Phase 2 Trial of Rituximab in Acetylcholine Receptor Antibody-Positive Generalized Myasthenia Gravis: The BeatMG Study

Abstract

Objective: To determine whether rituximab is safe and potentially beneficial, warranting further investigation in an efficacy trial for acetylcholine receptor antibody-positive generalized MG (AChR-Ab+ gMG).

Methods: The B-Cell Targeted Treatment in MG (BeatMG) study was a randomized, double-blind, placebo-controlled, multicenter phase-2 trial that utilized a futility design. Individuals 21-90 years of age, with AChR-Ab+ gMG (MG Foundation of America Class II-IV) and receiving prednisone ≥15 mg/day were eligible. The primary outcome was a measure of steroid-sparing effect, defined as the proportion achieving ≥75% reduction in mean daily prednisone dose in the 4-weeks prior to week 52 and with clinical improvement or no significant worsening as compared to the 4-week period prior to randomization. The co-primary outcome was safety. Secondary outcomes included MG-specific clinical assessments. Fifty-two individuals were randomized (1:1) to either a two-cycle rituximab/placebo regimen, with follow-up through 52-weeks.

Results: Of the 52 participants included, mean (±SD) age at enrollment was 55.1 (±17.1) years; 23 (44.2%) were female, and 31 (59.6%) were MGFA Class II. The mean (±SD) baseline prednisone dose was 22.1 (±9.7) mg/day. The primary steroid-sparing outcome was achieved in 60% of those on rituximab vs. 56% on placebo. The study reached its futility endpoint (p=0.03) suggesting that the pre-defined clinically meaningful improvement of 30% due to rituximab over placebo was unlikely to be achieved in a subsequent, larger trial. No safety issues identified.

Conclusions: While rituximab was safe and well-tolerated, these results suggest that there is a low probability of observing the defined clinically meaningful steroid-sparing effect over a 12-month period in a phase-3 trial of mild-moderately symptomatic AChR-Ab+ gMG.

Classification of evidence: This study provides Class I evidence that for mild-to-moderate AChR-Ab+ gMG, compared with placebo, rituximab is safe but unlikely to reduce steroid use by an absolute difference of at least 30% at 1 year.

Trial registration: ClinicalTrials.gov Identifier: NCT02110706.

Figure 1. CONSORT Flow Diagram

AE = adverse event; FVC = forced vital capacity; MG = myasthenia gravis.

Figure 2. Steroid-Sparing Effect

Mean prednisone dose over time for participants undergoing a forced steroid taper in the rituximab and placebo arms over 52 weeks. The area under the dose time curve (AUDTC) was compared for 47 participants completing the study through week 52 utilizing a nonparametric rank-based analysis. CI = confidence interval.

Figure 3. Clinical Outcome Measures

(A) Mean Myasthenia Gravis Composite (MGC) score over time by treatment group. (B) Mean Quantitative Myasthenia Gravis (QMG) score over time by treatment group. (C, D) Responder analysis: graphs show minimum point improvement at week 52 in the MGC and QMG scores for 47 participants completing the study. The initial threshold compares the percentage of participants achieving at least a 3-point improvement in MGC and QMG scores from baseline. (Due to convergence issues, the moderate/high dose prednisone strata variable was dropped from these models.) The upper threshold corresponded to an improvement of 8 points or greater for the MGC and 8 points or greater for the QMG scores. MGC score data were available for all 47 participants who completed the 52-week study period. QMG score data were available for 43 participants (3 participants in the rituximab group were either missing a baseline or 52-week score; 1 participant in the placebo group was missing a baseline score). (E) Median acetylcholine receptor (AChR) antibody levels (horizontal lines) at baseline (BL), week 24, and week 52 in the rituximab group were 4.2 (range 0.02–193), 3.47 (range 0.36–183), and 3.42 (range 0.41–100) nmol/L vs 1.5 (range 0–12.4), 0.9 (range 0.03–17.7), and 1.6 (range 0.07–20.1) nmol/L in the placebo group. Laboratory reference range: positive >0.02 nmol/L. (F) Median B-cell counts (horizontal lines) at BL, week 24, and week 52 for each participant. Normal reference range denoted by horizontal dashed lines: 120–725 cells/μL (CD19+/CD20– plus CD19+/CD20+ cells). CI = confidence interval.