethyl fumarate within three months of discontinuation of natalizumab. A total of 1,386 relapsing-remitting multiple sclerosis (RRMS) patients from 79 centers across 26 countries were included in the analysis. The mean age (standard deviation) was 41.3 (10.6) years, with 823 (59.4%) patients switching to fingolimod, 425 (30.7%) patients switching to ocrelizumab, and 138 (9.9%) patients switching to dimethyl fumarate. The median follow-up on these treatments after medication change was 3.5, 2.1, and 2.0 years, respectively. The primary end points were annualized relapse rate (ARR) and time to first relapse. Secondary outcomes were confirmed disability worsening or improvement and treatment discontinuation. The statistical method of inverse probability of treatment weighing (IPTW) was used to minimize baseline differences between the three treatment groups.

The IPTW annualized relapse rate for patients taking ocrelizumab was 0.06 (95% confidence interval [CI], 0.04-0.08), 0.26 (95% CI, 0.12-0.48) for patients taking fingolimod, and 0.27 (95% CI, 0.12-0.56) for patients who transitioned to dimethyl fumarate. Ocrelizumab was associated with a significantly lower ARR when compared to both fingolimod and dimethyl fumarate. Patients taking fingolimod or dimethyl fumarate had a significantly higher risk of first relapse than those taking ocrelizumab with IPTW hazard ratios (HRs) of 4.02 (95% CI, 2.83-5.70) and 3.30 (95% CI, 2.35-5.84), respectively. Switching to fingolimod was associated with a 49% higher risk for disability accumulation compared to ocrelizumab (IPTW HR 1.49; 95% CI, 1.07-2.07). A comparison between ocrelizumab and dimethyl fumarate was not done because of the small numbers of patients taking dimethyl fumarate. When compared with ocrelizumab, fingolimod and dimethyl fumarate had an increased rate of treatment discontinuation with an IPTW HR of 2.57 (95% CI, 1.74-3.80) for fingolimod and 4.26 (95% CI, 2.65-6.84) for dimethyl fumarate. The most common reason for discontinuation of ocrelizumab (11/31, 35%) was adverse events. For fingolimod (135/285, 48%) and dimethyl fumarate (15/51, 31%) discontinuation most commonly was because of a lack of efficacy.

COMMENTARY

With an expanding number of therapeutic options for multiple sclerosis, strategies for optimal treatment continue to evolve. Natalizumab is an effective and convenient disease-modifying treatment for multiple sclerosis, but when treatment must be discontinued, especially in the context of seroconversion to JC virus antibody positivity, choosing the next option should take into consideration the maintenance of disease control without a significant increase in adverse events. Medications that often are used include dimethyl fumarate, fingolimod, and ocrelizumab.

Based on the findings from this study, among these treatments, ocrelizumab appeared to be the best in terms of disease control and treatment adherence. Ocrelizumab is a good option to consider; however, we need to follow these patients for a longer duration to better understand the sustained efficacy and long-term safety.