Human leukocyte antigen variants associate with BNT162b2 mRNA vaccine response.

BACKGROUND: Since the beginning of the anti-COVID-19 vaccination campaign, it has become evident that vaccinated subjects exhibit considerable inter-individual variability in the response to the vaccine that could be partly explained by host genetic factors. A recent study reported that the immune response elicited by the Oxford-AstraZeneca vaccine in individuals from the United Kingdom was influenced by a specific allele of the human leukocyte antigen gene HLA-DQB1. METHODS: We carried out a genome-wide association study to investigate the genetic determinants of the antibody response to the Pfizer-BioNTech vaccine in an Italian cohort of 1351 subjects recruited in three centers. Linear regressions between normalized antibody levels and genotypes of more than 7 million variants was performed, using sex, age, centers, days between vaccination boost and serological test, and five principal components as covariates. We also analyzed the association between normalized antibody levels and 204 HLA alleles, with the same covariates as above. RESULTS: Our study confirms the involvement of the HLA locus and shows significant associations with variants in HLA-A, HLA-DQA1, and HLA-DQB1 genes. In particular, the HLA-A*03:01 allele is the most significantly associated with serum levels of anti-SARS-CoV-2 antibodies. Other alleles, from both major histocompatibility complex class I and II are significantly associated with antibody levels. CONCLUSIONS: These results support the hypothesis that HLA genes modulate the response to Pfizer-BioNTech vaccine and highlight the need for genetic studies in diverse populations and for functional studies aimed to elucidate the relationship between HLA-A*03:01 and CD8+ cell response upon Pfizer-BioNTech vaccination.

It is known that people respond differently to vaccines. It has been proposed that differences in their genes might play a role. We studied the individual genetic makeup of 1351 people from Italy to see if there was a link between their genes and how well they responded to the BNT162b2 mRNA COVID-19 vaccine. We discovered certain genetic differences linked to higher levels of protection in those who got the vaccine. Our findings suggest that individual's genetic characteristics play a role in vaccine response. A larger population involving diverse ethnic backgrounds will need to be studied to confirm the generalizability of these findings. Better understanding of this could facilitate improved vaccine designs against new SARS-CoV-2 variants.

Long-term safety and efficacy of zilucoplan in patients with generalized myasthenia gravis: interim analysis of the RAISE-XT open-label extension study.

Background: Generalized myasthenia gravis (gMG) is a chronic, unpredictable disease associated with high treatment and disease burdens, with a need for more effective and well-tolerated treatments. Objectives: To evaluate the long-term safety, tolerability, and efficacy of zilucoplan in a mild-to-severe, acetylcholine receptor autoantibody-positive (AChR+) gMG population. Design: Ongoing, multicenter, phase III open-label extension (OLE) study. Methods: Eligible patients had completed a qualifying randomized, placebo-controlled phase II or phase III zilucoplan study and received daily, self-administered subcutaneous 0.3 mg/kg zilucoplan. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary efficacy endpoints included change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score. Results: In total, 200 patients enrolled. At the cut-off date (8 September 2022), median (range) exposure to zilucoplan in RAISE-XT was 1.2 (0.11-4.45) years. Mean age at OLE baseline was 53.3 years. A total of 188 (94%) patients experienced a TEAE, with the most common being MG worsening (n = 52, 26%) and COVID-19 (n = 49, 25%). In patients who received zilucoplan 0.3 mg/kg in the parent study, further improvements in MG-ADL score continued through to Week 24 (least squares mean change [95% confidence interval] from double-blind baseline -6.06 [-7.09, -5.03]) and were sustained through to Week 60 (-6.04 [-7.21, -4.87]). In patients who switched from placebo in the parent study, rapid improvements in MG-ADL score were observed at the first week after switching to zilucoplan; further improvements were observed at Week 24, 12 weeks after switching (-6.46 [-8.19, -4.72]), and were sustained through to Week 60 (-6.51 [-8.37, -4.65]). Consistent results were observed in other efficacy endpoints. Conclusion: Zilucoplan demonstrated a favorable long-term safety profile, good tolerability, and sustained efficacy through to Week 60 with consistent benefits in a broad AChR+ gMG population. Additional long-term data will be available in future analyses. Trial registration: ClinicalTrials.gov identifier: NCT04225871 (https://clinicaltrials.gov/ct2/show/NCT04225871).

