This study is a phase 3, randomized, double-blind, placebo-controlled study, to be conducted at approximately 120 study sites. Approximately 230 participants (188 acetylcholine receptor antibody positive \[AChR-Ab+\] and 42 muscle-specific tyrosine kinase antibody positive \[MuSK-Ab+\]) will be enrolled. Participants with Myasthenia Gravis (MG) who are positive for anti-AChR or anti-MuSK antibodies will be enrolled and analyzed. Patients who do not have anti-AChR or anti-MuSK antibodies will not be enrolled. Patients with Myasthenia Gravis Foundation of America (MGFA) classification II, III, or IV disease, Myasthenia Gravis Activities of Daily Living (MG-ADL) score at screening and randomization between 6 and 10 with \> 50% of this score attributed to non-ocular items, or an MG-ADL score \>=11, Quantitative Myasthenia Gravis (QMG) score \>= 11 at the time of screening and randomization, and use of a corticosteroid and/or non-steroidal immunosuppressant will be included in the study. All subjects who complete the randomized controlled period (RCP) will have the option to enroll in a 3-year (156 weeks) open-label period. Study acquired from Horizon in 2024.

N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the most common causes of autoimmune encephalitis, with prevalence exceeding herpes encephalitis in industrialized nations. Typically, the disease affects patients age 10-50 causing prominent psychiatric symptoms, altered consciousness, seizures, movement disorders and life-threatening dysautonomia. Intensive care, including cardiorespiratory support is required in 75% of cases. The diagnosis is confirmed by detection of IgG autoantibodies against central nervous system NMDAR in the cerebrospinal fluid. Despite the severity of the illness, NMDAR encephalitis is a treatable neurological disease, with retrospective case series establishing the benefit of off-label intravenous steroids and immunoglobulins. These treatments are presumed to work through effects on IgG NMDAR autoantibody levels in the CSF, although prospective data informing predictors of treatment responses are limited. Even with prompt treatment, \~50% of patients remain disabled, requiring prolonged hospital admissions. Various off-label therapies have been proposed as \"second-line\" treatments in NMDAR encephalitis. The majority of second-line treatments target circulating B-cells with various degrees of blood brain penetrance and efficacy, and poor consensus on the timing, dose and route of delivery of candidate agents. High-quality evidence is needed to inform the treatment of NMDAR encephalitis. Inebilizumab is a promising therapeutic monoclonal antibody for the treatment of NMDAR encephalitis. This humanized monoclonal antibody against the B-cell surface antigen CD19 was recently shown to be safe and efficacious in the treatment of neuromyelitis optica spectrum disorder-another antibody-mediated disorder of the central nervous system. Compared to other off label B-cell depleting therapies, such as rituximab, inebilizumab not only depletes CD20+ B-cells, but also CD20- plasmablasts and plasma cells, resulting in robust and sustained suppression of B-cell expression. The ExTINGUISH Trial will randomize 116 participants with moderate-to-severe NMDAR encephalitis to receive either inebilizumab or placebo in addition to first-line therapies. Patient outcomes will be ascertained at standard intervals using the modified Rankin scale and accepted safety measures (primary outcomes at 16 weeks), together with comprehensive validated neuropsychological tests, bedside cognitive screening tools, quality of life/ functional indices, and outcome prediction measures. Clinical data will be combined with quantitative measures of NMDAR autoantibody titers and cytokines implicated in B-cell activation and antibody production within the intrathecal compartment to identify treatment responders, inform the biologic contributors to outcomes, and evaluate for biomarkers that may serve as early predictors of favorable outcomes in future clinical trials in NMDAR encephalitis. The ExTINGUISH Trial will prospectively study an optimized B-cell depletion therapy to promote better long-term outcomes in NMDAR encephalitis, to determine more meaningful cognitive endpoints, and to identify better biologic biomarkers to predict outcome.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease characterized by recurrent optic neuritis and transverse myelitis often resulting in severe disability. Anti-AQP4-immunoglobulin G (IgG) is a pathogenic product of CD19-positive plasma cells found in most, but not all, individuals with NMOSD and is associated with immune-mediated neurologic injury. Inebilizumab, an afucosylated humanized IgG1κ, anti-CD19 monoclonal antibody, may target pathogenic CD19-expressing B cells. In a Phase II/III trial, inebilizumab significantly reduced the proportion of participants experiencing an NMOSD attack and was well tolerated versus placebo. Fewer treated participants had worsening disability than those receiving placebo. Inebilizumab was approved in 2020 by the US FDA for treatment of anti-AQP4 antibody positive NMOSD.

