Treatment Of Neuromyelitis Optica Spectrum Disorder Research Articles

Safety and efficacy of interleukin-6-receptor inhibitors in the treatment of neuromyelitis optica spectrum disorders: a meta-analysis

BackgroundInterleukin-6-receptor inhibitors like Tocilizumab and Satralizumab are showing promising results in the treatment of Neuromyelitis Optica spectrum disorder (NMOSD). We aimed to investigate the efficacy and safety of various Interleukin-6-receptor inhibitors in the management of NMO/NMOSD.MethodsPubMed, Embase, and The Cochrane Library were systematically searched for suitable studies. Change in Annualized Relapse Ratio (ARR), Change in Extended Disability Status Scale (EDSS) s, the proportion of relapse-free patients and proportion of patients with adverse events, including serious adverse events and mortality were the parameters considered for the meta-analysis for Tocilizumab. Mean difference (MD) with 95% CI was used to quantify the change in ARR and change in EDSS before and after treatment. A forest plot was prepared to indicate the efficacy and adverse effects outcomes. The results were compared with those of Satralizumab included in two trials.ResultsA total of nine studies with 202 patients were included in our study. Tocilizumab found a good proportion (76.95% CI: 0.61–0.91; p < 0.001) of relapse free patients at follow up. It also significantly reduced mean ARR (mean difference: -2.6, 95% CI: − 2.71 to − 1.68; p < 0.001) and but did not show significant difference in change in EDSS score (mean difference = − 0.79, 95% CI: − 1.89 to − 0.31; p = 0.16). Also, the toxicity profile of Tocilizumab was acceptable considering the proportions of patients with adverse events 56% (95% C.I.;0.27–0.85, I2 = 88.95%, p < 0.001), proportions of patients with serious adverse events 11% (95% C.I.; 0.05 to 0.17, I2 = 0%, p < 0.001) and zero treatment related deaths. SAkura studies for Satralizumab showed similar relapse free patients (70% to 80%) and reduction of ARR and EDSS from baseline. Some studies of Tocilizumab have shown to reduce pain and fatigue while trials of Satralizumab had non-significant findings.ConclusionInterleukin-6-receptor inhibitors therapy showed a promising result with good efficacy and acceptable adverse events profile for treatment of NMOSD.

Hope for patients with neuromyelitis optica spectrum disorders - from mechanisms to trials.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare inflammatory CNS disease that primarily manifests as relapsing episodes of severe optic neuritis and myelitis. Diagnosis of NMOSD is supported by the detection of IgG autoantibodies that target the aquaporin 4 (AQP4) water channel, which, in the CNS, is an astrocyte-specific protein. AQP4 antibody binding leads to AQP4 internalization, complement-dependent and antibody-dependent cellular cytotoxicity, and water channel dysfunction. Cumulative attack-related injury causes disability in NMOSD, so the prevention of attacks is expected to prevent disability accrual. Until recently, no regulator-approved therapies were available for NMOSD. Traditional immunosuppressant therapies, including mycophenolate mofetil, azathioprine and rituximab, were widely used but their benefits have not been assessed in controlled studies. In 2019 and 2020, five phase II and III randomized placebo-controlled trials of four mechanism-based therapies for NMOSD were published and demonstrated that all four effectively prolonged the time to first relapse. All four drugs were monoclonal antibodies: the complement C5 antibody eculizumab, the IL-6 receptor antibody satralizumab, the B cell-depleting antibody inebilizumab, which targets CD19, and rituximab, which targets CD20. We review the pathophysiology of NMOSD, the rationale for the development of these mechanism-based drugs, the methodology and outcomes of the five trials, and the implications of these findings for the treatment of NMOSD.

