By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: Eculizumab, a monoclonal antibody that inhibits the C-5 complement terminal complex formation, is a safe and effective treatment for generalized myasthenia gravis with acetylcholine receptor auto-antibodies, even after failed treatment with other immunosuppressive regimens.
SOURCE: Siddiqi ZA, Nowack RJ, Mozaffar T, et al. Eculizumab in refractory generalized myasthenia gravis previously treated with rituximab: Subgroup analysis of REGAIN and its extension study. Muscle Nerve 2021;64:662-669.
Chronic immunosuppressive therapy, including azathioprine and mycophenolate, is one of the mainstays of myasthenia gravis (MG) treatment, both for maintenance therapy and as long-term steroid sparing agents. For the 10% of patients who remain refractory to conventional immunosuppressive therapy, individualized treatment is warranted with agents such as rituximab and eculizumab. Is eculizumab safe and effective in MG refractory to rituximab?
REGAIN was a Phase III, randomized, double-blind, placebo-controlled, multicenter trial across 76 hospitals in 17 countries worldwide to determine the safety and efficacy of eculizumab in refractory, seropositive, generalized MG. MG Activities of Daily Living (MG-ADL) scale score did not statistically change, as measured by worst-rank analysis, over the 26-week primary endpoint, but an open-label extension (OLE) over three years demonstrated a rapid sustained improvement in MG-ADL. Some REGAIN enrollees had received rituximab prior to study entry, and this report is a post hoc analysis of these patients.
Eligible patients for REGAIN and OLE were designated as refractory if they remained symptomatic after 12 months of treatment, comprising at least two immunosuppressive agents, or one immunosuppressive agent coupled with intravenous immunoglobulin or plasma exchange. All had received Neisseria meningitidis vaccination and were eligible for enrollment if they had received rituximab more than six months prior to screening.
Eculizumab dosing comprised a four-week induction of 900 mg at day 1 and at weeks 1, 2, and 3, and 1,200 mg at week 4, followed by a maintenance dose of 1,200 mg every two weeks for 26 weeks, which continued during the OLE period. Assessments of response included the MG-ADL, Quantitative MG (QMG), MG composite (MGC), and 15-item MG Quality of Life (MG-QOL15) questionnaire scores, and the MG Foundation of America (MGFA) post-intervention status. Statistical analysis was performed by quantifying change in scores using a restricted maximum-likelihood-based repeated-measures analysis of change from baseline, with the data presented as least-squares (LS) means and 95% confidence intervals.
Of 125 REGAIN participants, 14 previously had received rituximab, of which seven each were in the eculizumab and placebo arms, and all but one continued in the OLE. Those who received rituximab had been treated with a variety of regimens a median of 18.6 or 20.9 months prior to enrollment in the eculizumab or placebo arms, respectively. Compared to baseline, MG-ADL scores at 130 weeks significantly improved in both groups, with 66.7% and 65%, respectively, achieving an MGFA post-intervention status of minimal manifestations. Safety profiles were similar for both groups. Eculizumab appears to be safe and effective for refractory seropositive generalized MG, regardless of prior rituximab treatment.
COMMENTARY
Approved for seropositive generalized myasthenia gravis (gMG) treatment, eculizumab is a C5 complement inhibitor, inhibiting the terminal complement complex, but also acting on lymphocytes. Reduced activation markers in memory cluster of CD4+ Tfh subsets, reduced frequencies of CXCR5+HLA-DR+CCR7+ Tfh subsets and CD11b+ migratory memory B cells, and increased regulatory T cell populations were found when comparing acetylcholine receptor autoantibody positive gMG patients after three or more months of eculizumab therapy to baseline. CD8+ T cell subsets that were terminally differentiated and senescent also were found to have increased, suggesting that eculizumab, through complement inhibition, modulates adaptive immunity in MG.1
REFERENCE
- Yingkai L, Yi JS, Howard JF Jr, et al. Cellular changes in eculizumab early responders with generalized myasthenia gravis. Clin Immunol 2021;231:108830.