After a screening period of up to 28 days, subjects with IgG4-RD at high risk of flare due to multi-organ disease and recent active disease will be randomized in a 1:1 ratio to receive intravenous (IV) inebilizumab or placebo after premedication during the 52-week randomized control period (RCP). All subjects will receive an initial tapering dose of glucocorticoids (GCs) to complete treatment of their active disease. Flares occurring during study will be treated. The primary endpoint is time to a first adjudication committee-determined, investigator-treated disease flare during the RCP. The primary analysis will be conducted when the last subject completes the RCP visit or discontinues the RCP. This study includes an optional 3-year open-label treatment period. The study also includes a Safety Follow-up Period (SFUP) after IP discontinuation of up to 730 days. The expected duration of each subject\'s participation in this study is up to 400 days (screening and RCP), plus up to 1095 days for eligible subjects who enroll in the optional open label period (OLP), and up to 730 days for the SFUP after IP discontinuation, for a total maximum duration of up to 2273 days (screening, RCP, interval between RCP and OLP, OLP, and FSUP). Study acquired from Horizon in 2024.

BACKGROUND: Efficacy and safety of inebilizumab for treatment of neuromyelitis optica spectrum disorder in adults seropositive for aquaporin-4 (AQP4)-immunoglobulin (Ig) G were demonstrated in the 28-week randomized controlled period of the N-MOmentum study. OBJECTIVE: To assess efficacy and safety of long-term inebilizumab treatment. METHODS: Post hoc analysis was performed in 75 AQP4-IgG-seropositive participants receiving inebilizumab for ⩾4 years in the randomized controlled period and open-label extension of the N-MOmentum study. RESULTS: Eighteen attacks occurred in 13 participants during inebilizumab treatment (annualized attack rate, 0.052 attacks/person-year). Twelve attacks occurred during the first year of treatment, and two each occurred in years 2-4. Disability scores remained stable throughout ⩾4 years of treatment. Inebilizumab was well tolerated, with two (2.7%) serious treatment-emergent adverse events related to inebilizumab and no deaths. Immunoglobulin G levels decreased over time; however, correlation between severe infections and low IgG levels could not be determined because of their small numbers. CONCLUSION: These results from the N-MOmentum study continue to support use of inebilizumab for treatment of neuromyelitis optica spectrum disorder. Furthermore, the findings suggest that efficacy of inebilizumab may be enhanced after the first year of treatment, warranting additional long-term investigation.

OBJECTIVE: To assess treatment effects on Expanded Disability Status Scale (EDSS) score worsening and modified Rankin Scale (mRS) scores in the N-MOmentum trial of inebilizumab, a humanized anti-CD19 monoclonal antibody, in participants with neuromyelitis optica spectrum disorder (NMOSD). METHODS: Adults (N = 230) with aquaporin-4 immunoglobulin G-seropositive NMOSD or -seronegative neuromyelitis optica and an EDSS score ≤8 were randomized (3:1) to receive inebilizumab 300 mg or placebo on days 1 and 15. The randomized controlled period (RCP) was 28 weeks or until adjudicated attack, with an option to enter the inebilizumab open-label period. Three-month EDSS-confirmed disability progression (CDP) was assessed using a Cox proportional hazard model. The effect of baseline subgroups on disability was assessed by interaction tests. mRS scores from the RCP were analyzed by the Wilcoxon-Mann-Whitney odds approach. RESULTS: Compared with placebo, inebilizumab reduced the risk of 3-month CDP (hazard ratio [HR]: 0.375; 95% CI: 0.148-0.952; p = 0.0390). Baseline disability, prestudy attack frequency, and disease duration did not affect the treatment effect observed with inebilizumab (HRs: 0.213-0.503; interaction tests: all p > 0.05, indicating no effect of baseline covariates on outcome). Mean EDSS scores improved with longer-term treatment. Inebilizumab-treated participants were more likely to have a favorable mRS outcome at the end of the RCP (OR: 1.663; 95% CI: 1.195-2.385; p = 0.0023). CONCLUSIONS: Disability outcomes were more favorable with inebilizumab vs placebo in participants with NMOSD. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with NMOSD, inebilizumab reduces the risk of worsening disability. N-MOmentum is registered at ClinicalTrials.gov: NCT02200770.