Inebilizumab for treatment of neuromyelitis optica spectrum disorder in patients with prior rituximab use from the N-MOmentum Study

Background: The B-cell–depleting agent rituximab (anti-CD20) was historically used to prevent attacks in neuromyelitis optica spectrum disorder (NMOSD). Inebilizumab, which targets and depletes CD19-expressing B cells, plasmablasts, and some plasma cells, received approval from the US Food and Drug Administration for treatment of NMOSD based on results from the randomized, placebo-controlled, phase 2/3 N-MOmentum trial. Because of their closely related mechanisms of action, consideration as to whether inebilizumab may be a suitable treatment option for patients with prior rituximab experience is important. This post hoc analysis of data from N-MOmentum assessed inebilizumab efficacy and tolerability in participants previously treated with rituximab.Methods: Adjudicated attacks, secondary efficacy outcomes, and treatment-emergent adverse events were assessed by prior rituximab use during a 6-month randomized control period and open-label period.Results: Seventeen participants in N-MOmentum had prior rituximab use, of whom 13 were randomly assigned to the inebilizumab treatment group. Seven of these participants had breakthrough attacks prior to enrollment (annualized attack rate, 0.78 attacks/person-year) despite rituximab use. While they were receiving inebilizumab in the randomized control period, 1 of 13 participants with prior rituximab use had an attack (hazard ratio vs all placebo, 0.16; 95% confidence interval: 0.02 1.20; p = 0.07). Two additional participants with prior rituximab use experienced attacks on inebilizumab during the open-label period, with an overall annualized attack rate of 0.08 (95% confidence interval: 0.02 0.34) attacks/person-year. This annualized attack rate was similar to that of participants without prior rituximab use (0.10 [95% confidence interval: 0.07 0.15]). None of the 7 participants who experienced attacks while taking rituximab experienced an attack while receiving inebilizumab. Two (12%) participants with prior rituximab use experienced serious treatment-emergent adverse events related to inebilizumab, with serious or grade ≥3 infections occurring in 3 (18%) participants each. No deaths or opportunistic infections were reported in this cohort.Conclusions: These findings support the efficacy of inebilizumab in participants with NMOSD who had previously been treated with rituximab. Infections occurred in nearly all study participants with prior rituximab exposure, highlighting a need for clinical vigilance in such individuals. Further studies are necessary to determine potential safety concerns of inebilizumab, including risk of infection, in rituximab-experienced patients.ClinicalTrials.gov identifier: NCT02200770

B-Cell Targeted Treatments for Neuromyelitis Optica Spectrum Disorder: A Focus on CD19 and CD20.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare relapsing autoimmune disease of the central nervous system that preferentially targets the optic nerves and spinal cord, leading to visual loss and impaired mobility. Until 2019, no medications were FDA-approved for NMOSD treatment, and standard of care was based on mostly empiric and retrospective data. Therapies that target B cells emerged as a treatment strategy due to their fundamental role in disease pathogenesis. We explore different monoclonal antibodies directed at either CD20+ or CD19+ B cells that may have utilization in the treatment of NMOSD, discussing what is known regarding their efficacy and safety.

Randomized controlled trials for neuromyelitis optica spectrum disorder: a systematic review of trial architecture

