Phase 2 Trial of Rituximab in Acetylcholine Receptor Antibody-Positive Generalized Myasthenia Gravis

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

Corticosteroid Treatment-Resistance in Myasthenia Gravis

“…Existing data supports MuSK MG being primarily a disease of short-lived plasma cells, which are more sensitive to GC treatment, compared to long-lived plasma cells of AChR antibody positive MG ( 31 , 44 ). The better response to anti-CD20 treatment of MuSK MG than AChR MG supports that short-lived CD20 expressing plasma cells are critical in disease pathology compared to long-lived plasma cells, which do not express CD20 ( 45 , 46 ). GC-resistance may change over time with the potential for long-lived plasma cells becoming the major driver of pathology, compared to earlier in the disease may also induce resistance itself.…”

Heterogeneity of acetylcholine receptor autoantibody-mediated complement activity in patients with myasthenia gravis

“…Immunomodulatory therapy and thymectomy did not reveal diminished complement activity. Autoantibody titer often persists following such treatments 40,41 , thus our findings suggest that these treatments may not alter either the properties or relative frequency of complement activating autoantibodies.…”

Molecular Therapy in Myasthenia Gravis

“…Rituximab did not have a steroid-sparing effect compared with placebo (60% on rituximab versus 56% on placebo). 83 Also, no significant differences in disease-severity outcomes were noted. The trial result shows that in mild-to-moderate AChR antibody-positive MG, rituximab is unlikely to produce a clinically meaningful steroid-sparing effect over 12 months.…”