Switching to Ocrelizumab Following Natalizumab Associated With Lowest Relapse, Discontinuation Rates

Chao Zhu, PhD

In a recently published observational cohort study of patients with relapsing-remitting multiple sclerosis (RRMS) who switched off natalizumab (Tysabri; Biogen), findings showed that ocrelizumab (Ocrevus; Genentech) was associated with the lowest annualized relapse rate (ARR) and discontinuation rate, along with the longest time to first relapse. Investigators concluded these findings can help inform subsequent disease-modifying therapy selection for these patients.

Using the MSBase registry from 2010 to 2021, among 66,840 patients with RRMS, 1744 had used natalizumab for 6 months or longer and were switched to dimethyl fumarate (Tecfidera; Biogen), fingolimod (Gilyena; Novartis), or ocrelizumab within 3 months of natalizumab discontinuation. In terms of effectiveness, the inverse probability of treatment weighting (IPTW) ARR was 0.06 (95% CI, 0.04-0.08) for those on ocrelizumab, 0.26 (95% CI, 0.12-0.48) for those on fingolimod, and 0.27 (95% CI, 0.12-0.56) for those on dimethyl fumarate.

"Given that patients treated with natalizumab typically have high intrinsic relapse risk and natalizumab cessation is associated with risk of rebound as its biological effect declines quickly, our study is not, therefore, generalizable to other treatment switch scenarios or first-line therapy," lead investigator Chao Zhu, PhD, research fellow, University of Monash, and colleagues, noted.

The median follow-up for patients was 2.7 years, with the mean age of the 3 treatment groups differing significantly. Those on dimethyl fumarate were the oldest (44.0 [SD, 11.4] years), followed by the ocrelizumab group (42.8 [SD, 11.2] years), and the fingolimod group (40.1 [SD, 10.0]). Patients who had experienced more relapses in the previous year were more likely to receive fingolimod, followed by ocrelizumab and dimethyl fumarate.

When comparing individual treatments, ocrelizumab use was associated with a significant reduction in ARR vs fingolimod (IPTW-weighted ARR ratio, 4.33; 95% CI, 0.12-0.56), and dimethyl fumarate (ARR ratio, 4.50; 95% CI, 2.89-7.03). Additionally, investigators found that patients who switched to fingolimod and dimethyl fumarate had a significantly higher risk of experiencing the first relapse than those taking ocrelizumab, with IPTW-weighted HRs of 4.02 (95% CI, 2.83-5.70) and 3.70 (95% CI, 2.35-5.84), respectively.

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In the study, participants were required to have at least 2 subsequent visits with a minimum 6-month gap and with recorded Expanded Disability Status Scale (EDSS) scores during the follow-up to allow for the ascertainment of disability accumulation or improvement. Excluding dimethyl fumarate because of low numbers, a comparison between fingolimod and ocrelizumab showed that fingolimod was associated with a 49% higher risk for disability accumulation (IPTW-weighted HR, 1.49; 95% CI, 1.07-2.07). Notably, there was no difference in confirmed disability improvement rates (IPTW-weighted HR, 1.01; 95% CI, 1.01; 95% CI, 0.64-1.57).

"The superiority of ocrelizumab to dimethyl fumarate and fingolimod might be explained by the different immunologic mechanisms of action between the treatment classes,” the study authors wrote. "This includes the onset of treatment effect and relative treatment effectiveness in patients at very high risk of relapse. However, in MSBase, we currently do not have enough patient medical records to examine whether our findings are a class effect (eg, other anti-CD20 DMTs, such as rituximab or ofatumumab, or other sphingosine-1 phosphate inhibitors beyond fingolimod or diroximel fumarate)."

In subgroup analyses, ocrelizumab significantly interacted with baseline EDSS score and the number of previous therapies on the primary outcomes (P <.05), with the greater association seen in patients with lower EDSS score (< 3; adjusted ARR, 9.73; 95% CI, 5.21-20.02; P = .004) and those with exposure to fewer DMTs (EDSS score < 3; adjusted ARR, 7.79; 95% CI, 4.48-14.48; P =.02) before natalizumab. Compared with ocrelizumab, fingolimod and dimethyl fumarate-treated patients were significantly associated with increased treatment discontinuation rates over time, with an IPTW-weighted HR of 2.57 (95% CI, 1.74-3.80) and 4.26 (95% CI, 2.65-6.84), respectively.

REFERENCE
1. Zhu C, Kalincik T, Horakova D, et al. Comparison between dimethyl fumarate, fingolimod, and ocrelizumab after natalizumab cessation. JAMA Neurol. Published online June 5, 2023. doi:10.1001/jamaneurol.2023.1542.