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is a relapsing inflammatory disease that primarily affects the optic nerves and the spinal cord. Randomized controlled trials (RCTs) assessing treatments for NMOSD have been performed only in the past decade, and to date, there are three drugs approved by the U.S. Food and Drug Administration for anti-aquaporin-4 IgG seropositive NMOSD. This review assesses the characteristics and challenges of RCTs when evaluating treatments for NMOSD.MethodsWe conducted a systematic review using the search term [“neuromyelitis optica” OR “NMO” OR “NMOSD”] AND “clinical trial” in any language on December 28, 2020.ResultsSeven RCTs were included (see reference list below), and the trials’ architectures were analyzed and synthesized. Overall, 794 patients were randomized (monoclonal antibody intervention group, n=493 [62.1%]; placebo, n=196 [24.7%]; active control, n=105 [13.2%]); 709 (89.3%) were women; and 658 (82.9%) were anti-aquaporin IgG seropositive. The primary outcome was time to relapse in 6/7 of the trials, and annualized relapse rate in the remaining one. Four RCTs used placebo in their design. Among the seven published RCTs, the trial designs differed by the criteria used to define NMOSD relapse, selection of patients, proportion of anti-aquaporin-4 IgG seronegative patients, and baseline characteristics indicating NMOSD disease severity.ConclusionEthical considerations for the use of placebo should change in light of the approval of three therapies for seropositive NMOSD. Remaining challenges for clinical trials in NMOSD include the assessment of long-term safety and efficacy, standardization of trial design and endpoints, and head-to-head study designs. Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing inflammatory disease that primarily affects the optic nerves and the spinal cord. Randomized controlled trials (RCTs) assessing treatments for NMOSD have been performed only in the past decade, and to date, there are three drugs approved by the U.S. Food and Drug Administration for anti-aquaporin-4 IgG seropositive NMOSD. This review assesses the characteristics and challenges of RCTs when evaluating treatments for NMOSD. We conducted a systematic review using the search term [“neuromyelitis optica” OR “NMO” OR “NMOSD”] AND “clinical trial” in any language on December 28, 2020. Seven RCTs were included (see reference list below), and the trials’ architectures were analyzed and synthesized. Overall, 794 patients were randomized (monoclonal antibody intervention group, n=493 [62.1%]; placebo, n=196 [24.7%]; active control, n=105 [13.2%]); 709 (89.3%) were women; and 658 (82.9%) were anti-aquaporin IgG seropositive. The primary outcome was time to relapse in 6/7 of the trials, and annualized relapse rate in the remaining one. Four RCTs used placebo in their design. Among the seven published RCTs, the trial designs differed by the criteria used to define NMOSD relapse, selection of patients, proportion of anti-aquaporin-4 IgG seronegative patients, and baseline characteristics indicating NMOSD disease severity. Ethical considerations for the use of placebo should change in light of the approval of three therapies for seropositive NMOSD. Remaining challenges for clinical trials in NMOSD include the assessment of long-term safety and efficacy, standardization of trial design and endpoints, and head-to-head study designs.

Inebilizumab-cdon: USFDA Approved for the Treatment of NMOSD (Neuromyelitis Optica Spectrum Disorder).

Inebilizumab-cdon (Uplizna™) was currently approved by the United States Food and Drug Administration (USFDA) for the treatment of NMOSD (neuromyelitis optica spectrum disorder). It was developed by Viela Bio (Nasdaq: VIE) USA. Inebilizumab-cdon (formerly MEDI-551) is a humanized antibody, which induces CD19 + B cell depletion by increasing antibody-dependent cell cytotoxicity (ADCC) and cell phagocytosis (ADCP) of effector cells. Various clinical trials exhibit its safe and effective pharmacokinetic and pharmacodynamic profile. In June 2019, Viela Bio submitted Biologics License Application (BLA) to the FDA based on the findings obtained from the N-Momentum trial. This article summarizes the milestones in the development of Inebilizumab-cdon leading to this approval for the treatment of advanced NMOSD.

Recent advances in the treatment of neuromyelitis optica spectrum disorders.

This review examines recently published randomized placebo-controlled trials for the treatment of neuromyelitis optica spectrum disorders (NMOSD). Until recently, treatments for NMOSD were used-off label and had not been subjected to randomized placebo-controlled trials. Increased understanding of the pathophysiology of NMOSD, particularly aquaporin-4-IgG seropositive NMOSD, lead to the investigation of eculizumab, inebilizumab, and satralizumab for maintenance therapy. Eculizumab inhibits the cleavage of the terminal complement protein C5, inebilizumab depletes immune cells of B-lymphocyte lineage, and satralizumab inhibits interleukin-6 receptors. International, phase 3, randomized, placebo-controlled trials have demonstrated that each of these therapies reduces the risk of NMOSD relapse. In some cases, the studied therapies were administered in conjunction with other immunosuppressants. Each therapy has important safety considerations, notably risk of meningococcal infection with eculizumab and risks of infection and hypogammaglobulinemia with inebilizumab. Reviewing trial design highlights future areas of inquiry for the treatment of NMOSD. Eculizumab, inebilizumab, and satralizumab are effective maintenance therapies approved for the treatment of AQP-4 seropositive NMOSD.

Effectiveness of treatments in Neuromyelitis optica to modify the course of disease in adult patients. Systematic review of literature.

