- A randomized trial showed that rituximab was noninferior to ocrelizumab in preventing new MRI lesions over 2 years in people with newly diagnosed relapsing MS.
- Relapse rates, disability progression, and cognitive outcomes were similar in each group.
- Rituximab led to more infections, mostly mild upper respiratory tract infections.
Off-label rituximab was noninferior to ocrelizumab (Ocrevus) in people with newly diagnosed relapsing multiple sclerosis (MS) and recent disease activity, the phase III OVERLORD-MS trial showed.
At 2 years, the estimated probability of having no new or enlarging lesions on T2-weighted MRI was 92.2% with rituximab and 94.8% with ocrelizumab, reported Øivind Torkildsen, MD, PhD, of the University of Bergen in Norway, and co-authors.
The risk difference (-2.6 percentage points, 95% CI -9.4 to 4.3) met the prespecified noninferiority criterion for the 218-person study, the researchers wrote in the New England Journal of Medicine.
Annualized relapse rates were low in both study groups -- 0.09 for rituximab and 0.04 for ocrelizumab. Additionally, disability outcomes and cognitive performance profiles appeared similar between the two groups, Torkildsen and colleagues said.
"Our trial provides randomized controlled evidence comparing two anti-CD20 therapies that are already widely used in clinical practice," Torkildsen told MedPage Today. "Although rituximab has been used off-label for many years in multiple sclerosis, uncertainty has remained about its comparative efficacy and safety relative to approved anti-CD20 therapy because direct head-to-head evidence has been lacking."
The OVERLORD-MS findings may have important implications for healthcare systems, Torkildsen suggested. "Rituximab is substantially less expensive than ocrelizumab in many countries, and wider use could free up considerable healthcare resources while maintaining access to highly effective treatment," he pointed out.
"This is the first reasonably large randomized controlled trial of rituximab versus ocrelizumab in newly diagnosed MS patients. It suggests that rituximab should be strongly considered as a first-line CD20 drug at a much lower cost," agreed John Corboy, MD, MA, of the University of Colorado Anschutz School of Medicine, Aurora, who wasn't involved in the trial.
Corboy also noted that rituximab is also cheaper than most other drugs for MS, not just the CD20 drugs.
"This is important information that should be considered when people are making decisions about using these medications," Corboy added. "Ultimately, doctors are the ones who prescribe the medications. We are, in fact, part of the problem when we go out of our way to not use drugs that are cheaper and yet are equivalent."
Rituximab, which is approved to treat non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and other indications, has been used off-label for MS for many years. Ocrelizumab was approved in 2017 to treat relapsing and primary forms of MS.
In the phase III noninferiority OVERLORD-MS trial, Torkildsen and colleagues randomly assigned Swedish or Norwegian adults with newly diagnosed relapsing MS and recent disease activity to receive rituximab or ocrelizumab every 6 months for 24 months. Patients who had prior exposure to MS disease-modifying therapy were excluded.
The primary endpoint was the absence of new or enlarging T2-weighted MRI lesions between months 6 and 24. Noninferiority was established if the lower boundary of the 95% confidence interval for the risk difference was no less than -10 percentage points.
Overall, 216 participants received treatment: 132 assigned to rituximab (mean age 37.4 years, 72% women) and 84 assigned to ocrelizumab (mean age 36.6 years, 68% women). A large proportion of participants had contrast-enhancing lesions at baseline: 42% in the rituximab group and 40% in the ocrelizumab group.
Confirmed disability progression that was sustained for at least 6 months occurred in 3% of the rituximab group and 7% of the ocrelizumab group. No neoplasms were reported in the rituximab group, and one malignant melanoma occurred in the ocrelizumab group.
Infections occurred more frequently among participants receiving rituximab than among those receiving ocrelizumab (82% vs 69%), though the proportion of participants experiencing serious adverse events was comparable between groups (8% and 7%, respectively). Most infections were mild upper respiratory tract infections. Serious infections were rare, occurring in four participants in each group. No opportunistic infections were seen.
Follow-up was limited to 30 months and potential longer-term differences cannot be ruled out, Torkildsen and colleagues acknowledged. While the trial was powered to assess its primary endpoint, the low number of MRI and clinical events limited the precision of secondary analyses, they added. In addition, participants were mainly of Northern European ancestry.
Three other randomized trials are comparing rituximab and ocrelizumab in relapsing MS. The researchers have formed the ROC-MS collaborative initiative to pool individual participant data into a prospective meta-analysis.
Disclosures
This trial was supported by grants from the Research Council of Norway and from Klinbeforsk. Additional funding was provided by the Swedish Research Council, Region Stockholm, the Swedish Brain Fund, the Erling Persson Foundation, and the Horizon Europe Framework Program.
Torkildsen reported relationships with Biogen, F. Hoffman-LaRoche, Horizon 2020, Merck, Norway Grants, Sanofi, and Teva.
Co-authors reported relationships with Alexion, Biogen, Horizon Europe, Merck, H. Lundbeck, Klinbeforsk, the Research Council of Norway, Sanofi, Novartis, Janssen, Pfizer, Ipsen, and the Independent Order of Odd Fellows.
Corboy had no conflicts of interest.