FM19G11-loaded nanoparticles modulate energetic status and production of reactive oxygen species in myoblasts from ALS mice.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Considerable evidence indicates that early skeletal muscle atrophy plays a crucial role in the disease pathogenesis, leading to an altered muscle-motor neuron crosstalk that, in turn, may contribute to motor neuron degeneration. Currently, there is no effective treatment for ALS, highlighting the need to dig deeper into the pathological mechanisms for developing innovative therapeutic strategies. FM19G11 is a novel drug able to modulate the global cellular metabolism, but its effects on ALS skeletal muscle atrophy and mitochondrial metabolism have never been evaluated, yet. This study investigated whether FM19G11-loaded nanoparticles (NPs) may affect the bioenergetic status in myoblasts isolated from G93A-SOD1 mice at different disease stages. We found that FM19G1-loaded NP treatment was able to increase transcriptional levels of Akt1, Akt3, Mef2a, Mef2c and Ucp2, which are key genes associated with cell proliferation (Akt1, Akt3), muscle differentiation (Mef2c), and mitochondrial activity (Ucp2), in G93A-SOD1 myoblasts. These cells also showed a significant reduction of mitochondrial area and networks, in addition to decreased ROS production after treatment with FM19G11-loaded NPs, suggesting a ROS clearance upon the amelioration of mitochondrial dynamics. Our overall findings demonstrate a significant impact of FM19G11-loaded NPs on muscle cell function and bioenergetic status in G93A-SOD1 myoblasts, thus promising to open new avenues towards possible adoption of FM19G11-based nanotherapies to slow muscle degeneration in the frame of ALS and muscle disorders.

Efficacy of ravulizumab in patients with generalized myasthenia gravis by time from diagnosis: A post hoc subgroup analysis of the CHAMPION MG study.

INTRODUCTION/AIMS: The CHAMPION MG study demonstrated that ravulizumab significantly improved Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) total scores versus placebo in adults with acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR+ gMG). This post hoc analysis aimed to assess these outcomes by time from MG diagnosis. METHODS: Changes from baseline to week 26 in MG-ADL and QMG total scores were analyzed by time from MG diagnosis to study entry (≤2 vs. >2 years). Within each subgroup, least-squares (LS) mean changes for ravulizumab and placebo were compared using mixed models for repeated measures. RESULTS: In ravulizumab-treated patients, differences in LS mean (standard error of the mean) changes from baseline to week 26 were not statistically significant in the ≤2-years subgroup versus the >2-years subgroup for MG-ADL (-4.3 [0.70] vs. -2.9 [0.37]; p = .0511) or QMG (-4.3 [0.94] vs. -2.5 [0.50]; p = .0822) scores. No clear trends were observed in the placebo group. LS mean changes from baseline were significantly greater for ravulizumab versus placebo in both the ≤2 and >2 years from diagnosis subgroups for MG-ADL and QMG scores (all p < .05). The difference in treatment effect between the ≤2-years and >2-years subgroups was not statistically significant. No clinically meaningful between-subgroup differences in treatment-emergent adverse events were observed in ravulizumab-treated patients. DISCUSSION: Ravulizumab treatment improved clinical outcomes for patients with AChR+ gMG regardless of time from diagnosis. A numerical trend was observed favoring greater treatment effect with earlier versus later treatment after diagnosis. Further studies are required for confirmation.

Efgartigimod in generalized myasthenia gravis: A real-life experience at a national reference center.

BACKGROUND AND PURPOSE: Inhibition of the neonatal Fc receptor (FcRn) for IgG is a promising new therapeutic strategy for antibody-mediated disorders. We report our real-life experience with efgartigimod (EFG) in 19 patients with generalized myasthenia gravis (gMG) along a clinical follow-up of 14 months. METHODS: EFG was administered according to the GENERATIVE protocol (consisting of a Fixed period of two treatment cycles [given 1 month apart] of four infusions at weekly intervals, followed by a Flexible period of re-cycling in case of worsening). Eight patients were positive for acetylcholine receptor antibody, four for muscle-specific tyrosine kinase antibody, and two for lipoprotein-related protein 4 antibody, and five were classified as triple negative. Efficacy of EFG was assessed by the Myasthenia Gravis Activities of Daily Living, Myasthenia Gravis Composite, and Quantitative Myasthenia Gravis scales. RESULTS: Fifty-three percent of patients needed three treatment cycles, 26% needed four, and 21% needed five along the 14-month clinical follow-up. Meaningful improvement was observed at the end of each cycle with the clinical scores adopted. EFG had a dramatic effect on disease course, as during the year before treatment eight of 19 patients (42%) were hospitalized, and 15 of 19 (79%) needed treatment with plasma exchange or immunoglobulins; three of 19 (16%) were admitted to the intensive care unit. During EFG, none of the patients was hospitalized and only one patient required plasma exchange and intravenous immunoglobulins. No major side effects or infusion-related reactions occurred. CONCLUSIONS: We observed that EFG was safe and modified significantly the course of the disease along a 14-month follow-up. Our experience strengthens the role of FcRn inhibition as an effective new tool for long-term treatment of gMG.