Neuromyelitis Optica spectrum disorder (NMOSD) is an inflammatory disease, which manifests mostly as recurrent episodes of optic neuritis or myelitis that cause important disability. Early diagnosis and prompt initiation of immunosuppressive therapy are crucial in reducing relapses, disability, and mortality. Even though, there are few prospective randomized controlled trials, several drugs have proved to be both effective and safe. Azathioprine and Rituximab represent the standard of care and are used as first-line treatment agents worldwide. However, recent studies have unveiled new therapies, such as monoclonal antibodies. To make treatment recommendations and management guidelines, it is imperative to define an appropriate standard of care. A systematic literature review was performed in MEDLINE, EMBASE, and LILACS databases using the following terms: "(NMO OR Devic OR Neuromyelitis Optica) AND (Azathioprine OR Prednisone OR Rituximab OR Tocilizumab OR Bortezomib OR Inebilizumab OR Eculizumab OR Satralizumab)" including both, randomized clinical trials and observational studies published between January 2006 and January 2021. The inclusion criteria comprised patients aged 18 or older, NMOSD diagnosis following the Wingerchuck criteria, two or more therapies been compared, and the evaluation of both efficacy and safety outcomes. All studies comparing treatment only with placebo were excluded. Quality was assessed according with the design of the study, and results were synthesized through comparative tables for each outcome evaluated, differentiating the results of randomized and non-randomized studies. Thirteen studies with 1447 patients were included. Twelve studies evaluated the expanded disability status scale (EDSS) before and after treatment; in five of seven evaluating rituximab, it outperformed its comparators in improving the disability degree. Eleven studies assessed the annual relapse rate (ARR). Again, in six of seven evaluating rituximab, it was superior to other therapies. Time to relapse (TTR) was reported in five studies. The three studies that included Rituximab revealed a longer time to relapse in this arm of treatment. Finding were consistent in randomized and non-randomized studies. The new molecules Satralizumab, Eculizumab and Tocilizumab were evaluated in one study each, proving to be highly effective and safe. The safety profile analysis showed a higher number of adverse events for Azathioprine. This systematic review demonstrates a superiority tendency of Rituximab upon the other treatments strengthening the available evidence about NMOSD management. Superiority in EDSS outcomes, annual relapse rate, time to first relapse and relapses during treatment time was evidenced in the Rituximab group compared to other medications, with lower rates of adverse events. New molecules Tocilizumab, Eculizumab and Satralizumab also showed superiority in the evaluated results, especially in the relapses during treatment time outcome, although with subtle differences in EDSS and ARR outcomes. Our results suggest that monoclonal antibodies are highly effective and safe for the treatment of NMOSD; Rituximab showed better performance on multiple outcomes and has more evidence available. New molecules: Eculizumab, Tocilizumab, Satralizumab are good options for treatment. Drugs like Azathioprine and Mycophenolate are effective, but with a worse risk-benefit ratio, therefore, they are useful alternatives in places that do not have access to monoclonal antibodies.

Identification and temporal trends of patients with neuromyelitis optica spectrum disorder in a US insurance claims database

Background This US claims-based study aimed to identify and characterize temporal trends in diagnostic pathways for patients likely to have neuromyelitis optica spectrum disorder (NMOSD). Methods Patients were identified from IBM MarketScan Commercial Databases if, within 1 year, they had two NMOSD claims separated by ≥ 60 days; two transverse myelitis (TM) or optic neuritis (ON) claims separated by ≥ 60 days, and one additional symptom (TM, ON, or area postrema syndrome); or one NMOSD claim and one additional symptom. The first NMOSD or TM/ON claim was the index date, and the second claim was the diagnosis date. Similar methodology was used in temporal trend and incidence and prevalence analyses. Results Among 1,901 patients with NMOSD, 34.2% were identified by two NMO claims, 53.2% by ON or TM +1 symptom, and 12.6% by one NMOSD claim +1 symptom. Anti–aquaporin-4 immunoglobin G (AQP4-IgG) autoantibody tests and magnetic resonance imaging was used for 23.0% and 71.9% of cases, respectively. Across cohorts, 21.4–49.1% had multiple sclerosis (MS) diagnosis claims prior to index date, and 37.3–60.6% had an MS diagnosis, 14.9–31.0% had MS disease-modifying therapy (DMT) claims and 6.3–44.8% had immunosuppressive therapy (IST) claims <1 year after diagnosis. Over time, there were slight changes in MS diagnosis claims, AQP4-IgG autoantibody testing, and DMT and IST use before and after NMOSD diagnosis. Limitations This study is limited by the information available in US claims databases, which included the potential for misclassification of NMOSD based solely on claims codes and lack of reimbursement for AQP4-IgG testing by insurance companies. Conclusions Among patients likely to have NMOSD, low AQP4-IgG testing rates, IST use, frequent MS diagnosis claims, and DMT use highlight the need for a diagnostic algorithm and timely treatment of NMOSD.

