QuestionIs vemircopan efficacious in adults with acetylcholine receptor antibody-positive generalized myasthenia gravis?FindingsIn this double-blind, multicenter, phase 2 randomized clinical trial, differences in the proportion of participants achieving the primary endpoint (>= 2-point reduction from baseline in total Myasthenia Gravis-Activities of Daily Living score for 4 consecutive weeks during the 8-week primary evaluation period, without rescue therapy use) were not statistically significant between vemircopan and placebo groups. No significant differences were observed in secondary efficacy end points either.MeaningThe trial was terminated, as the minimal efficacy threshold was not met; inhibition of the complement alternative pathway as a potentially viable and efficacious strategy to treat patients with acetylcholine receptor antibody-positive generalized myasthenia gravis requires further investigation in clinical settings. ImportanceInhibition of terminal complement component 5 has proven effective in acetylcholine receptor antibody-positive (AChR-Ab+) generalized myasthenia gravis (gMG) but requires intravenous or daily subcutaneous administration and is associated with an increased meningococcal infection risk. Targeting the complement alternative pathway (AP) may offer similar benefits while sparing the classical and lectin pathways, preserving some immune responses against infection.ObjectiveTo evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of vemircopan, an oral, selective factor D inhibitor that blocks AP-mediated complement activation and amplification, in adults with AChR-Ab+ gMG.Design, Setting, and ParticipantsThis double-blind, parallel-group, placebo-controlled phase 2 randomized clinical trial was conducted between April 14, 2022, and April 3, 2024, at 60 sites across 8 countries. Adults with AChR-Ab+ gMG, Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 5 or greater, and Myasthenia Gravis Foundation of America classes II through IV classification were eligible for inclusion. Data were unblinded in June 2024; final analysis was completed October 2024.InterventionRandomization 2:1:2 to twice-daily oral vemircopan, 180 mg or 120 mg, or placebo.Main Outcomes and MeasuresThe primary end point was the proportion of participants achieving a 2-point or greater reduction in MG-ADL total score from baseline for 4 consecutive weeks, without rescue therapy, during the 8-week, double-blind primary evaluation period. Secondary end points were change from baseline to week 8 in MG-ADL total score, Quantitative Myasthenia Gravis total score, and Neurological Disorders Fatigue questionnaire score.ResultsOf 99 individuals screened, 70 met eligibility criteria, and 29 were excluded. Of 70 participants randomized (vemircopan, 180 mg: n = 28; vemircopan, 120 mg: n = 14; placebo: n = 28), 38 participants (54%) were female; mean (SD) age at diagnosis was 45.4 (18.5) years. The proportion of participants achieving the primary end point did not differ significantly between placebo (18 of 28 [64%]; 90% CI, 47%-79%) and either vemircopan group (180 mg: 16 of 28 [57%]; 90% CI, 40%-73%; 120 mg: 8 of 14 [57%]; 90% CI, 33%-79%). No significant differences were observed for the secondary end points. No cases of meningococcal infection were reported; 1 participant died due to hepatic failure and 1 discontinued study treatment due to herpes simplex meningitis.Conclusions and RelevanceIn this double-blind, parallel-group, placebo-controlled phase 2 randomized clinical trial, vemircopan did not meet the prespecified threshold for efficacy, and consequently, the study was terminated.Trial RegistrationClinicalTrials.gov Identifier: NCT05218096 This phase 2 randomized clinical trial evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of vemircopan in adults with acetylcholine receptor antibody-positive generalized myasthenia gravis.