BACKGROUND: In the N-MOmentum trial, the risk of an adjudicated neuromyelitis optica spectrum disorder (NMOSD) attack was significantly reduced with inebilizumab compared with placebo. OBJECTIVE: To demonstrate the robustness of this finding, using pre-specified sensitivity and subgroup analyses. METHODS: N-MOmentum is a prospective, randomized, placebo-controlled, double-masked trial of inebilizumab, an anti-CD19 monoclonal B-cell-depleting antibody, in patients with NMOSD. Pre-planned and post hoc analyses were performed to evaluate the primary endpoint across a range of attack definitions and demographic groups, as well as key secondary endpoints. RESULTS: In the N-MOmentum trial (ClinicalTrials.gov: NCT02200770), 174 participants received inebilizumab and 56 received placebo. Attack risk for inebilizumab versus placebo was consistently and significantly reduced, regardless of attack definition, type of attack, baseline disability, ethnicity, treatment history, or disease course (all with hazard ratios < 0.4 favoring inebilizumab, p < 0.05). Analyses of secondary endpoints showed similar trends. CONCLUSION: N-MOmentum demonstrated that inebilizumab provides a robust reduction in the risk of NMOSD attacks regardless of attack evaluation method, attack type, patient demographics, or previous therapy.The N-MOmentum study is registered at ClinicalTrials.gov: NCT2200770.

Objective: To assess the impact of long‐term inebilizumab, an anti‐CD19 B‐cell depleting antibody, on pain and quality of life (QoL) in patients with neuromyelitis optica spectrum disorder (NMOSD). Background: Pain is a common, debilitating symptom of NMOSD that has a detrimental impact on the QoL of patients. Correlations were previously reported between 11‐point Pain Numeric Rating Scale (NRS‐11) scores and 36‐Item Short‐Form Survey Body Pain Sub scores (SF36‐BPS) in the N‐MOmentum study (NCT02200770), in which inebilizumab significantly improved SF36‐BPS after first dose in participants with moderate‐to‐severe pain (SF36‐BPS <40) at baseline (Kim et al., 2021). Methods: N‐MOmentum was a double‐blind trial in 230 participants, randomized 3:1 to inebilizumab 300mg: placebo with an open‐label extension period of ≥2 years. Pain, QoL, and disability were measured using the SF36‐BPS, SF36‐Physical Component Score (PCS), and Expanded Disability Status Scale (EDSS), respectively (Cree et al., 2019). Results: 213 participants were included in the pain analyses (inebilizumab, n = 161; placebo, n = 52). At baseline, there were no differences in pain scores between the two treatment groups (Kim et al., 2021). NRS pain scores increased modestly during NMOSD attacks in the five areas assessed: arm, eye, legs, lower back, and upper back. Among participants with reduced QoL at baseline, 62/92 (75%) reported moderate or severe pain (NRS ≥4) in at least one of five body areas, compared with 32/125 (26%) for those with normal QoL at baseline. A strong correlation was observed between NRS scores and SF‐36 pain inventory scores in participants with average pain (Spearman R = −0.67, p < 0.0001) and/or worst pain (Spearman R = −0.66, p < 0.0001). At baseline, participants with reduced QoL had higher levels of disability. A strong correlation was found between the EDSS score and SF‐36‐PCS (Spearman R = −0.63, p < 0.0001). The proportion of participants reporting moderate or severe pain was reduced over time with inebilizumab treatment. The proportion of participants with severe pain reduced from 61% before treatment to 26% after 3.5–4.5 years (6–7 doses of inebilizumab). After three years of treatment with inebilizumab, proportionally fewer participants had an SF‐36 score of <40 in ‘Role physical,’ ‘Bodily pain,’ ‘General health,’ and PCS domains than before treatment Conclusions: Long‐term inebilizumab treatment over three years was associated with improved pain outcomes in patients with NMOSD. Correlations between measures of pain, QoL, and disability suggest all may be valid metrics of disease status and treatment effects in NMOSD.