New progress in the treatment of neuromyelitis optica spectrum disorder with monoclonal antibodies (Review).

Neuromyelitis optica spectrum disorder (NMOSD) is a group of immune-mediated inflammatory demyelinating diseases mainly affecting the central nervous system. It is characterized by high risk of relapse and progression to disability. The frequent recurrences of neuromyelitis optica spectrum disorder often exacerbate the neurological dysfunction and severely affect the patient's quality of life. Conventional treatments for neuromyelitis optica spectrum disorder, including acute treatment and sequential therapy, aim to decrease the degree of disability and recurrences. In recent years, new monoclonal antibodies have yielded encouraging results. The present review discusses the research status and recent progress in the treatment of NMOSD with monoclonal antibodies.

Satralizumab in the treatment of neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare and debilitating autoimmune astrocytopathy with apredominantly relapsing disease course. Satralizumab, a humanized monoclonal antibody, was designed to treat NMOSD by targeting the IL-6 receptor. Satralizumab builds on positive experiences of off-label usetocilizumab in recentyears. Before 2019, no medications were approved for the treatment of NMOSD. In 2020, satralizumab became the third compound to enter the US market, adding to the complement inhibitor eculizumab and the CD19 inhibitor inebilizumab. Here, we review the two randomized, double-blind, Phase III trials that investigated the subcutaneous administration of satralizumab as add-on treatment and monotherapy. Both studies revealed positive effects concerning the reduction of relapse risk for AQP4seropositive NMOSD patients and generally good tolerability.

Aquaporin-4 and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Optic Neuritis: Diagnosis and Treatment

Optic neuritis (ON) is a frequent manifestation of aquaporin-4 (AQP4) antibody-mediated neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disorders, MOGAD). The past few years have seen major advances in the diagnosis and treatment of these two relatively new entities: international diagnostic criteria for NMOSD and MOG-EM have been proposed, improved antibody assays developed, and consensus recommendations on the indications and methodology of serological testing published. Very recently, the results of four phase III trials assessing new treatment options for NMOSD have been presented. With eculizumab, a monoclonal antibody inhibiting complement factor C5, for the first time a relapse-preventing long-term treatment for NMOSD - which has so far mostly been treated off-label with rituximab, azathioprine, and other immunosuppressants - has been approved. Data from recent retrospective studies evaluating treatment responses in MOG-ON suggest that rituximab and other immunosuppressants are effective also in this entity. By contrast, many drugs approved for the treatment of multiple sclerosis (MS) have been found to be either ineffective or to cause disease exacerbation (e.g., interferon-β). Recent studies have shown that not only NMOSD-ON but also MOG-ON usually follows a relapsing course. If left untreated, both disorders can result in severe visual deficiency or blindness, though MOG-ON seems to have a better prognosis overall. Acute attacks are treated with high-dose intravenous methylprednisolone and, in many cases, plasma exchange (PEX) or immunoadsorption (IA). Early use of PEX/IA may prevent persisting visual loss and improve the long-term outcome. Especially MOG-ON has been found to be frequently associated with flare-ups, if steroids are not tapered, and to underlie many cases of "chronic relapsing inflammatory optic neuropathy" (CRION). Both NMOSD-ON and MOG-ON are often associated with simultaneous or consecutive attacks of myelitis and brainstem encephalitis; in contrast to earlier assumptions, supratentorial MRI brain lesions are a common finding and do not preclude the diagnosis. In this article, we review the current knowledge on the clinical presentation, epidemiology, diagnosis, and treatment of these two rare yet important differential diagnoses of both MS-associated ON und idiopathic autoimmune ON.