Effect of efgartigimod on muscle group subdomains in participants with generalized myasthenia gravis: post hoc analyses of the phase 3 pivotal ADAPT study.

BACKGROUND AND PURPOSE: Generalized myasthenia gravis (gMG) is a rare, chronic, neuromuscular autoimmune disease mediated by pathogenic immunoglobulin G (IgG) autoantibodies. Patients with gMG experience debilitating muscle weakness, resulting in impaired mobility, speech, swallowing, vision and respiratory function. Efgartigimod is a human IgG1 antibody Fc fragment engineered for increased binding affinity to neonatal Fc receptor. The neonatal Fc receptor blockade by efgartigimod competitively inhibits endogenous IgG binding, leading to decreased IgG recycling and increased degradation resulting in lower IgG concentration. METHODS: The safety and efficacy of efgartigimod were evaluated in the ADAPT study. Key efficacy outcome measures included Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores. Efgartigimod demonstrated significant improvement in both the MG-ADL and QMG scores. This post hoc analysis aimed to determine whether all subdomains of MG-ADL and QMG improved with efgartigimod treatment. Individual items of MG-ADL and QMG were grouped into four subdomains: bulbar, ocular, limb/gross motor and respiratory. Change from baseline over 10 weeks in each subdomain was calculated for each group. RESULTS: Greater improvements from baseline were seen across MG-ADL subdomains in participants treated with efgartigimod compared with placebo. These improvements were typically observed 1 to 2 weeks after the first infusion and correlated with reductions in IgG. Similar results were observed across most QMG subdomains. CONCLUSIONS: These post hoc analyses of MG-ADL and QMG subdomain data from ADAPT suggest that efgartigimod is beneficial in improving muscle function and strength across all muscle groups, leading to the observed efficacy in participants with gMG.

Respiratory function in a large cohort of treatment-naïve adult spinal muscular atrophy patients: a cross-sectional study.

Due to poor data in literature, we aimed to investigate the respiratory function in a large cohort of naïve Italian adult (≥18 years) SMA patients in a multi-centric cross-sectional study. The following respiratory parameters were considered: forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and need for non-invasive ventilation (NIV). We included 145 treatment-naïve adult patients (SMA2=18, SMA3=125; SMA4=2), 58 females (40 %), with median age at evaluation of 37 years (range 18-72). Fifty-six (37 %) and 41 (31 %) patients had abnormal (<80 %) values of FVC and FEV1, respectively. Fourteen (14 %) patients needed NIV, started at median age of 21 (range 4-68). Motor function, measured by Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module as well as SMA2, loss of walking ability, surgery for scoliosis, use of NIV, and cough assisting device (CAD) were all significantly associated to lower FVC and FEV1 values, while no association with age at baseline, disease duration, gender or 6 min walking test was observed, except for a correlation between FVC and age in SMA3 walkers (p < 0.05). In conclusion, respiratory function in adult SMA patients is relatively frequently impaired, substantially stable, and significantly correlated with motor function and disease severity.

Impact of Ravulizumab on Patient Outcomes and Quality of Life in Generalized Myasthenia Gravis.