BACKGROUND:Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is an immune-mediated neuropathy with heterogeneous presentation and variable treatment response. Blood-based biomarkers remain lacking, and interpretation is confounded by widespread immunoglobulin (IG) therapy. The primary aim was to identify serum inflammatory proteomic signatures associated with CIDP; exploratory aims included associations with disease activity, phenotype, and treatment response. METHODS:In this case-control study, 92 proteins were quantified using multiplex proximity extension assay and ELISA in 358 sera samples from patients with CIDP, multiple sclerosis (MS), and IG-treated myasthenia gravis (MG) as well as age- and sex- matched healthy controls (HC). Logistic regression with Bonferroni correction, principal component analysis, and correlation analyses were applied to identify differential expression across diagnoses and CIDP subgroups. FINDINGS:Seven proteins, TNFSF14, CD40, SIRT2, CCL3, IL8, TGFα, and uPA, consistently distinguished CIDP from HC, MS, and IG-treated MG, representing disease-specific signatures independent of IG exposure. Six additional proteins (STAMBP, CASP-8, EN-RAGE, OSM, HGF, and CXCL6) were IG-responsive. CXCL9, CDCP1, and CCL20 correlated with muscle weakness, while calprotectin and neurofilament light chain reflected broader inflammatory and axonal injury signatures. Patients with unstable active disease exhibited higher CCL4, IL-8, CCL3, FGF-21, and IL-17A. IL-8, EN-RAGE, and CASP-8 predicted clinical improvement, and IL-5 tracked longitudinal disability changes. INTERPRETATION:CIDP is characterised by distinct serum inflammatory proteomic signatures comprising disease-specific and IG-responsive signatures. These candidate biomarkers may support improved patient stratification, disease monitoring, and prediction of treatment response, advancing individualised therapy in CIDP. FUNDING:Erling-Persson Foundation, Sweden (#2022_0030 to ARP) and the German Research Foundation, Germany (KFO5023 TP8 to AM).

Abstract Involvement of the complement system in myasthenia gravis (MG) depends on the IgG subclass of the mediating antibody. LRP4 antibodies (LRP4-ab) are typically of the IgG1 or IgG2 subclass, implying distinct capacities to activate complement. The extent and pattern of complement involvement in LRP4-ab⁺ MG remain insufficiently characterized at the human neuromuscular junction (NMJ). We examined intercostal muscle biopsies from seven patients with LRP4-ab⁺ generalized MG using immunohistochemistry, immunofluorescence including IgG-subtyping, electron microscopy (EM), and qPCR for complement-associated gene expression. AChR-ab⁺ MG patients and non-disease controls served as comparators. C5b-9 deposition at NMJs was observed in all LRP4-ab⁺ biopsies, affecting 6–96% of identified endplates. Co-localization with IgG1 was consistently detected, whereas IgG2 and IgG4 were absent. One double-seropositive patient showed focal IgG3 staining. Complement transcript levels (C1QC, C3) were higher in LRP4-ab⁺ and AChR-ab⁺ MG compared with controls. Ultrastructural analysis revealed reduced and shortened postsynaptic clefts in 3/4 evaluable LRP4-ab⁺ patients. One therapy-refractory LRP-ab + MG patient with complement deposition and endplate destruction improved after targeted complement inhibition was introduced to his therapeutic regimen, which was based on the biopsy finding. Our findings provide in situ evidence of classical complement pathway activation and associated structural alterations at the human NMJ in LRP4-ab⁺ MG. These tissue-based data contribute to a better understanding of the pathophysiology in this rare MG subgroup.