Satralizumab: First Approval.

Satralizumab (Enspryng®), a humanized anti-interleukin-6 (IL-6) receptor monoclonal recycling antibody, has been developed by Chugai Pharmaceutical and Roche for the treatment of neuromyelitis optica spectrum disorder (NMOSD). In June 2020, based on positive results from two pivotal phase III trials, subcutaneous satralizumab received its first global approval in Canada for the treatment of NMOSD in adults and children aged ≥ 12 years who are aquaporin 4 water channel autoantibody (AQP4-IgG) seropositive. Satralizumab was subsequently approved in Japan, Switzerland and the USA. Satralizumab is under regulatory review in the EU, and is undergoing clinical development in several countries worldwide. This article summarizes the milestones in the development of satralizumab leading to this first approval for the treatment of NMOSD.

Precision therapy for neuromyelitis optica spectrum disorder: A retrospective analysis of the use of class-switched memory B-cells for individualised rituximab dosing schedules

BackgroundB-cell depleting treatments are widely used to modify the course of neuromyelitis optica spectrum disorder (NMOSD). Despite recent successful Phase 3 trials of several novel NMOSD therapies, limited availability and high cost constrains their clinical use, and rituximab (RTX) remains a core treatment in many centres. Since 2013, the Royal Prince Alfred Hospital Neuroimmunology Clinic (NIC) has regularly measured class-switched memory B-cells (SMB-cells) in the peripheral blood of patients with NMOSD, who have been treated with RTX, in order to guide retreatment intervals. ObjectiveTo assess the management and outcomes of the treated patients, and to determine the effect of SMB-cell monitoring in guiding retreatment intervals. MethodsA retrospective analysis of hospital records, clinic letters and laboratory data was performed. ResultsSixteen patients with NMOSD received individualised rituximab dosing at NIC between 2013 and 2018. Fourteen (87.5%) were aquaporin-4 antibody (AQP4-Ab) positive; 1 (6.25%) was myelin oligodendrocyte glycoprotein antibody (MOG-Ab) positive and 1 (6.25%) was seronegative. After commencement of RTX, individually dosed according to regular measurements of serum SMB-cells, there was a 77.5% reduction in annualised relapse rate over a mean follow-up time of 46.1 months in our recently active NMOSD patients. Their mean retreatment interval was 50.9 weeks. ConclusionsThis study provides real-world evidence supporting individualised rituximab dosing in the treatment of NMOSD.

Efficacy and Safety of Monoclonal Antibody Therapy in Neuromyelitis Optica Spectrum Disorders: Evidence from Randomized Controlled Trials

Background: Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune inflammatory disorders in central nervous system (CNS) characterized by symptoms of optic nerve, spinal cord, brainstem and cerebrum injuries. Recent studies have shown that monoclonal antibodies (Rituximab, Eculizumab, Inebilizumab, Satralizumab, etc.) were effective for the treatment of NMOSD. We performed a meta-analysis to evaluate the efficacy and safety of these monoclonal antibodies in NMOSD. Methods: The MEDLINE, EMBASE, Central Register of Controlled Trials (CENTRAL) and clinicaltrials.gov database were searched for randomized controlled trials (RCTs) which had assessed the therapy of monoclonal antibody in NMOSD patients. Results: We pooled 524 (monoclonal antibody group, n = 344 and placebo group, n = 180) from 4 RCTs and 444 patients (84.7%) were AQP4-IgG seropositive. Monoclonal antibody therapy reduced annualized relapse rate (mean -0.27, 95% CI, -0.36 to -0.18, P <0.0001), on-trial relapse risk (RR 0.25, 95% CI 0.12 to 0.52, P = 0.0003), EDSS (Expanded disability status scale) score (mean -0.51, 95% CI, -0.92 to -0.11, P = 0.01) and serious adverse events (RR 0.59, 95% CI 0.37 to 0.96, P = 0.03) but didn't show any significant differences in total adverse events or mortality. In the subgroup analysis, we found that comparing with other monoclonal antibodies, Eculizumab might be more effective in decreasing on-trial relapse risk (Chi2 =9.84, P =0.002) for AQP-4 positive patients. Conclusions: Monoclonal antibody therapy was effective and safe in NMOSD treatment. More RCTs were expected to assess monoclonal antibodies in NMOSD.

