Despite displaying safety, after accounting for baseline differences between groups, statistically significant clinical improvement was not observed in key secondary outcomes, exploratory clinical outcomes, or responder analyses.
Results from the B-Cell Targeted Treatment in MG (BeatMG) study (NCT02110706), a randomized, placebo-controlled phase 2 trial, showed that rituximab (Rituxan; Genentech) is safe in patients with acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR-Ab+ gMG); however, investigators found no significant difference in the prespecified measure of steroid-sparing effect between the rituximab and placebo groups.1
Led by Richard Nowak, MD, MS, assistant professor of neurology, Yale School of Medicine, the futility analysis also indicated that there was a low probability of observing a clinically meaningful steroid-sparing effect difference in a phase 3 trial of a similar population at 1-year. The BeatMG study was designed to follow-up on a previously conducted single-center pilot study, also conducted at Yale, where 82% of patients with gMG who completed 2-cycle rituximab regimen achieved at least a 75% reduction in the prednisone dose at 52 weeks (95% CI, 48%-98%).2
In total, 52 participants who were 21-90 years of age, were randomized 1:1 to either rituximab or placebo, with randomization stratified on baseline prednisone dose (≤35 mg/day vs >35 mg/day) and concomitant immunosuppressive (IST) therapy use at baseline. The primary outcome used the MG Composite (MGC) score, a measure of steroid-sparing effect. Patients were considered to have achieved this end point successful showed at least a 75% reduction in mean daily prednisone dose in the 4-weeks prior to week 52 compared to the 4-week period prior to randomization and with clinical improvement or no significant worsening of symptoms.
At the conclusion of the study, 60% (15 of 25) of patients on rituximab vs 56% on placebo achieved the primary steroid-sparing outcome (OR, 1.14 [90% 1-sided CI, 0-2.4]). Investigators noted that based on the model used, the estimated difference in percent of success between groups was a 6% increase in success rates with rituximab, and an upper 90% 1-sided CI of 24%.1
Safety, the second primary end point, showed a similar proportion of participants on rituximab (100%) and placebo (96%) who had treatment-emergent adverse events (TEAEs). Common AEs experienced by more than 15% of participants included arthralgia, headache, upper respiratory infection, fatigue, back pain, nausea, muscular weakness, and paresthesia. Both treatment-related AEs (rituximab, 76%; placebo, 82%; P = .63) and treatment-related serious AEs were similar between the groups (rituximab, 24%; placebo, 30%; P = .65).
Novak and colleagues concluded that, "additional analyses are planned to delve deeper into these results, and to further explore the role of B-cell depletion in this population, including the full impact of disease severity, B-cell counts, and use of concomitant ISTs at time of enrollment. Further insights are anticipated from the observational, post-intervention study, which include follow-up through 96- weeks."
Findings were similar for both key secondary outcomes, with neither showing a statistically significant difference over time. The change in mean MGC score was –5.7 vs –4.0, while the change in mean Quantitative MG score was –4.0 vs –1.7, for the rituximab and placebo groups, respectively. From baseline to week 52, changes in mean MG-Activities of Daily Living and MG-Quality of Life showed no statistically significant model-adjusted differences between the groups.
Successful B-cell depletion was achieved in the treatment group, with median B-cell counts that were 124 (range, 26-488), 2 (range, 0-27), and 4 (range, 0-107) at baseline, weeks 24 and 52, respectively. In total, 42% (22 of 52) of participants had B-cell counts below the lower limit of normal (LLN), defined as less than 120 cells/microliter, at baseline, with no significant differences in the proportion of participants between groups (rituximab: 12 [48%] vs placebo: 10 [37%]; P = .42). Notably, 15 participants (63%) in the placebo group continued to have B-cell count levels below the LLN at both week 24 and 52, compared to the rituximab group where all were below the LLN.
Of the 10 participants on rituximab who did not achieve the primary end point, 5 did not show at least 75% prednisone dose reduction but had no clinical worsening, 2 did not achieve the prednisone dose reduction and had clinical worsening, 1 achieved the 75% prednisone dose reduction but had clinical worsening, and 2 that withdrew from the study.