NORWAY — The phase III OVERLORD-MS trial, published in the New England Journal of Medicine, found rituximab to be noninferior to ocrelizumab in treating adults with newly diagnosed relapsing multiple sclerosis. The trial compared the two treatments in patients with recent disease activity.

The primary endpoint was the absence of new or enlarging T2-weighted MRI lesions from month 6 to month 24. Noninferiority was defined as the lower boundary of the 95% confidence interval for the risk difference being no less than -10 percentage points.

A total of 216 participants recruited from Sweden and Norway received either rituximab or ocrelizumab every six months for 24 months. Patients with prior exposure to multiple sclerosis disease-modifying therapy were excluded.

At two years, the estimated probability of having no new or enlarging lesions was 92.2% with rituximab and 94.8% with ocrelizumab. The risk difference was -2.6 percentage points, with a 95% confidence interval ranging from -9.4 to 4.3, meeting the prespecified noninferiority criterion.

The annualized relapse rate was 0.09 for the rituximab group and 0.04 for the ocrelizumab group. Confirmed disability progression sustained for at least six months occurred in 3% of the rituximab group and 7% of the ocrelizumab group. Infections occurred in 82% of participants receiving rituximab and 69% of those receiving ocrelizumab, with most being mild upper respiratory tract infections. Serious adverse events were reported in 8% of the rituximab group and 7% of the ocrelizumab group. Serious infections occurred in four participants in both treatment groups. One case of malignant melanoma occurred in the ocrelizumab group, while no neoplasms were reported in the rituximab group.

Rituximab is approved for non-Hodgkin's lymphoma and chronic lymphocytic leukemia and has been used off-label for multiple sclerosis for years. Ocrelizumab was approved in 2017 for relapsing and primary forms of multiple sclerosis. "Our trial provides randomized controlled evidence comparing two anti-CD20 therapies that are already widely used in clinical practice," said Øivind Torkildsen, a professor at the University of Bergen and consultant neurologist at Haukeland University Hospital. "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."

John Corboy, affiliated with the University of Colorado Anschutz School of Medicine, described the study as the first reasonably large randomized controlled trial comparing the drugs in newly diagnosed MS patients. "This is the first reasonably large randomized controlled trial of rituximab versus ocrelizumab in newly diagnosed MS patients," Corboy said. "It suggests that rituximab should be strongly considered as a first-line CD20 drug at a much lower cost."

The study was coordinated by Neuro-SysMed and publicly funded through the Norwegian national clinical trials program KLINBEFORSK. Other randomized trials are also comparing rituximab and ocrelizumab in relapsing multiple sclerosis, and researchers have formed the ROC-MS collaborative initiative to pool individual participant data for a prospective meta-analysis.