Cost effectiveness of rituximab and mycophenolate mofetil for neuromyelitis optica spectrum disorder in Thailand: Economic evaluation and budget impact analysis.

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory condition of the central nervous system. The extent of disability depends on the severity of the disease and the number of relapses. Although azathioprine is currently the main treatment for patients with NMOSD in Thailand, patients often relapse during its use. Hence, it is argued that there are other drugs that would be more effective. The purpose of this study is to evaluate, from a societal perspective and from the economic impact on Thailand's healthcare system, the cost utility of treatment with mycophenolate mofetil (MMF) and rituximab in patients resistant to azathioprine. The Markov model with a one-year cycle length was applied to predict the health and cost outcomes in patients with NMOSD over a lifetime. The results showed that rituximab exhibited the highest quality-adjusted life year (QALY) gains among all the options. Among the rituximab-based treatments, the administration of a rituximab biosimilar with CD27+ memory B cell monitoring proved to be the most cost-effective option. At the willingness-to-pay threshold of 160,000 Thai baht (THB), or 5,289 US dollar (USD), per QALY gained, the treatment exhibited the highest probability of being cost effective (48%). A sensitivity analysis based on the adjusted price of a generic MMF determined that the treatment was cost effective, exhibiting an incremental cost-effectiveness ratio of -164,653 THB (-5,443 USD) and a 32% probability of being cost effective. The calculated budget impact of treating patients resistant to conventional therapy was 1-6 million THB (33,000-198,000 USD) for the first three years, while after the third year, the budget impact stabilized at 3-4 million THB (99,000-132,000 USD). These data indicate that, in Thailand, treatment of drug resistant NMOSD with a rituximab biosimilar with CD27+ memory B cell monitoring or treatment with a generic MMF would be cost effective and would result in a low budget impact. Therefore, the inclusion of both the rituximab biosimilar and a generic MMF in the National Drug List of Essential Medicine for the treatment of NMOSD may be appropriate.

Efficacy of Satralizumab (SA237) As Add-on Therapy in Pre-Specified Additional Analyses of Sakurasky, a Double-Blind Placebo-Controlled Phase 3 Study in Patients with Neuromyelitis Optica Spectrum Disorders (NMOSD)

A central role of interleukin-6 (IL-6) as key player in the pathophysiology of NMOSD, is strongly supported by the significant reduction in risk of relapse as previously demonstrated in the SAkuraSky study of the IL-6R inhibitor satralizumab for treatment of NMOSD as an add-on therapy. Here, we report the results of additional analyses (ClinicalTrials.gov number, NCT020728884). 83 patients meeting NMOSD diagnostic criteria with/without AQP4-Ab and at least two relapses in the last 2 years were randomly assigned to receive satralizumab 120 mg subcutaneously or placebo at week 0, 2 and 4 and every 4 weeks thereafter, added to stable immunosuppressant treatment. The primary endpoint was time to first protocol-defined relapse. Pre-specified additional analyses included efficacy in AQP4-Ab positive vs. negative subgroups, and effect on annualized relapse rate (ARR). Hazard ratios (HRs) were based on Cox proportional hazards model. Satralizumab added to baseline treatment significantly reduced risk of protocol-defined relapse by 62% vs placebo; HR, 0.38; 95% confidence interval (CI), 0.16 to 0.88; P=0.0184. Pre-specified additional analyses showed a 79% relapse risk reduction with satralizumab vs placebo in AQP4-Ab(+) patients (n=55; HR, 0.21; 95% CI, 0.06 to 0.75) and 34% in AQP4-Ab(-) patients (HR 0.66; 95% CI, 0.20 to 2.24). In the overall study population, ARR was 0.11 (95% CI, 0.05 to 0.21) when treated with satralizumab vs 0.32 (95% CI, 0.19 to 0.51) with placebo. Treatment with satralizumab as add-on to baseline immunosuppressant therapy significantly reduced relapse risk, particularly in AQP4-Ab(+) NMOSD patients.

