Fatigue is an important yet understudied symptom of MG [12]. To our knowledge, this is the first analysis of T-score transformation of Neuro-QoL Short Form Fatigue scores in patients with MG in a Phase 3 study, allowing us to assess the clinical meaningfulness of these data. Patients receiving zilucoplan in RAISE and its OLE experienced clinically meaningful improvements in fatigue compared with placebo, thus demonstrating a positive effect of zilucoplan on fatigue. The improvements in fatigue observed during the double-blind period of RAISE further continued into RAISE-XT, the ongoing OLE study, and were sustained up to Week 60, indicating that zilucoplan consistently improved fatigue in patients with MG in the long term. Most patients experienced moderate to severe fatigue at the start of the study, but patients on zilucoplan showed significant improvement in their fatigue severity at Week 12, with more patients on zilucoplan reporting clinically meaningful improvements in fatigue at Week 12 versus placebo. Furthermore, most of these patients with moderate or severe fatigue at baseline had no or mild fatigue after 60 weeks. RAISE-XT is ongoing, and at the time of the data cut-off, a large majority of patients were still enrolled. There may be a potential effect of study discontinuations on the efficacy data, however, most discontinuations were due to voluntary withdrawal and not due to a lack of efficacy.

This post-hoc analysis used T-scores, transformed from raw Neuro-QoL Short Form Fatigue data. Meaningful change thresholds, responder definitions, and severity thresholds have already been defined for T-scores and allow for an easier interpretation of the effect of change [5, 16, 18]. The improvements in fatigue observed here with T-score data were aligned with the improvements in raw scores observed in RAISE [21]. Using T-scores in this way provides us with a way to highlight clinically meaningful changes in fatigue in MG, which are important for the daily living of patients with MG, in addition to the clinically established measures such as MG-ADL and QMG scores. Another strength of this study is that the Neuro-QoL Short Form Fatigue scale was used, a validated, disease-agnostic, easy-to-use PRO measure with only eight items.

The known-groups validity analysis used MGFA disease classification scores at screening to assess whether the Neuro-QoL Short Form Fatigue scale differentiates between these groups. The mean fatigue T-scores for MGFA Disease Class II were lower than for the pooled MGFA Disease Class III/IV, but this difference was not statistically significant. This may be because the MGFA disease classification is subjective in nature, especially when it comes to distinction between classes [24], but in Tran et al., clear and significant differences were observed [5]. A limitation of our analysis is that it is possible that the inclusion criteria of our study, an MG-ADL score of ≥ 6 and a QMG score of ≥ 12 [21], resulted in more patients at the higher end of MGFA Disease Class II, making it harder to distinguish these patients from those in the pooled MGFA Disease Class III/IV. This explanation is supported by a higher mean T-score for MGFA Disease Class II in this study as compared with Tran et al.[5]. However, through the course of the OLE, Neuro-QoL Short Form Fatigue scores correlated positively with both the clinician-reported outcomes of QMG and the PROs of MG-ADL and MG-QoL 15r, highlighting the clinical relationship between MG-specific symptoms and fatigue. Fatigue is the most common patient-reported treatment goal for their MG [12], and therefore, should not be underestimated as a contributor to patients’ health-related QoL (HRQoL). It is important for clinicians to routinely measure fatigue as part of the overall assessment of MG symptoms in their patients, in addition to MG-specific outcomes.

Both Neuro-QoL Short Form Fatigue and MG-QoL 15r assess HRQoL and the impact MG has on patients’ lives; MG-QoL 15r is focused on MG more generally [25], while Neuro-QoL Short Form Fatigue is focused on the impact of fatigue specifically [17]. Both of these measures deal directly with the impact of MG on HRQoL and, as expected, there was a high correlation between them in our study at baseline, which further increased at Week 60. This high correlation further substantiates that a reduction in fatigue leads to an improvement in HRQoL in patients with MG. The items in the QMG scale focus on muscle fatiguability, with items that measure how long the patient can keep their arms outstretched at 90 degrees while sitting, legs at 45 degrees while supine, and hand grip [26]. Similarly, MG-ADL covers activities of daily living, such as impairment of ability to brush teeth or comb hair, and impairment of ability to rise from a chair [27]. While these symptoms do not necessarily reflect fatigue and are distinct concepts from those assessed by the Neuro-QoL Short Form Fatigue scale, there was a moderate, but statistically significant, positive correlation at baseline, supporting the known-groups validity analysis, which increased during the course of the study. The correlations at baseline indicate that there is a relationship between fatigue and muscle fatiguability, and the increase in correlations observed throughout the study is likely a result of the treatment effect of zilucoplan, causing patients, on average, to report improvement on all scales [21, 22].

The differences in magnitude of the correlations between Neuro-QoL Short Form Fatigue and MG-ADL, QMG, and MG-QoL 15r scores support the convergent and divergent validity of Neuro-QoL Short Form Fatigue in MG. The stronger correlations were observed with instruments assessing more comparable concepts (MG-QoL 15r assessing HRQoL) and less strong correlations with instruments assessing more distal concepts (MG-ADL assessing symptoms and the impact on daily activities, and QMG assessing muscle fatiguability). Taken together, the observed psychometric properties of the Neuro-QoL Short Form Fatigue scale in our study support its use in gMG.

The impact of fatigue on MG has not been studied widely despite its substantial impact on patients’ lives. The effect of other complement C5 inhibitors, eculizumab and ravulizumab, on fatigue in their Phase 3 and OLE studies was assessed using the raw scores on an alternative, longer instrument—the 19-item Neuro-QoL fatigue subscale—and variable degrees of reduction from baseline were reported, highlighting that complement C5 inhibitors can reduce fatigue in patients with MG [28,29,30]. However, zilucoplan is the first C5 inhibitor to show a clinically meaningful reduction in fatigue. To conclude, daily subcutaneous injections of the complement C5 inhibitor zilucoplan led to rapid and clinically meaningful improvements in fatigue that were sustained for more than a year in patients with gMG. The data showed rapid benefits in fatigue for patients receiving zilucoplan, with sustained and meaningful improvements across all baseline fatigue severity levels, including severe fatigue where the effect is especially debilitating for patients. The majority of patients reported no or mild fatigue at Week 60, improving from severe or moderate fatigue at baseline. These data highlight that treatment with zilucoplan can result in a sustained reduction in fatigue, a symptom known to be particularly debilitating for patients with gMG.