By Chris Berrie
PRAGUE, CZECH REPUBLIC -- October 17, 2007 -- A single course of rituximab is safe and well tolerated, and compared with placebo, significantly reduces magnetic resonance imaging (MRI) and clinical evidence of inflammatory activity in patients with relapsing-remitting multiple sclerosis (RRMS), according to a multicenter, randomized, placebo-controlled, phase 2 trial.
The findings were presented here on October 13 at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
"For a decade or more, people have mostly looked at treatment that affects T cells in MS, although within the past 10 years there has actually been increased interest in B cells and their products," said principal investigator Emmanuelle Waubant, MD, PhD, Associate Professor of Neurology, Department of Neurology, University of California at San Francisco, San Francisco, California.
Past research has shown that the action of the genetically-engineered chimeric monoclonal anti-CD20 antibody rituximab, in its depletion of pre-B and B cells via binding to their CD20 antigen, could provide an alternative approach in the modulation of MS pathophysiology.
"So this is a proof-of-concept study, to determine whether, in human MS, targeting B cells has an impact on the course of the disease," Dr. Waubant said. The design aim was to evaluate the safety and efficacy of a single treatment cycle of rituximab over 48 weeks in patients with RRMS.
Study subjects were 18 to 55 years old and had a confirmed diagnosis of MS, at least one relapse in the previous year, and an expanded disability status scale (EDSS) score of 0 to 5. They were excluded if they had secondary progressive, primary progressive, or progressive-relapsing MS, and patients who had received various previous treatments were also excluded.
The 104 patients with RRMS enrolled were randomized to placebo (n = 35; mean age, 41.5 years; male, 17.1%) or rituximab 1,000 mg IV infusion on days 1 and 15 (n = 69; mean age, 39.6 years; male, 24.6%).
The primary endpoint was the total number of Gd-enhancing T1 brain lesions on serial MRI scans at weeks 12, 16, 20, and 24. A series of exploratory efficacy outcome measures were used as secondary endpoints: proportion of patients relapsing; annualized relapse rate; total number of new Gd-enhancing T1 lesions; and annualized relapse rate and T2 lesion volume change.
Baseline clinical characteristics between placebo and rituximab treatment groups were essentially the same with respect to number of relapses in the previous year (about 75% of patients had one relapse), mean EDSS score (2.7 vs 2.8, respectively), MS therapy in the previous 2 years (generally glatiramer acetate, interferon beta-1a, and methylprednisone), and lesion counts and volumes.
When compared with the placebo group, rituximab treatment satisfied the primary endpoint, with a significant 91% reduction in mean total Gd-enhancing lesion counts at weeks 12, 16, 20, and 24 (5.5 vs 0.5, respectively; P <.001). Significance was reached at week 12 (P =.003) and continued through the full 48 weeks of monitoring (P <.0001).
For the secondary endpoints, rituximab significantly reduced the number of new Gd-enhancing lesions at weeks 12, 16, 20, and 24, as compared with placebo (P <.001). From week 12, rituximab significantly reduced the number of new Gd-enhancing lesions at each assessment (P =.002 to P <.001).
Rituximab treatment also showed a trend in these patients towards lower annualized relapse rates that reached significance compared with placebo by week 24 (0.84 vs 0.37, respectively; P =.04), although this significance did not carry through to week 48.
For the safety assessments, while all other safety aspects examined were the same across the treatment groups, after the first infusion there were significantly greater infusion-associated adverse events with rituximab than placebo (78.3% vs 40.0%, respectively). However, this effect was reversed after the second infusion (40.0% vs. 20.9%, respectively).
Overall, rituximab was safe, well tolerated, and efficacious through the full 48 weeks of follow-up.
"We demonstrate a very rapid effect of depletion of B cells on the course of MS, measured by MRI, and clinical course, which suggests that it is probably not an effect that is promoted by interfering with the antibodies or immunoglobulin in MS, but it's more likely to be through B cells and their direct cellular effects on T cells and cytokines," Dr. Waubant indicated.
Funding for this study was provided by Genentech Inc.
[Presentation title: Safety and Efficacy of Rituximab in Adults With Relapsing-Remitting Multiple Sclerosis: Results of a Phase 2, Placebo-Controlled, Multicentre Trial Through 48 Weeks. Abstract P554]