Myasthenia gravis (MG) is an autoimmune ion channel disorder in which antibodies to different end-plate antigens impair neuromuscular transmission, ultimately leading to muscle weakness and fatigability. In about 85% of patients with MG, autoantibodies against the acetylcholine receptor (AChR) activate the complement cascade, causing damage to the neuromuscular junction. MG is a chronic disorder for which standard therapies with corticosteroids, immunosuppressive drugs, and immunomodulation with plasma exchange or intravenous immunoglobulins modify the course of the disease, but the residual burden of physical, psychological, and social disability highlights several unmet needs, among these the need for specific, targeted, and well tolerated therapies able to improve the patients' quality of life. Complement inhibition paved the way to precision medicine in MG since, for the first time, a specific therapy targeting a crucial pathogenetic step has been designed, tested, and proven to be effective in a controlled fashion. Ravulizumab represents the first long-acting complement inhibitor approved for treatment of patients with generalized MG, able to provide rapid, complete, and sustained complement inhibition. Ravulizumab improved the MG Activity of Daily Living scale and other clinical parameters up to 26 weeks as shown by the CHAMPION MG trial, and by its open label extension, with the added value of being administered every 8 weeks. The schedule of administration is likely to improve patients' adherence and hence their quality of life. The introduction of complement inhibition will considerably change the traditional therapeutic strategy for MG.

Current drug treatment of myasthenia gravis.

PURPOSE OF REVIEW: Myasthenia Gravis (MG) is a rare neurological disorder affecting the neuromuscular junction. Clinical hallmarks are fatigability and weakness affecting the extraocular, axial, limb and/or respiratory muscles. Despite immunosuppressive treatment, mainly based on corticosteroids and nonsteroidal immunosuppressants, the burden of MG is still significant, both in terms of inadequate disease control and burdensome side effects. Driven by such limits, the past years have been characterized by an escalation of MG drug development, with novel molecules which now focuses on having a more targeted effect, with a higher safety and efficacy profile. RECENT FINDINGS: As the pathogenic mechanism of MG are slowly being unravelled, new potential targets for treatments are being considered. This has led since 2017 to the Food and Drug Administration (FDA)-approval of three new drugs that either act by blocking the complement system (i.e., eculizumab and ravulizumab) or by blocking the neonatal Fc receptor thus preventing immunoglobulin recycling and reducing imunoglobulin G (IgG) antibodies (i.e., efgartigimod). Other drugs, with similar mechanism of action, are currently under review for approval. SUMMARY: The repertoire of available and developmental therapies for MG is rapidly expanding, finally responding to the unmet need of a more targeted and effective therapeutic approach in MG.

Toll-like receptors and IL-7 as potential biomarkers for immune-mediated necrotizing myopathies.

We aimed to verify whether the immune system may represent a source of potential biomarkers for the stratification of immune-mediated necrotizing myopathies (IMNMs) subtypes. A group of 22 patients diagnosed with IMNM [7 with autoantibodies against signal recognition particle (SRP) and 15 against 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR)] and 12 controls were included. A significant preponderance of M1 macrophages was observed in both SRP+ and HMGCR+ muscle samples (p < 0.0001 in SRP+ and p = 0.0316 for HMGCR+ ), with higher values for SRP+ (p = 0.01). Despite the significant increase observed in the expression of TLR4 and all endosomal Toll-like receptors (TLRs) at protein level in IMNM muscle tissue, only TLR7 has been shown considerably upregulated compared to controls at transcript level (p = 0.0026), whereas TLR9 was even decreased (p = 0.0223). Within IMNM subgroups, TLR4 (p = 0.0116) mRNA was significantly increased in SRP+ compared to HMGCR+ patients. Within IMNM group, only IL-7 was differentially expressed between SRP+ and HMGCR+ patients, with higher values in SRP+ patients (p = 0.0468). Overall, innate immunity represents a key player in pathological mechanisms of IMNM. TLR4 and the inflammatory cytokine IL-7 represent potential immune biomarkers able to differentiate between SRP+ and HMGCR+ patients.

Real world study on prevalence, treatment and economic burden of myasthenia gravis in Italy.

The purpose of this study was to investigate the epidemiology, management, and economic burden of myasthenia gravis in settings of real clinical practice. The analysis used administrative databases covering around 12 million subjects across Italy and included all adult patients with hospitalization discharge diagnosis or active exemption code for myasthenia gravis or with ≥1 pyridostigmine prescription from 2011 to 2018. The estimated prevalence of myasthenia gravis during 2018 was in the range 13.5-29.3/100,000 people (depending on the criteria applied), corresponding to 8190-17,728 alive patients, when reproportioning data to the entire Italian population. Overall 4397 patients with myasthenia gravis (mean age 61.7 years, 46.6% males) were included. A large pyridostigmine use was observed (84.0%-46.8% from 1st to 3rd year of follow-up), followed by corticosteroids (54.5%-44.6% from 1st to 3rd year of follow-up) and non-steroidal immunosuppressants (16% over follow-up). Total direct healthcare costs for myasthenia gravis were 4-times higher than those of the general population (€3771 and €869, respectively), and up to 9-fold increased when considering patients with exacerbation (€7827). These findings showed the epidemiologic burden of myasthenia gravis and the complexity of the therapeutic management for the affected patients, with large use of treatments and elevated healthcare expenditures.

