Safety of MabThera in RA
The body of evidence generated from clinical trials shows that MabThera® is well tolerated and that the safety profile is consistent across trials (Edwards et al. 2004; Emery et al. 2006; Cohen et al. 2006). This is because MabThera selectively targets CD20-positive B cells, leaving acquired immunity intact. Adverse events occurring at a greater frequency following treatment with MabThera compared with placebo are primarily infusion-related events. The majority of these were of mild-to-moderate intensity and reduced with further infusions.
The infection rate that occurs during treatment with MabThera lies within the normal range seen for RA patients. Subsequent courses of MabThera treatment do not appear to bring any additional safety signals beyond those identified in the original studies (van Vollenhoven et al. 2006).
Adverse Events
In the REFLEX (Randomized Evaluation oF Long-term Efficacy of rituXimab in RA) study (Cohen et al. 2006), the overall incidence of adverse events occurring in patients receiving MabThera was similar to that observed in patients receiving placebo; 88% of patients receiving placebo reported an adverse event compared with 85% of those receiving MabThera. Adverse events that occurred at a marginally higher level in the MabThera-treated group, compared with the methotrexate-treated group, were infusion-related (e.g. nasopharyngitis, pyrexia, hypertension and dizziness). The majority of these were of mild-to-moderate intensity and reduced with further infusions.
The signs and symptoms of acute infusion reactions (e.g. pruritus, urticaria/rash, angioedema, fever, chills, rigors, sneezing, throat irritation/tightness, cough, bronchospasm, with or without hypotension or hypertension) were experienced by a greater proportion of MabThera-treated patients (23%) than placebo-treated patients (18%) during the first infusion. However, the likelihood of patients experiencing an infusion-related reaction diminished with the second infusion, where acute infusion reactions occurred in fewer patients receiving MabThera (8%) than placebo (11%) (Cohen et al. 2006).
Serious adverse events occurred at a higher incidence in placebo-treated patients (10%) than in MabThera-treated patients (7%). There were no events that raised significant safety concerns. The tolerability data from the REFLEX study are consistent with those reported in the Phase IIa and DANCER (Dose-ranging Assessment iNternational Clinical Evaluation of Rituximab in RA) studies (Emery et al. 2006; Edwards et al. 2004).
A preliminary analysis of long-term safety in open-label extension studies looking at subsequent courses of MabThera showed that the overall incidence of adverse events declined. The incidence of adverse events, including infusion reactions, decreased from 88% after the first treatment course of MabThera to 55% following course four (Moreland et al. 2006). Adverse events decreased from 939 events per 100 patient-years during the first 3 months to 212 per 100 patient-years at 10–12 months. Serious adverse events occurred at the same rate in both MabThera-treated and placebo-treated patients (22%). The incidence of serious adverse events declined with subsequent treatment courses from 29 events per 100 patient-years during the first 3 months to 11–21 events per 100 patient-years from 4–24 months. Infusion reactions decreased with subsequent courses and the incidence of human antichimeric antibodies (HACA) remained below 10% (Moreland et al. 2006).
In the REFLEX study, the observed incidence of infections over 24 weeks was slightly higher in MabThera-treated patients (41%) than in placebo-treated patients (38%). Conversely, however, when the duration of response was taken into consideration, the overall infection rate per 100 patient-years was slightly higher in placebo-treated patients (154.6 per 100 patient-years) than in MabThera-treated patients (138.2 per 100 patient-years). Rates of serious infections were 3.7 per 100 patient-years (three serious infections) for placebo versus a marginally higher 5.2 per 100 patient-years for MabThera (seven serious infections). Importantly, there were no reports of tuberculosis or opportunistic infections over the 24 weeks of this study (Cohen et al. 2006).
Subsequent courses of MabThera do not appear to be associated with an increased rate of infection or serious infection. Analysis of the data by treatment course shows that when the duration of observation was taken into account (i.e. expressed in terms of the rate per 100 patient-years), the rate of all infections appears to be relatively constant across the first three treatment courses (81–83 infections per 100 patient-years) ( Moreland et al. 2006 ). Moreover, no cases of tuberculosis were reported and there was no indication of an increased risk of malignancy with additional courses of treatment.