BackgroundEfgartigimod is a human immunoglobulin (IgG1) antibody Fc fragment that reduces IgG levels through neonatal Fc receptor blockade. ADAPT-SC+ assessed the long-term safety, tolerability, and efficacy of subcutaneous (SC) efgartigimod PH20 in adult participants with generalized myasthenia gravis (gMG). Previously, ADAPT-SC demonstrated noninferiority of efgartigimod PH20 SC to intravenous efgartigimod.MethodsADAPT-SC+ was a single-arm, multicenter, open-label extension study. Efgartigimod PH20 SC 1000 mg was administered in treatment cycles of 4 once-weekly injections, with timing of cycles individualized based on clinical evaluation. During the first year of the study, ≥4 weeks were required between cycles; in the second year and onward, participants consenting to a protocol amendment could have ≥1 week between cycles.ResultsA total of 184 participants rolled over from ADAPT+ and ADAPT-SC, and 180 participants received ≥1 dose of efgartigimod PH20 SC. The mean (SD) treatment plus follow-up time was 2.6 (0.9) years, corresponding to 459.4 total participant years of follow-up, with a maximum of 33 treatment cycles. Overall, 169 (93.9%) participants experienced ≥1 treatment-emergent adverse event (TEAE), and the most frequent TEAEs were injection site reactions (ISRs; n = 83, 46.1%), COVID-19 (n = 53, 29.4%), and headache (n = 48, 26.7%). ISRs were mild or moderate in severity. No new safety signals were observed in participants with more frequent dosing (<4 weeks between cycles) after the protocol amendment. Rapid and clinically meaningful improvements (CMI, reduction of ≥2 points) in mean Myasthenia Gravis Activities of Daily Living (MG-ADL) total scores were observed. During the study, 95.1% of participants with acetylcholine receptor antibody–positive (AChR-Ab+) gMG and 94.7% of participants with AChR-Ab− gMG achieved CMI at any point. Many participants demonstrated substantial clinical improvements, with 59.2% of participants with AChR-Ab+ gMG and 34.2% of participants with AChR-Ab− gMG achieving minimal symptom expression (MSE; MG-ADL, 0–1). The majority of participants who achieved MSE (83.3% with AChR-Ab+ gMG, 53.8% with AChR-Ab− gMG) experienced sustained MSE at consecutive assessments covering ≥8 weeks.DiscussionThe results of ADAPT-SC+ demonstrate long-term safety, tolerability, and sustained efficacy of efgartigimod PH20 SC across various dosing approaches, building on previous studies to broaden options for individualizing treatment for patients with gMG.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT04818671, NCT04818671.

Single-cell studies have revealed substantial microglial diversity in development, homeostasis and disease. However, a framework enabling comparison and stratification of microglial states across contexts is needed. Here we generated an atlas of myeloid cell states by single-cell RNA sequencing more than one million central nervous system cells from more than 30 physiological and pathological conditions. This atlas enables us to establish a comprehensive taxonomy of myeloid cell states across brain disorders and related mouse models, comprising 27 superclusters and 192 clusters that are prevalent across diseases and largely conserved. We augment this taxonomic framework with spatial transcriptomics to map how immune cell states are organized within tissue and interact with their local cellular environment. Using in vivo perturbations, we also show that activation-associated microglial states are dependent on interferon and colony-stimulating factor 1 receptor signaling. Together, these findings provide a spatially aware taxonomic framework for central nervous system immune cells in health and disease.

Introduction:We conducted an exploratory pilot feasibility study to assess the safety and feasibility of cardiopulmonary exercise testing (CPET) in patients with mild generalized myasthenia gravis (gMG), aiming to determine whether test termination results from systemic exertion or MG-specific neuromuscular fatigability and to evaluate short-term effects on fatigue. Methods:Nine patients with mild gMG (median age of 58 years, IQR 46.0-66.5) were included in this exploratory feasibility study and underwent a single maximal incremental CPET on a cycle ergometer with breath-by-breath gas exchange analysis and blood lactate measurements. Predefined exertion criteria (EC) included respiratory exchange rate (RER; ≥1.1), ventilatory equivalent for O2 (EQO2; ≥30), attainment of age-related maximum heart rate (ARMHR), peak blood lactate concentration (>6 mmol·L-1), and Borg Scale for Rated Perceived Exertion (RPE; ≥17). Repetitive nerve stimulation (RNS) was performed before and after CPET to assess neuromuscular fatigability. Fatigue was assessed using the Chalder Fatigue Scale (CFS) at baseline and 4 weeks after CPET. Results:CPET was completed by all participants without adverse events. All reported symptoms resolved within 30 min after exercise termination, and no participant required medical intervention. All participants completed the maximal incremental CPET according to the predefined protocol. Among the predefined EC, 44% of participants achieved an RER ≥1.1, 78% an EQO2 ≥30, 44% an ARMHR, 67% reached a peak blood lactate concentration >6 mmol·L-1-, and 67% an RPE ≥17. A decremental response in RNS was observed in 78% both before and after CPET. No relevant changes in CFS scores were detected over 4 weeks. Discussion:CPET appears safe and feasible in mild gMG, with exercise termination primarily driven by systemic exertion rather than MG-specific neuromuscular fatigue. CPET may complement clinical evaluation by supporting individualized training recommendations and the identification of cardiopulmonary limitations.

