Long-term efficacy and safety of ravulizumab in adults with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis: results from the phase 3 CHAMPION MG open-label extension

Abstract

Introduction: Ravulizumab demonstrated efficacy and an acceptable safety profile versus placebo in the randomized controlled period (RCP) of the phase 3 CHAMPION MG trial in patients with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis. We report an interim analysis of the ongoing open-label extension (OLE) designed to evaluate long-term treatment effects.

Methods: Following completion of the 26-week RCP, patients could enter the OLE; patients who received ravulizumab in the RCP continued the drug; patients who previously received placebo switched to ravulizumab. Patients receive body-weight-based maintenance dosing of ravulizumab every 8 weeks. Efficacy endpoints up to 60 weeks included Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores, with least-squares (LS) mean change and 95% confidence intervals (95% CI) reported.

Results: Long-term efficacy and safety in the OLE were analyzed in 161 and 169 patients, respectively. Improvements in all scores were maintained through 60 weeks in patients who received ravulizumab during the RCP; LS mean change from RCP baseline in MG-ADL score was - 4.0 (95% CI: - 4.8, - 3.1; p < 0.0001). Rapid (within 2 weeks) and sustained improvements occurred in patients previously receiving placebo; LS mean change in MG-ADL score from OLE baseline to Week 60 was - 1.7 (95% CI: - 2.7, - 0.8; p = 0.0007). Similar trends were seen in QMG scores. Ravulizumab treatment was associated with a decreased rate of clinical deterioration events compared with placebo. Ravulizumab was well tolerated; no meningococcal infections were reported.

Conclusion: Findings support the sustained efficacy and long-term safety of ravulizumab, administered every 8 weeks, in adults with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis.

Clinicaltrials: gov identifier: NCT03920293; EudraCT: 2018-003243-39.

Keywords: Generalized myasthenia gravis; Long-term; Open-label; Ravulizumab.

Fig. 1

Study design. IV, intravenous. From NEJM Evidence, Vu T, et al, Terminal complement inhibitor ravulizumab in generalized myasthenia gravis, 1, EvidDoa2100066. Copyright © 2022 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

Fig. 2

Patient disposition. ^aIndividuals may have had more than one reason for exclusion^{. b}One death was due to COVID-19 and one was due to cerebral hemorrhage. ^cBoth deaths were related to COVID-19. AE, adverse event; COVID-19, coronavirus disease 2019; FAS, full analysis set

Fig. 3

Least-squares mean change (95% CI) from RCP baseline in A MG-ADL total score, B QMG total score, C MG-QOL15r total score and D Neuro-QoL Fatigue score. *, **, and *** indicate two-sided p-values of < 0.05, < 0.01, and < 0.001, respectively, for the comparison of treatment groups in change from baseline during the RCP (p-values are nominal for comparisons at all timepoints except Week 26; endpoints at Week 26 were tested in a hierarchical manner). The RCP estimates are based on an MMRM that included treatment group, stratification factor region, baseline score, study visit, and study visit by treatment group interaction. Visits up to Week 26 were included in the model. The OLE estimates are based on an MMRM that included stratification factor region, baseline score, and study visit. A model was fit for the ravulizumab–ravulizumab and placebo–ravulizumab arms of the OLE analysis set separately. Data for the full analysis set are shown for the RCP; data for the OLE analysis set are shown for the OLE period. Data are offset for clarity. BL, baseline; CI, confidence interval; LS, least squares; MG-ADL, Myasthenia Gravis–Activities of Daily Living; MG-QOL15r, revised 15-item Myasthenia Gravis Quality of Life; MMRM, mixed model for repeated measures; Neuro-QoL, Neurological Quality of Life; OLE, open-label extension; QMG, Quantitative Myasthenia Gravis; RCP, randomized controlled period

Fig. 4

Least-squares mean change (95% CI) from OLE baseline in A MG-ADL total score, B QMG total score, C MG-QOL15r total score and D Neuro-QoL Fatigue score. *, **, and *** indicate two-sided nominal p-values of < 0.05, < 0.01, and < 0.001, respectively, for the change from OLE baseline (whether LS mean change equals zero). Estimates were based on an MMRM for each treatment sequence and included stratification factor region, baseline score, and study visit. Data for the OLE analysis set are shown. Data are offset for clarity. BL, baseline; CI, confidence interval; LS, least squares; MG-ADL, Myasthenia Gravis–Activities of Daily Living; MG-QOL15r, revised 15-item Myasthenia Gravis Quality of Life; MMRM, mixed model for repeated measures; Neuro-QoL, Neurological Quality of Life; OLE, open-label extension; QMG, Quantitative Myasthenia Gravis; RCP, randomized controlled period

Fig. 5

Clinical deterioration event rate per 100 patient-years. ^a1-year period, events reported by investigators. The event rates were calculated using a generalized estimating equation Poisson regression repeated measures model with the number of events as the dependent variable, the logarithm of patient-years as the offset variable, and the study or phase indicator (pre-study, placebo, and ravulizumab RCP + OLE) as the factors, assuming a compound symmetry correlation structure. OLE, open-label extension; PY, patient-years; RCP, randomized controlled period