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Observational Study
. 2025 Mar 24;96(4):310-321.
doi: 10.1136/jnnp-2024-334404.

C5 complement inhibition versus FcRn modulation in generalised myasthenia gravis

Niklas Huntemann #  1 , Lea Gerischer #  2   3 , Meret Herdick  2   3 , Christopher Nelke  1 , Frauke Stascheit  2   3 , Sarah Hoffmann  2   3 , Menekse Öztürk  1 , Christina B Schroeter  1 , Sophie Lehnerer  2   3 , Maike Stein  2   3 , Charlotte Schubert  4   5 , Christiane Schneider-Gold  6 , Steffen Pfeuffer  7 , Heidrun H Krämer  7 , Franz Felix Konen  8 , Thomas Skripuletz  8 , Marc Pawlitzki  1 , Stefanie Glaubitz  9 , Jana Zschüntzsch  9 , Valerie Scherwietes  10 , Andreas Totzeck  10 , Tim Hagenacker  10 , Sven G Meuth  1 , Andreas Meisel #  2   3   11 , Tobias Ruck #  12   13
Affiliations
Observational Study

C5 complement inhibition versus FcRn modulation in generalised myasthenia gravis

Niklas Huntemann et al. J Neurol Neurosurg Psychiatry. .

Abstract

Background: Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular junctions, leading to fluctuating muscle weakness. While many patients respond well to standard immunosuppression, a substantial subgroup faces ongoing disease activity. Emerging treatments such as complement factor C5 inhibition (C5IT) and neonatal Fc receptor (FcRn) antagonism hold promise for these patients. However, the current landscape is hindered by a paucity of comparative data that is crucial for treatment decisions.

Objective: This study aims to compare the effectiveness and safety of C5IT and FcRn antagonists in a real-world setting.

Methods: A retrospective analysis of 153 MG patients from 8 German specialised MG centres receiving either C5IT (26 eculizumab, 80 ravulizumab) or efgartigimod (47 patients) was conducted. Propensity score matching (PSM) was employed to compare changes in MG-specific outcome parameters within the first 6 months after treatment initiation, along with safety profiles and concomitant MG therapy.

Results: Both treatment strategies led to rapid clinical improvements and substantial reductions in prednisolone doses. However, insufficient response was noted in 20%-49.1% of patients based on Quantitative MG and MG Activities of Daily Living (MG-ADL) scores. We did not identify any new safety concerns. After PSM, 40 patients remained in each group. In both cohorts, reductions in MG-ADL as prespecified primary study endpoint were comparable. Moreover, analyses of secondary outcome parameters demonstrated similar results for C5IT versus FcRn.

Conclusion: In contrast to current meta-analyses and indirect comparisons of clinical trial data, our real-world study demonstrates comparable efficacy and safety of C5IT and FcRn antagonism in MG.

Keywords: FC RECEPTOR; MYASTHENIA.

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Conflict of interest statement