Introduction: Generalized myasthenia gravis (gMG) is a chronic autoimmune neuromuscular disorder characterized by fluctuating muscle weakness and exertional fatigue, often requiring long-term immunosuppressive or biologic treatment. Although international guidelines recommend achieving minimal manifestations as the primary treatment goal, the lack of a standardized measurement approach has limited its application in clinical settings and trials. Minimal Symptom Expression (MSE), defined as a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 0 or 1, has recently emerged as a practical, patient-centric endpoint that reflects minimal functional burden and aligns with regulatory priorities around patient-reported outcomes. Results: This position paper examines the rationale for MSE as a clinically meaningful, actionable treatment target in gMG. We summarize the strengths of the underlying MG-ADL scale and highlight phase 3 trial data showing that MSE is attainable with biologic therapies, including complement and neonatal Fc receptor inhibitors. Data also suggest that achieving MSE correlates with improvements in physician-assessed outcomes and quality of life metrics. However, inconsistencies in how sustained MSE is defined and reported limit comparability across trials. Conclusion: MSE, as a patient-centric endpoint, can be used alongside clinician-assessed measures and safety measures to support an integrated treatment goal that encompasses both efficacy and tolerability for the treatment of gMG. Future research should further define the clinical utility of MSE and sustained MSE and incorporate stakeholder input to validate MSE as a part of an integrated treatment goal in both clinical trials and real-world clinical practice.

The ADAPT phase 3 trial (NCT03669588) showed efgartigimod was well tolerated and efficacious in acetylcholine receptor antibody–positive (AChR-Ab +) patients with generalized myasthenia gravis (gMG). This analysis utilized data from the ADAPT trial to investigate the efficacy and safety of efgartigimod in different patient subgroups. ADAPT included a broad population of AChR-Ab + participants who received a stable dose of ≥ 1 (any) treatment for gMG and were randomized 1:1 to efgartigimod (10 mg/kg) or placebo (administered as four once-weekly infusions per cycle) for 26 weeks. Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) responder rates in cycles 1 and 2, and rates of treatment-emergent adverse events (TEAEs) were analyzed in the following patient subgroups: history of nonsteroidal immunosuppressive treatment (NSIST), concomitant use of gMG treatments throughout the study, and baseline patient and disease characteristics, including time since diagnosis, age, baseline MG-ADL score, body mass index (BMI), sex, and prior thymectomy. In total, 129 AChR-Ab + participants were included (efgartigimod, n = 65; placebo, n = 64). Across all subgroups, higher MG-ADL and QMG responder rates were observed in participants treated with efgartigimod versus placebo during cycles 1 and 2. Rates of TEAEs were similar between participants treated with efgartigimod and placebo, regardless of concomitant gMG treatment type. Similar to outcomes observed in the ADAPT overall population, efgartigimod was well tolerated and efficacious across a broad range of patients, regardless of NSIST treatment history, concomitant use of gMG treatments, or baseline patient and disease characteristics. ClinicalTrials.gov: NCT03669588 (registered September 13, 2018).

BACKGROUND: Adult hippocampal neurogenesis is altered after cerebral ischemia. Although stroke increases newborn neuron production, many cells display aberrant morphological and positional features that may impair functional integration and contribute to long-term cognitive deficits. Given the clinical heterogeneity of ischemic stroke and limited translational success of preclinical studies relying on single models, it remains unclear whether poststroke neurogenic alterations are conserved across experimental paradigms. This study aimed to identify common and model-specific features of hippocampal neurogenesis across focal ischemia models. METHODS: We conducted a multicenter, multimodel analysis within the Leducq-funded Stroke-Impact Transatlantic Network of Excellence using permanent and transient middle cerebral artery occlusion paradigms, including distal middle cerebral artery occlusion under normoxic or hypoxic conditions (distal middle cerebral artery occlusion+hypoxia), and filament-based transient middle cerebral artery occlusion, across 6 sites. Adult C57BL/6J mice were analyzed at 3 days, 7 days, and 2 months after ischemia, sham, or naïve conditions. Hippocampal proliferation (Ki67) and neuroblasts (DCX [doublecortin]) were quantified; morphological maturation of newborn neurons was assessed through high-resolution analyses of dendritic architecture and somatodendritic polarity. RESULTS: Across all stroke models, ischemia induced a robust bilateral increase in hippocampal proliferation, most pronounced at 3 days and still elevated at 7 days, returning to baseline by 2 months. Neuroblast density was similarly increased at 7 days, particularly in the ipsilateral hippocampus, but normalized over time. Despite recovery in cell number, long-term analyses revealed a consistent reduction in apical dendrite length and increased proportion of neurons with aberrant features, including ectopic positioning, polarity defects, and abnormal lateral growth, across models and centers. CONCLUSIONS: Aberrant hippocampal neurogenesis represents a robust hallmark of poststroke pathology in mice, independent of ischemia type or surgical approach, despite known differences in the spatial distribution of primary injury across models. Our findings underscore the importance of considering structural quality, and not only quantity, of newborn neurons when evaluating poststroke plasticity and developing therapeutic strategies.