Summary of Research: Terminal Complement Inhibitor Ravulizumab in Generalized Myasthenia Gravis.

This article provides a summary of a previously published paper: Terminal Complement Inhibitor Ravulizumab in Generalized Myasthenia Gravis. The paper reported the results of the CHAMPION-MG trial which investigated the drug ravulizumab in the rare disease, myasthenia gravis. Terminal Complement Inhibitor Ravulizumab in Generalized Myasthenia Gravis (MP4 594600 KB).

Concordance between patient- and physician-reported Myasthenia Gravis Activities of Daily Living (MG-ADL) scores.

INTRODUCTION/AIMS: Myasthenia gravis (MG) is a neuromuscular disease characterized by abnormal skeletal muscle fatiguability. The MG Activities of Daily Living (MG-ADL) scale assesses eight symptoms and is often used as primary endpoint in MG clinical trials where it is completed by neurologists. However, in observational studies, patients frequently complete the MG-ADL scale independently of their neurologist. In this study we aimed to assess the concordance between self- and physician-reported MG-ADL scores. METHODS: An international observational study was conducted among adult patients with MG scheduled for a routine visit or who entered the hospital via emergency services. Consenting patients and physicians completed the MG-ADL. Concordance between assessments was calculated using Gwet's agreement coefficient (Gwet's AC) for the MG-ADL individual items and the intraclass correlation coefficient (ICC) for the MG-ADL total score. RESULTS: Data were collected from 137 patients (63% female; mean age, 57.7 years). Physicians assessed the patient's symptoms as slightly more severe (8.1 vs 7.5 MG-ADL total score, respectively), corresponding to a difference of 0.6 on a range from 0 to 24. The ICC for the MG-ADL total score between the patient and the physician assessment was 0.94 (95% confidence interval, 0.89 to 0.95), showing excellent concordance. Gwet's AC showed substantial to almost perfect agreement for all items, except eyelid droop, for which the agreement was moderate. DISCUSSION: Our results demonstrate that patients and neurologists have a concordant assessment of the patient's MG symptoms when using the MG-ADL scale. This evidence supports patient self-administration of the MG-ADL in clinical practice and research.

Autoimmunity to neuronal nicotinic acetylcholine receptors.

Nicotinic acetylcholine receptors (nAChRs) are widely expressed in many and diverse cell types, participating in various functions of cells, tissues and systems. In this review, we focus on the autoimmunity against neuronal nAChRs, the specific autoantibodies and their mechanisms of pathological action in selected autoimmune diseases. We summarize the current relevant knowledge from human diseases as well as from experimental models of autoimmune neurological disorders related to antibodies against neuronal nAChR subunits. Despite the well-studied high immunogenicity of the muscle nAChRs where autoantibodies are the main pathogen of myasthenia gravis, autoimmunity to neuronal nAChRs seems infrequent, except for the autoantibodies to the ganglionic receptor, the α3 subunit containing nAChR (α3-nAChR), which are detected and are likely pathogenic in Autoimmune Autonomic Ganglionopathy (AAG). We describe the detection, presence and function of these antibodies and especially the recent development of a cell-based assay (CBA) which, contrary to until recently available assays, is highly specific for AAG. Rare reports of autoantibodies to the other neuronal nAChR subtypes include a few cases of antibodies to α7 and/or α4ß2 nAChRs in Rasmussen encephalitis, schizophrenia, autoimmune meningoencephalomyelitis, and in some myasthenia gravis patients with concurrent CNS symptoms. Neuronal-type nAChRs are also present in several non-excitable tissues, however the presence and possible role of antibodies against them needs further verification. It is likely that the future development of more sensitive and disease-specific assays would reveal that neuronal nAChR autoantibodies are much more frequent and may explain the mechanisms of some seronegative autoimmune diseases.

Adult-onset leukodystrophy with vanishing white matter: a case series of 19 patients.

