By Mary L. Vo, MD, PharmD
Assistant Professor of Neurology, Weill Cornell Medicine
SYNOPSIS: The B-Cell Targeted Treatment In Myasthenia Gravis (BeatMG) study was the first prospective, randomized, double-blind, placebo-controlled clinical trial to explore the role of targeted B-cell depletion in myasthenia patients. Although rituximab was found to be safe and well-tolerated, rituximab treatment did not confer a significant steroid-sparing effect compared to placebo. Results of a futility analysis suggested rituximab treatment would be unlikely to show a clinically meaningful improvement of 30% over placebo in a larger Phase III trial of mild to moderately symptomatic acetylcholine receptor autoantibody-positive generalized myasthenia gravis patients.
SOURCE: Nowak RJ, Coffey CS, Goldstein JM, et al, for the NeuroNEXT NN103 BeatMG Study Team. Phase 2 trial of rituximab in acetylcholine receptor antibody-positive generalized myasthenia gravis: The BeatMG study. Neurology 2021;98:e376-e389.
Generalized myasthenia gravis (gMG) is caused by immune-mediated destruction of the neuromuscular junction, resulting in fluctuating oculobulbar and extremity weakness. The majority of gMG patients harbor IgG1 and IgG3 isotype antibodies against the acetylcholine receptor (AChR), causing complement-mediated destruction of the post-synaptic AChR receptor. Standard treatment is immunosuppressive therapy (IST) with agents such as steroids, azathioprine, mycophenolate mofetil, rituximab, eculizumab, and intravenous immunoglobulin (IVIG).
Although steroid therapy remains the first-line treatment, its long-term use is fraught with symptom exacerbation during dosage taper as well as a multitude of debilitating adverse effects. Despite combination treatment, 10% to 15% of gMG patients remain medically refractory with significant symptoms affecting daily functioning. Such issues underscore the ongoing need for additional steroid-sparing immunosuppressant therapy.
The central role of autoreactive B cells in the immunopathogenesis of AChR autoantibody-positive (Ab+) MG has spurred interest in B-cell depleting therapy. Rituximab, a chimeric IgG1-kappa monoclonal immune globulin directed against CD20+ B lymphocytes, has increasingly been recognized as a well-tolerated, effective agent for maintenance treatment of MG.1,2
The goal of the current multicenter, randomized, double-blind, placebo-controlled Phase II trial was to determine the safety and efficacy of rituximab that would substantiate further investigation with a larger Phase III trial. The study enrolled 52 patients across 16 of the 26 National Institute of Neurological Disorders and Stroke-sponsored NeuroNEXT centers across the United States between August 2014 and July 2016. Patients were permitted to continue stable baseline IST with azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, and methotrexate. Subjects with a history of thymoma, thymectomy within six months of enrollment, prior rituximab treatment, or treatment with IVIG within four weeks of baseline were excluded.
Of the 52 participants, 25 were randomized to rituximab and 27 to placebo. The mean ± standard deviation (SD) age at enrollment was 55.1 ± 17.1 years; 23 (44.2%) were female and 31 (59.6%) were Myasthenia Gravis Foundation of America Class II. The mean ± SD baseline prednisone dose was 22.1 mg/d ± 9.7 mg/d. Baseline demographics, IST regimens, and mean prednisone dose were well-matched between the two groups.
The primary endpoint was the percent of subjects who achieved a ≥ 75% reduction in mean daily prednisone dose at 48-52 weeks and maintained clinical stability compared to baseline. Safety analysis focused on differences between treatment-associated adverse events in the two groups. Secondary outcomes were change in Myasthenia Gravis Composite (MGC) score and change in quantitative myasthenia gravis (QMG) score from baseline to 52 weeks.
Using an intention-to-treat paradigm, primary and secondary endpoints were carried out using a 0.10 level of significance. The primary futility hypothesis tested was that rituximab-treated participants would achieve at least a 30% absolute increase in the frequency of successful primary endpoints compared to placebo. Logistic regression was used to estimate the odds ratio (OR) and the 90% one-sided confidence interval (CI) such that the null hypothesis would be rejected if the upper limit of the CI excluded 3.5. The primary outcome of ≥ 75% prednisone dose reduction was achieved in 60% of those on rituximab vs. 56% on placebo (OR, 1.14%; 90% one-sided CI, 0-2.4), indicating no significant difference between the two groups. This finding indicates that rituximab was unlikely to confer a clinically meaningful steroid-sparing effect over 12 months.
The study reached its futility endpoint (P = 0.03), suggesting that clinically meaningful steroid-sparing effect from rituximab over 12 months was unlikely to be achieved in a larger Phase III trial of mild to moderately symptomatic AChR-Ab+ gMG. Safety analysis showed that a similar proportion of participants reported treatment-emergent adverse effects between the rituximab and placebo groups (100% vs. 96%), indicating that rituximab has a good safety and tolerability profile. The secondary outcome assessment showed no significant differences in MGC and QMG scores in either group. There were no significant differences in responder rate between rituximab and placebo groups (70% vs. 67%, respectively).
Further exploratory analysis showed that the placebo group had a threefold higher rate of clinical relapse requiring intravenous immunoglobulin or plasmapheresis with 0.036 in the placebo group compared to 0.010 in the rituximab group (P = 0.055). There were no significant differences in AChR antibody levels from baseline to week 52 in either group. Adequate B-cell depletion was achieved in the treatment group. Baseline B-cell counts did not differ between the two groups.
Lack of clinical improvement may be explained by rituximab treatment failure, adequate B-cell reduction from baseline IST regimen and prednisone doses, and inclusion of subjects with relatively mild disease manifestations. These factors also may have contributed to a higher-than-expected response rate in the placebo group.
COMMENTARY
The BeatMG study is the first prospective study to evaluate B-cell depletion in patients with AChR+ MG and establishes rituximab as a safe and well-tolerated treatment in patients with mild-to-moderate disease. Although rituximab treatment did not confer a steroid-sparing effect, the study did find a significantly lower rate of myasthenic exacerbation in the treated group. Rituximab remains an efficacious treatment option for mild-to-moderate AChR-Ab+ gMG refractory to other immunosuppressive therapies.
Although a steroid-sparing effect could not be attributed to rituximab treatment, this study provided valuable guidance for future trials with respect to optimizing the steroid-sparing outcome definition, quantifying the effect of baseline steroid and IST treatment on B-cell reduction, and exploring the effect of further B-cell depletion in patients treated with combination therapy.
REFERENCES
- Robeson KR, Kumar A, Keung B, et al. Durability of the rituximab response in acetylcholine receptor autoantibody-positive myasthenia gravis. JAMA Neurol 2017;74:60-66.
- Tandan R, Hehir MK 2nd, Waheed W, Howard DB. Rituximab treatment of myasthenia gravis: A systematic review. Muscle Nerve 2017;56:185-196.