Myasthenia gravis (MG) is a chronic autoimmune disease mediated by autoantibodies targeting the neuromuscular junction and leading to muscle weakness. Although there are autoantibodies of different specificities, most MG patients have autoantibodies directed against the nicotinic acetylcholine receptor (AChR), in particular against the extracellular domain of the α1 subunit (αECD), containing the main immunogenic region (MIR). Here, we demonstrate an original approach to selectively deplete plasma cells secreting autoantibodies targeting αECD. An antibody-mediated cytotoxicity-engager (ACE) consisting of an anti-hCD38-antibody conjugated to hAChR αECD (αECD) was used to deplete hAChR αECD-specific cells selectively in vivo. The reduction of pathogenic cells was accompanied by lower antibody titers, a reduction of MG disease score, protection of grip strength, and maintenance of body weight. Notably, antibody-secreting cells that are nonspecific for hAChR αECD were not affected. The resulting amelioration of MG pathology in ACE-treated animals highlights the decisive role of αECD-antibodies in the pathogenesis of MG and the clinical relevance of the novel therapeutic strategy.

INTRODUCTION/AIMS:Myasthenia gravis (MG) is a rare autoimmune disorder requiring individualized, specialized treatment, yet access to specialized care is limited and documentation fragmented. Several remote monitoring tools have emerged to address this gap, yet their integration into clinical care remains challenging. The aim was to better understand the nature and context of care-related interactions in order to inform the development of clinically meaningful and patient-centered digital health solutions for MG. METHODS:We conducted a survey among physicians and nurses at a tertiary MG center over an eight-week period regarding care-related inquiries, documented using a structured report form that captured the topic, urgency, communication channel, processing time, and clinician involved. RESULTS:About 576 care-related inquiries were recorded. Most inquiries addressed organizational (55.4%) or medical (41.3%) issues. Among medical topics, symptom worsening (30.7%) and treatment-specific questions regarding FcRn and complement inhibitor therapy (19.3%) were most frequent. Organizational topics were most frequently about appointments (43.6%) and prescriptions (35.7%). A total of 115 inquiries (20.0%) were time-critical (requiring same weekday response). Physicians answered 74.3% of inquiries. The most common communication channels were e-mail (42.4%) and telephone (29.0%), followed by the hospital information system (13.7%) and a telemedicine platform (6.9%). Medical inquiries took twice as long to process/respond as organizational ones (median 10 vs. 5 min). DISCUSSION:Our findings show that care-related inquiries in MG are diverse and answered through various communication channels. Remote monitoring solutions hold promise to complement existing care structures in MG and could support timely and structured care but require human-guided processes.