Competing interests: NH received honoraria for lecturing meetings from Argenx, Merck and Viatris; travel reimbursements and meeting attendance fees from Alexion, Argenx, Merck and Novartis. CN received speaker and travel fees from UCB, ArgenX, Alexion and Merck. FS received travel/accommodation/meeting expenses from Alexion Pharmaceuticals and argnx and received speaking honoria and honoria for attendance at advisory boards from Alexion Pharmaceuticals, argnx and UCB pharma and received research grants from Alexion Pharmaceuticals and Octapharma. SH has received received speaker' s honoraria and honoraria for attendance at advisory boards from Alexion. Argenx, Roche, UCB and Grifols and research funding from Argenx and Janssen. CS-G received speaker‘s and consulting honoraria from Alexion Pharmaceuticals, Amicus Therapeutics, Argenx, Hormosan Pharma, Immunovant, Janssen, Lupin Pharmaceuticals, Roche, Sanofi-Genzyme and UCB Pharma ravel and a travel grant from Alexion. SP received travel grants from Sanofi, Roche Pharma and Merck Healthcare, lecturing honoraria and consulting fees from Sanofi, Mylan, Novartis, Merck Healthcare, Biogen, Hexal, Alexion, Roche Pharma and research support from Diamed, Merck, Biogen, Novartis and the German Multiple Sclerosis Society North-Rhine-Westphalia of interests. HHK received honoraria for lecturing and consulting fees from Argenx, Alexion, UCB, Sanofi and Roche, travel grants from Alexion and Grifols, and research funding from ArgenX and Roche. FFK received compensation for travelling and lectures from Alexion, Merck and Novartis and is a Hannover Medical School-funded and German Research Foundation (DFG)-funded fellow as part of the Clinician Scientist Program (PRACTIS) at Hannover Medical School. MP received honoraria for lecturing from Argenx, Alexion. He received research funding from ArgenX. SG received honoraria for lecturing from Agrenx and travel and congress fees from Grifols. SG received honoraria for lecturing from Agrenx and travel and congress fees from Grifols. JZ has received payments for advisory boards, speakers honoraria, travel expenses, research projects from Alnylam, Biogen, Biotest, CSL Behring, Octapharma, Kedrion, Grifols, UCB, Hormosan, Alexion and Sanofi. TH received research support from Biogen, Novartis GeneTherapies, Roche and Sanofi Genzyme, speakers and consultant honoraria from Biogen, Hormosan, Roche, Alexion, Novartis, Roche, Sanofi-Genzyme, Alnylam and Argenx. SGM received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen Idec, Celgene, Diamed, Sanofi-Aventis, MedDay, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Chugai Pharma, QuintilesIMS and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Bundesinstitut für Risikobewertung (BfR), Deutsche Forschungsgemeinschaft (DFG), Else Kroener Fresenius Foundation, Gemeinsamer Bundesausschuss (G-BA), German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology and by Alexion, Almirall, Amicus Therapeutics Germany, Biogen Idec, Diamed, Fresenius Medical Care, Sanofi-Aventis, HERZ Burgdorf, Merck Serono, Novartis, ONOPharma, Roche, and Teva. AM has received speaker or consultancy honoraria or financial research support (paid to his institution) from Alexion Pharmaceuticals, argenx, Axunio, Desitin, Grifols, Hormosan Pharma, Janssen, Merck, Octapharma, UCB, and Xcenda. He serves as medical advisory board chairman of the German Myasthenia Gravis Society. TR reports grants from the German Ministry of Education, Science, Research and Technology, grants and personal fees from Sanofi-Aventis and Alexion, personal fees from Biogen Idec, Roche and Teva, and personal fees and nonfinancial support from Merck Serono, outside the submitted work. LG, MH, MÖ, CBS, CS, TS, VS and AT report no conflicts of interests.