BACKGROUND: Leukodystrophy with vanishing white matter (LVWM) is an autosomal recessive disease with typical pediatric-onset caused by mutations in one of the five EIF2B genes. Adult-onset (AO) cases are rare. METHODS: In this observational study, we reviewed clinical and laboratory information of the patients with AO-LVWM assessed at two referral centers in Italy and Portugal from Jan-2007 to Dec-2019. RESULTS: We identified 18 patients (13 females) with AO-LVWM caused by EIF2B5 or EIF2B3 mutations. Age of neurological onset ranged from 16 to 60 years, with follow-ups occurring from 2 to 37 years. Crucial symptoms were cognitive and motor decline. In three patients, stroke-like events were the first manifestation; in another, bladder dysfunction remained the main complaint across decades. Brain MRI showed white matter (WM) rarefaction in all cases, except two. Diffusion-weighted imaging documented focal hyperintensity in the acute stage of stroke-like events. 1H-spectroscopy primarily showed N-acetyl-aspartate reduction; 18fluorodeoxyglucose-PET revealed predominant frontoparietal hypometabolism; evoked potential studies demonstrated normal-to-reduced amplitudes; neuro-ophthalmological assessment showed neuroretinal thinning, and b-wave reduction on full-field electroretinogram. Interestingly, we found an additional patient with LVWM-compatible phenotype and monoallelic variants in two distinct eIF2B genes, EIF2B1 and EIF2B2. CONCLUSIONS: AO-LVWM presents varying clinical manifestations at onset, including stroke-like events. WM rarefaction is the most consistent diagnostic clue even in the latest onset cases. Spectroscopy and electrophysiological features are compatible with axon, rather than myelin, damage. Cerebral glucose metabolic abnormalities and retinal alterations can be present. LVWM might also be caused by a digenic inheritance affecting the eIF2B complex.

Safety and efficacy of rozanolixizumab in patients with generalised myasthenia gravis (MycarinG): a randomised, double-blind, placebo-controlled, adaptive phase 3 study.

BACKGROUND: Generalised myasthenia gravis is a chronic, unpredictable, and debilitating autoimmune disease. New treatments for this disease are needed because conventional therapies have limitations, such as side-effects (eg, increased infection risk) or inadequate control of symptoms. Rozanolixizumab is a neonatal Fc receptor blocker that might provide a novel therapeutic option for myasthenia gravis. We aimed to assess the safety and efficacy of rozanolixizumab for generalised myasthenia gravis. METHODS: MycarinG is a randomised, double-blind, placebo-controlled, adaptive phase 3 study done at 81 outpatient centres and hospitals in Asia, Europe, and North America. We enrolled patients (aged ≥18 years) with acetylcholine receptor (AChR) or muscle-specific kinase (MuSK) autoantibody-positive generalised myasthenia gravis (Myasthenia Gravis Foundation of America class II-IVa), a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 3 (non-ocular symptoms), and a quantitative myasthenia gravis score of at least 11. Patients were randomly assigned (1:1:1) to receive subcutaneous infusions once a week for 6 weeks of either rozanolixizumab 7 mg/kg, rozanolixizumab 10 mg/kg, or placebo. Randomisation was stratified by AChR and MuSK autoantibody status. Investigators, patients, and people assessing outcomes were masked to random assignments. The primary efficacy endpoint was change from baseline to day 43 in MG-ADL score, assessed in the intention-to-treat population. Treatment-emergent adverse events (TEAEs) were assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03971422) and EudraCT (2019-000968-18); an open-label extension study has been completed (NCT04124965; EudraCT 2019-000969-21) and another is underway (NCT04650854; EudraCT 2020-003230-20). FINDINGS: Between June 3, 2019, and June 30, 2021, 300 patients were assessed for eligibility, of whom 200 were enrolled. 66 (33%) were randomly assigned to rozanolixizumab 7 mg/kg, 67 (34%) to rozanolixizumab 10 mg/kg, and 67 (34%) to placebo. Reductions in MG-ADL score from baseline to day 43 were greater in the rozanolixizumab 7 mg/kg group (least-squares mean change -3·37 [SE 0·49]) and in the rozanolixizumab 10 mg/kg group (-3·40 [0·49]) than with placebo (-0·78 [0·49]; for 7 mg/kg, least-squares mean difference -2·59 [95% CI -4·09 to -1·25], p<0·0001; for 10 mg/kg, -2·62 [-3·99 to -1·16], p<0·0001). TEAEs were experienced by 52 (81%) of 64 patients treated with rozanolixizumab 7 mg/kg, 57 (83%) of 69 treated with rozanolixizumab 10 mg/kg, and 45 (67%) of 67 treated with placebo. The most frequent TEAEs were headache (29 [45%] patients in the rozanolixizumab 7 mg/kg group, 26 [38%] in the rozanolixizumab 10 mg/kg group, and 13 [19%] in the placebo group), diarrhoea (16 [25%], 11 [16%], and nine [13%]), and pyrexia (eight [13%], 14 [20%], and one [1%]). Five (8%) patients in the rozanolixizumab 7 mg/kg group, seven (10%) in the rozanolixizumab 10 mg/kg group, and six (9%) in the placebo group had a serious TEAE. No deaths occurred. INTERPRETATION: Rozanolixizumab showed clinically meaningful improvements in patient-reported and investigator-assessed outcomes in patients with generalised myasthenia gravis, for both 7 mg/kg and 10 mg/kg doses. Both doses were generally well tolerated. These findings support the mechanism of action of neonatal Fc receptor inhibition in generalised myasthenia gravis. Rozanolixizumab represents a potential additional treatment option for patients with generalised myasthenia gravis. FUNDING: UCB Pharma.

Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Generalised myasthenia gravis is a chronic, unpredictable, and debilitating rare disease, often accompanied by high treatment burden and with an unmet need for more efficacious and well tolerated treatments. Zilucoplan is a subcutaneous, self-administered macrocyclic peptide complement C5 inhibitor. We aimed to assess safety, efficacy, and tolerability of zilucoplan in patients with acetylcholine receptor autoantibody (AChR)-positive generalised myasthenia gravis. METHODS: RAISE was a randomised, double-blind, placebo-controlled, phase 3 trial that was done at 75 sites in Europe, Japan, and North America. We enrolled patients (aged 18-74 years) with AChR-positive generalised myasthenia gravis (Myasthenia Gravis Foundation of America disease class II-IV), a myasthenia gravis activities of daily living (MG-ADL) score of least 6, and a quantitative myasthenia gravis score of at least 12. Participants were randomly assigned (1:1) to receive subcutaneous zilucoplan 0·3 mg/kg once daily by self-injection, or matched placebo, for 12 weeks. The primary efficacy endpoint was change from baseline to week 12 in MG-ADL score in the modified intention-to-treat population (all randomly assigned patients who received at least one dose of study drug and had at least one post-dosing MG-ADL score). Safety was mainly assessed by the incidence of treatment-emergent adverse events (TEAEs) in all patients who had received at least one dose of zilucoplan or placebo. This trial is registered at ClinicalTrials.gov, NCT04115293. An open-label extension study is ongoing (NCT04225871). FINDINGS: Between Sept 17, 2019, and Sept 10, 2021, 239 patients were screened for the study, of whom 174 (73%) were eligible. 86 (49%) patients were randomly assigned to zilucoplan 0·3 mg/kg and 88 (51%) were assigned to placebo. Patients assigned to zilucoplan showed a greater reduction in MG-ADL score from baseline to week 12, compared with those assigned to placebo (least squares mean change -4·39 [95% CI -5·28 to -3·50] vs -2·30 [-3·17 to -1·43]; least squares mean difference -2·09 [-3·24 to -0·95]; p=0·0004). TEAEs occurred in 66 (77%) patients in the zilucoplan group and in 62 (70%) patients in the placebo group. The most common TEAE was injection-site bruising (n=14 [16%] in the zilucoplan group and n=8 [9%] in the placebo group). Incidences of serious TEAEs and serious infections were similar in both groups. One patient died in each group; neither death (COVID-19 [zilucoplan] and cerebral haemorrhage [placebo]) was considered related to the study drug. INTERPRETATION: Zilucoplan treatment showed rapid and clinically meaningful improvements in myasthenia gravis-specific efficacy outcomes, had a favourable safety profile, and was well tolerated, with no major safety findings. Zilucoplan is a new potential treatment option for a broad population of patients with AChR-positive generalised myasthenia gravis. The long-term safety and efficacy of zilucoplan is being assessed in an ongoing open-label extension study. FUNDING: UCB Pharma.