Introduction:Emerging evidence suggests a role of neuronal autoantibodies (nAbs) for long-term stroke outcomes. However, data remain limited and many domains unexamined. We present a comprehensive analysis of nAbs and their association with a broad range of outcome measures at multiple timepoints in the six months following moderate stroke. Methods:In this explorative analysis of the multicenter, randomized-controlled PHYS-STROKE trial, serum samples from stroke patients were tested for 40 nAbs at baseline (5-45 days post-stroke), post-intervention (4 weeks after baseline), and at three and six months after stroke. Generalized estimating equation (GEE)-models were used to evaluate the dynamics of nAbs over time. Multiple linear regression models were applied to investigate the prognostic role of nAbs on various outcomes at three and six months. Results:Two hundred stroke patients (41% female; mean age: 69 ± 12 years, median acute National Institutes of Health Stroke Scale: 8) were enrolled. Cell-based seroreactivity decreased from baseline to six months (39 of 183 patients [21%] vs. 18 of 137 patients [13%]). while tissue-based reactivity increased (4 of 183 patients [2%] vs. 9 of 137 patients [7%]). The GEE applied to the imputed dataset indicated a statistically significant decreased likelihood of seroreactive nAbs in cell-based assays from baseline to six months (95%CI = 0.36 to 0.98; p = 0.041), while tissue-based analyses showed an inverse effect for the same time period (95%CI = 1.11 to 8.51; p = 0.032). The most frequently detected antibody was anti-N-Methyl-D-Aspartate receptor GluN1 (NMDAR (IgM, IgA, IgG), 30 patients [15.1%]). Baseline nAB seropositivity was associated with worse depression scores (95%CI = 0.03 to 7.82; p = 0.048) and poorer subjective mobility (95%CI=0.04 to 0.99; p = 0.033) at six months post-stroke. NMDAR-antibodies at baseline were linked to a lower subjective overall health rating (95%CI = -17.96 to -0.16; p = 0.046) and lower maximum walking speed (95%CI = -0.57 to -0.03; p = 0.027) at six months. No associations were found with outcomes at three months. Conclusions:Antibody seropositivity was associated with poorer outcomes in certain neuropsychological and motor outcome measures at six but not three months post-stroke. These findings require confirmation in larger cohorts and emphasize the need for future studies with longer follow-up periods in this patient population. Trial registration:clinicaltrials.gov NCT01953549.

Maternal antibodies against the fetal acetylcholine receptor (fAChR) can cause fetal acetylcholine receptor antibody-related disorders (FARAD), a rare but important cause of arthrogryposis multiplex congenita (AMC) and Fetal Akinesia Deformation Sequence (FADS), with recurrence rates up to 100%. Unlike genetic causes, FARAD may respond to maternal immunotherapy, yet standardized treatment protocols are lacking. We report four pregnancies in an asymptomatic mother with confirmed fAChR antibodies. After three fetal losses due to FARAD and two unsuccessful treatment attempts initiated only after sonographic abnormalities, a healthy infant was delivered in the fourth pregnancy following a pre-planned preemptive approach. Treatment, initiated at week 10 of gestation, consisted of plasmapheresis (PLEX) and subsequent weekly high-dose intravenous immunoglobulin (IVIg). Fetal serum after birth confirmed fAChR antibodies on cell-based assays (live and fixed). This case series underscores the importance of recognizing fAChR antibodies as differential diagnosis of AMC in asymptomatic mothers and of early, consistent antibody-reducing therapy to prevent FARAD-related pregnancy losses.

Abstract INTRODUCTION Myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) are autoimmune diseases of the neuromuscular junction resulting in fatigable muscle weakness. Rituximab (RTX) is used to treat patients refractory to standard immunosuppression, but evidence for its efficacy remains inconsistent. Here, we analyzed real-world data on the clinical course and side effects of RTX in MG and LEMS patients. METHODS This was a single-center study of all patients diagnosed with MG (n=64) or LEMS (n=5) treated with RTX from 2011 until 2021. Outcomes of RTX treatment were recorded retrospectively with Myasthenia Gravis Foundation of America Post-Intervention Status (MGFA-PIS), number of rescue therapies, myasthenic crises, and steroid dose at 1-year and 2-year follow-ups. RESULTS MGFA-PIS improved at both 1-year (y) and 2-y follow-up compared with baseline. Incidence rates of rescue therapies per 100 person-months (95% CI) decreased from 15.0 (11.8–18.8) at baseline to 7.5 (4.7–12.3) at 1-y and 4.3 (2.5–7.8) at 2y-follow-up. The number of patients without myasthenic crises within one year increased from baseline (49, 86.0%) to 1y-follow-up (55, 96.5%). Median (IQR) daily steroid dose decreased from 10 (5– 22.5) mg/d at baseline to 4 (0–10) mg/d at 1y-follow-up, and to 2.5 (0–10) mg/d at 2y-follow-up. CONCLUSION This study indicates that RTX was associated with a stabilized clinical course and decreased steroid use in patients with autoimmune myasthenic syndromes, including those with thymoma-associated MG. Our data suggest that therapeutic benefit is apparent within the first year of treatment and is maintained through two years.