INTRODUCTION: Immunoglobulin G4-related disease (IgG4-RD) is a debilitating multiorgan disease characterized by recurring flares leading to organ dysfunction, decreased quality of life, and mortality. Glucocorticoids, the standard of care for IgG4-RD, are associated with substantial treatment-related toxicity. Inebilizumab, an antibody directed against CD19, mediates the rapid and durable depletion of CD19+ B cells thought to be involved in IgG4-RD pathogenesis. We describe the first international, prospective, double-blind, placebo-controlled trial to evaluate the safety and efficacy of B-cell depletion for flare prevention in IgG4-RD (MITIGATE). METHODS: The study was designed by an international panel of physicians with expertise in IgG4-RD. Critical trial design decisions included the selection of participants, definition of clinically meaningful primary and secondary endpoints, accommodation of standard of care, and development of flare diagnostic criteria. The study is approved for conduct in 22 countries. PLANNED OUTCOMES: The primary efficacy endpoint is time from randomization to the occurrence of the first centrally adjudicated and investigator-treated disease flare during the 1-year randomized controlled period. A set of novel, organ-specific flare diagnostic criteria were developed specifically for this trial, incorporating symptoms and signs, laboratory findings, imaging study results, and pathology data. MITIGATE aims to accrue 39 flares for the primary endpoint, which provides sufficient power to detect a relative risk reduction of 65% in the inebilizumab group. It is anticipated that enrollment of 160 participants will achieve this goal. Additional endpoints include safety, annualized flare rate, flare-free complete remission, quality-of-life measures, and cumulative glucocorticoid use. MITIGATE represents the first randomized, double-blind, placebo-controlled trial of any treatment strategy conducted in IgG4-RD. Data from this study will provide insights into the natural history and pathophysiology of IgG4-RD and the efficacy and safety of B-cell depletion as a therapeutic avenue. TRIAL REGISTRATION: NCT04540497.

AIMS: Neuromyelitis optica spectrum disorders (NMOSD) is an autoantibody-mediated, B cell-driven disease. Inebilizumab is a humanized, affinity-optimized, afucosylated IgG1 κ monoclonal antibody that binds to the B-cell specific surface antigen CD19, resulting in rapid, profound and sustained depletion of circulating peripheral B cells in NMOSD subjects (pivotal study). The objective of this study was to conduct population modelling of B-cell response following inebilizumab treatment in adult subjects with NMOSD, and to assess the impact of drug exposure to outcome. METHODS: A haematopoietic transit model was developed to describe the joint effects of reducing influx from pro-B cells and accelerating CD20+  B-cell depletion in the blood by inebilizumab. Furthermore, the relationships between inebilizumab pharmacokinetic (PK) exposure and the primary efficacy endpoint and key secondary efficacy endpoints were evaluated. RESULTS: At the 300-mg dose, there was no apparent relationship between efficacy (reduction in disease attack risk, risk of worsening from baseline in Expanded Disability Status Scale, cumulative total active MRI lesions, and the number of NMOSD-related in-patient hospitalizations) and PK exposure. Subjects with low, medium and high PK exposure had a similar hazard ratio of NMOSD attack vs. placebo group. CONCLUSION: The pharmacodynamic modelling confirmed effective depletion of B cells is achieved with a 300 mg intravenous dose of inebilizumab administered on Day 1 and Day 15 and every 6 months thereafter. The PK variability between patients had no apparent effect on clinical efficacy.