Figures

Figure 1
Figure 1. Clinical outcomes in patients receiving C5 complement inhibition therapies. (A) The left panel displays individual changes in MG-ADL scores at months 1, 3 and 6 after BL for patients treated with eculizumab or ravulizumab (grey), along with the mean trajectory (orange). The centre-left diagram illustrates the minimum improvement in MG-ADL based on the best individual response. The centre-right panel shows the proportion of patients achieving PASS as defined by Mendoza et al (MG-ADL score ≤2 points). On the right side, the proportion of patients is shown who experienced an MG-ADL deterioration (red), a stable MG-ADL (MG-ADL reduction ≤1 point, grey) or a significant improvement (MG-ADL reduction ≥2 points; green). (B) On the left, individual QMG scores are depicted 1, 3 and 6 months after BL of patients treated with eculizumab or ravulizumab (grey) and for the mean trend (orange). The central-left diagram displays the minimal QMG improvement. On the centre-right, the percentage of patients achieving PASS based on the QMG score is presented (QMG score ≤7). On the right side, the proportion of patients is shown who exhibit a QMG deterioration (red), a stable QMG (QMG reduction of 0–2 points, grey) or a significant improvement (QMG reduction ≥3 points; green). (C–E) Shown are the individual (grey) and the mean courses (orange) for MG-QoL15 (C), dosage of prednisolone (D) and dosage of pyridostigmine (E) in patients undergoing C5IT. BL, baseline; C5IT, complement C5 inhibition therapy; d, day; MG-ADL, Myasthenia Gravis Activities of Daily Living; MG-QoL15, Myasthenia Gravis Quality of Life 15-Item Questionnaire; PASS, Patient-acceptable Symptom State; QMG, Quantitative Myasthenia Gravis.
Figure 2
Figure 2. Clinical outcome parameters of patients treated with efgartigimod. (A) In the left panel, the MG-ADL scores of patients at months 1, 3 and 6 after initiation of FcRn inhibition therapy are individually shown in grey, with the group’s average trajectory displayed in blue. The diagram in the centre-left shows the cumulative percentage of the minimal improvement in MG-ADL scores. On the centre-right, the proportion of patients meeting the PASS criteria established by Mendoza et al is indicated (MG-ADL score ≤2). On the right side, the proportion of patients is shown who experienced an MG-ADL deterioration (red), a stable MG-ADL (MG-ADL reduction of 0–1 points, grey) or a significant improvement (MG-ADL reduction ≥2 points; green). (B) On the left, individual QMG scores (grey) and the overall trajectory (blue) are depicted for the first 6 months after BL in patients treated with efgartigimod. The diagram in the middle-left shows the cumulative percentage of the minimum QMG improvement. The centre-right panel indicates the proportion of patients achieving a PASS based on the best individual response (QMG score ≤7). On the right side, the proportion of patients is shown who exhibit a QMG deterioration (red), a stable QMG (QMG reduction of 0–2 points, grey) or a significant improvement (QMG reduction ≥3 points; green). (C–E) The individual trajectories (grey) and mean courses (blue) for patients treated with FcRn inhibition are presented concerning MG-QoL15 (C), doses of prednisolone (D) as well as of pyridostigmine (E). BL, baseline; d, day; FcRn, neonatal Fc receptor; MG-ADL, Myasthenia Gravis Activities of Daily Living; MG-QoL15, MG Quality of Life 15-Item Questionnaire; PASS, Patient-acceptable Symptom State; QMG, Quantitative Myasthenia Gravis.
Figure 3
Figure 3. Flow chart detailing patient inclusion. 80 patients were included for the final comparison. C5IT, complement C5 inhibition therapy.
Figure 4
Figure 4. Comparison of clinical outcome parameters in patients treated with ravulizumab or efgartigimod. Clinical outcome measures for patients receiving add-on treatment with ravulizumab (red) or efgartigimod (blue) were examined. Cohort comparability was established through propensity score matching considering sex, age at treatment initiation, use of concomitant immunosuppressive therapy, thymoma status, LOMG status, steroid dosage at BL, MG-ADL scores at BL and QMG scores at BL. (A) presents the mean MG-ADL scores after 1, 3 and 6 months (left), the maximal reduction in MG-ADL score (centre-left), the proportion of patients achieving PASS based on the MG-ADL score (MG-ADL ≤2 points; centre) and minimal improvements in MG-ADL score (centre-right). The right diagram depicts the proportion who experienced an MG-ADL deterioration (red), a stable MG-ADL (reduction of 0–1 points, grey) or a relevant improvement (MG-ADL reduction ≥2 points; green). (B) illustrates the average QMG scores at months 1, 3 and 6 post-BL (left), the maximum decrease in QMG score (centre-left), the percentage of patients meeting PASS criteria based on the QMG score (QMG ≤7 points; centre) and the minimum improvement in total QMG scores (centre-right). The right graph shows the proportion of patients with a QMG deterioration (red), a stable QMG (QMG reduction of 0–2 points, grey) or a significant improvement (QMG reduction ≥3 points; green). (C–E) Left panels show the mean course and the right diagrams the maximal reductions in MG-QoL15 scores (C), daily prednisolone (D) as well as pyridostigmine doses (E). Error bars represent the mean with 95% CI. Quantitative variables were analysed using a two-sided Student’s t-test. A p<0.05 was considered statistically significant. BL, baseline; d, day; FcRn, neonatal Fc receptor; MG-ADL, Myasthenia Gravis Activities of Daily Living; LOMG, late-onset Myasthenia Gravis; MG-QoL15, MG Quality of Life 15-Item Questionnaire; PASS, Patient-acceptable Symptom State; QMG, Quantitative Myasthenia Gravis.
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