BACKGROUND:Autoantibody-mediated complement activation drives pathology in acetylcholine receptor (AChR) antibody-positive generalised myasthenia gravis. Newer targeted therapies lower overall antibody concentrations or inhibit complement activity. We aimed to evaluate an siRNA (cemdisiran) targeting complement component 5 (C5) as monotherapy and in combination with a C5 antibody (pozelimab) in generalised myasthenia gravis. METHODS:NIMBLE is a randomised, double-blind, placebo-controlled, phase 3 trial conducted at 86 centres in 13 countries. We enrolled patients aged 18 years or older with a diagnosis of generalised myasthenia gravis, positive serology for anti-AChR or anti-LRP4 antibodies, and a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or greater. Patients were randomly allocated to receive cemdisiran monotherapy (600 mg every 12 weeks; cemdisiran group), pozelimab monotherapy (200 mg every 4 weeks; pozelimab group), combined cemdisiran (200 mg every 4 weeks) and pozelimab (200 mg every 4 weeks; combination group), or placebo, all administered subcutaneously, during a 24-week double-blind treatment period. The primary endpoint was change from baseline in MG-ADL scores at week 24, assessed in the modified intention-to-treat (mITT) primary analysis set (the first 245 randomly allocated patients who received any dose of study treatment and had at least one post-baseline assessment). A prespecified hierarchal statistical testing strategy was used; multiplicity was controlled for comparisons of cemdisiran versus placebo and combination versus placebo (pozelimab was not statistically tested against placebo and was used only to assess the contribution of components to the combination treatment). Safety was mainly assessed by recording of treatment-emergent adverse events in all patients who received any dose of study treatment. This study is registered with ClinicalTrials.gov (NCT05070858); the current status is active, not recruiting. FINDINGS:Between Jan 20, 2022 and July 18, 2025, 390 participants were screened and, as of the data cut-off presented in this report (July 8, 2025), 284 were randomly allocated to the cemdisiran group (79 [28%] patients), pozelimab group (50 [18%]), combination group (80 [28%]), and placebo group (75 [26%]). Of 277 patients who received any study treatment, 263 (95%) completed the double-blind treatment period. In the mITT primary analysis set, at week 24, the least-squares mean change from baseline in MG-ADL total score was -4·5 (SE 0·4) in the cemdisiran group (n=64), -4·0 (0·4) in the combination group (n=67), and -2·2 (0·5) in the placebo group (n=59). Placebo-adjusted least-squares mean differences in MG-ADL score at week 24 were -2·3 (SE 0·7; 95% CI -3·6 to -1·0; p=0·0005) in the cemdisiran group and -1·7 (0·7; -3·0 to -0·4; p=0·0086) in the combination group. The proportion of participants with at least one adverse event during the double-blind treatment period was 54 (69%) of 78 in the cemdisiran group, 65 (81%) of 80 in the combination group, 40 (82%) of 49 in the pozelimab group, and 54 (77%) of 70 in the placebo group. The most common adverse event in the cemdisiran group was upper respiratory tract infection (nine [12%] of 78 patients), which occurred at a similar incidence in the placebo group (eight [11%] of 70). No serious or meningococcal infections occurred in the cemdisiran group. Adverse events leading to treatment discontinuation occurred in two participants (3%) in the placebo group and one participant (2%) in the pozelimab group. No deaths occurred during the double-blind treatment period. Two deaths occurred after the double-blind treatment period, one of which was assessed as treatment-related by the investigator but not treatment-related by the sponsor. INTERPRETATION:Cemdisiran monotherapy and combination therapy were effective in the treatment of generalised myasthenia gravis, and were generally well tolerated. Subcutaneous dosing of cemdisiran, administered every 3 months, could provide a convenient treatment approach for generalised myasthenia gravis. FUNDING:Regeneron Pharmaceuticals.