Eculizumab improves fatigue in refractory generalized myasthenia gravis

Abstract

Purpose: To evaluate the effect of eculizumab on perceived fatigue in patients with anti-acetylcholine receptor antibody-positive, refractory, generalized myasthenia gravis (MG) using the Quality of Life in Neurological Disorders (Neuro-QOL) Fatigue subscale, and to evaluate correlations between improvements in Neuro-QOL Fatigue and other clinical endpoints.

Methods: Neuro-QOL Fatigue, MG Activities of Daily Living (MG-ADL), Quantitative MG (QMG), and the 15-item MG Quality of Life (MG-QOL15) scales were administered during the phase 3, randomized, placebo-controlled REGAIN study (eculizumab, n = 62; placebo, n = 63) and subsequent open-label extension (OLE). Data were analyzed using repeated-measures models. Correlations between changes in Neuro-QOL Fatigue and in MG-ADL, QMG, and MG-QOL15 scores were determined at REGAIN week 26.

Results: At REGAIN week 26, eculizumab-treated patients showed significantly greater improvements in Neuro-QOL Fatigue scores than placebo-treated patients (consistent with improvements in MG-ADL, QMG, and MG-QOL15 scores previously reported in REGAIN). Improvements with eculizumab were sustained through OLE week 52. Correlations between Neuro-QOL Fatigue and MG-QOL15, MG-ADL, and QMG scores were strong for eculizumab-treated patients at REGAIN week 26, and strong, moderate, and weak, respectively, for placebo-treated patients.

Conclusions: Compared with placebo, eculizumab was associated with improvements in perceived fatigue that strongly correlated with improvements in MG-specific outcome measures. Trial ID Registration: NCT01997229, NCT02301624.

Keywords: Complement; Eculizumab; Fatigue; Myasthenia gravis; Neuro-QOL Fatigue; Quality of life; Terminal complement inhibition.

Conflict of interest statement

Henning Andersen, MD, DMSci, PhD, has received research and travel support, and speaker honoraria from CSL Behring, Eisai, Octapharma, Pfizer, Sanofi Genzyme and UCB Pharma and has served as a consultant on advisory boards for NMD Pharma, UCB Pharma and Sanofi Genzyme. Renato Mantegazza, MD, received funding for research and congress participation from Bayer, BioMarin, Sanofi Genzyme and Teva, and participated in Scientific Advisory Boards for Alexion Pharmaceuticals, Argenx BVBA and BioMarin. Jing Jing Wang, MD, was formerly employed by, and owns stock in, Alexion Pharmaceuticals. Fanny O’Brien, PhD, and Kaushik Patra, PhD, are employees of, and own stock in, Alexion Pharmaceuticals. James F. Howard, Jr, MD, obtained: research support from Alexion Pharmaceuticals during the conduct of the study; grants from Alexion Pharmaceuticals; research support from Research Triangle Institute/Centers for Disease Control and Prevention; grants from National Institutes of Health (including the National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases); research support from the Muscular Dystrophy Association; honoraria from Alexion Pharmaceuticals, Argenx BVBA and Ra Pharmaceuticals; and non-financial support from Alexion Pharmaceuticals, Argenx BVBA, Ra Pharmaceuticals and Toleranzia AB, outside of the submitted work.

Figures

Fig. 1

Change in Neuro-QOL Fatigue subscale total score from REGAIN baseline to week 52 of the open-label study using a repeated-measures model.aaA repeated-measures model using the restricted maximum likelihood for the changes from baseline was used to compare the two treatment groups at each assessment visit and over time. The model included the following terms: treatment, visit, treatment by visit interaction, pooled Myasthenia Gravis Foundation of America (MGFA) randomization stratification variable (based on their MGFA classification at screening, patients were assigned to one of two categories: IIa/IIIa/IVa [a, symptoms predominantly affecting limb or axial muscles, or both] or IIb/IIIb/IVb [b, symptoms predominantly affecting oropharyngeal or respiratory muscles, or both]), and Neuro-QOL Fatigue total score at baseline. bNumber of patients who completed the assessment at each time point. Some patients did not complete all items of the questionnaire at every timepoint. When this occurred, total scores could not be computed at that time point. Missing scores were not imputed. BL baseline, CI confidence interval, Neuro-QOL Fatigue Quality of Life in Neurological Disorders Fatigue subscale, REGAIN Eculizumab for REfractory GenerAlIzed MyastheNia Gravis

Fig. 2

Correlation between change from REGAIN baseline to week 26, in Neuro-QOL Fatigue subscale total score and a MG-ADL, b QMG, and c MG-QOL15 total scores by treatment group (eculizumab, n = 54; placebo, n = 58). Improvements in Neuro-QOL Fatigue total score correlated with improvements in a MG-ADL, b QMG, and c MG-QOL15 total scores more strongly in patients treated with eculizumab than in those who received placebo. Within treatment arms, the null hypothesis was r = 0.4 (the lower limit for moderate correlations). CI confidence interval, MG-ADL Myasthenia Gravis-Activities of Daily Living, MG-QOL15 15-item Myasthenia Gravis Quality of Life, Neuro-QOL Fatigue Quality of Life in Neurological Disorders Fatigue subscale, QMG quantitative myasthenia gravis