Novel emerging treatments for NMOSD.

Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory demyelinating diseases of the central nervous system (CNS) that cause optic neuritis, transverse myelitis, and some other CNS syndromes. Recently, diagnosis and understanding of these diseases has been markedly enhanced by the discovery that serum autoantibodies that target aquaporin-4 (AQP4) are strongly associated with the disease. This spectrum includes also a potential subset of patients with a phenotype of NMOSD who have anti-myelin oligodendrocyte glycoprotein (MOG) antibody. Although steroids and immunosuppressive drugs have been widely used for NMOSD treatment, until recently there was no approved therapy for these diseases. With improved understanding of the pathophysiology of NMOSD, numerous new therapeutic strategies have recently been evaluated. The results of these studies, involving monoclonal antibodies (mAbs) inhibiting terminal complement protein cleavage interfering with interleukin-6 receptor (IL-6 R) signaling and depleting CD19-positive B cells, have been published in recent months. All of these new therapeutics have shown a high degree of efficacy in diminishing NMOSD activity and inhibiting disability progression. At the same time, all these mAbs have demonstrated favorable safety and tolerability profiles, with a limited rate of adverse events. The first of these new drugs, eculizumab, have been approved in USA and Europe for NMOSD treatment within the last couple of months and it is expected that the other novel, effective and safe treatments for NMOSD will be approved in the near future.

Angiotensin AT2 receptor–induced interleukin-10 attenuates neuromyelitis optica spectrum disorder–like pathology

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing inflammatory central nervous system (CNS) disease for which there is no cure. Immunoglobulin G autoantibodies specific for the water channel aquaporin-4 are a serum biomarker, believed to induce complement-dependent astrocyte damage with secondary demyelination. Objective: To investigate the effect of angiotensin AT2 receptor (AT2R) stimulation on NMOSD-like pathology and its underlying mechanism. Methods: NMOSD-like pathology was induced in mice by intracerebral injection of immunoglobulin-G isolated from NMOSD patient serum, with complement. This mouse model produces the characteristic histological features of NMOSD. A specific AT2R agonist, Compound 21 (C21), was given intracerebrally at day 0 and by intrathecal injection at day 2. Results: Loss of aquaporin-4 and glial fibrillary acidic protein was attenuated by treatment with C21. Administration of C21 induced mRNA for interleukin-10 in the brain. NMOSD-like pathology was exacerbated in interleukin-10-deficient mice, suggesting a protective role. C21 treatment did not attenuate NMOSD-like pathology in interleukin-10-deficient mice, indicating that the protective effect of AT2R stimulation was dependent on interleukin-10. Conclusion: Our findings identify AT2R as a novel potential therapeutic target for the treatment of NMOSD. Interleukin-10 signaling is an essential part of the protective mechanism counteracting NMOSD pathology.

Neuromyelitis optica spectrum disorders: Emerging therapies

AbstractNeuromyelitis optica or neuromyelitis optica spectrum disorders (NMOSD) are autoimmune diseases associated with a disease‐specific autoantibody directed against the water channel protein aquaporin‐4. While almost all patients with NMOSD show a relapsing‐remitting course, just 2% of patients present with a progressive course, suggesting that preventing acute attacks can lead to stable remission and avoid progression of the condition. Standard immunotherapy, immunosuppressive agents, and corticosteroids can prevent acute attacks and maintain remission in the majority of patients with NMOSD. However, there is a strong need for alternative options for patients who are refractory to standard treatments. Emerging therapies targeting specific molecules related to the pathogenicity of NMOSD are currently being developed. In addition to standard intravenous high‐dose corticosteroid and plasma exchange/plasmapheresis, therapies targeted at inhibiting granulocytes, complement, and vascular endothelial growth factor are anticipated for acute attacks. With regard to preventive treatment of NMOSD, randomized clinical trials using monoclonal immunoglobulin G antibody targeting CD19 and CD20 on B cells, interleukin‐6, and complement protein C5 are underway. There are many preclinical therapeutic agents that target aquaporin‐4 and the pathogenic anti‐aquaporin‐4 antibody itself: complement inhibitor and T helper 17 cells based on the specific NMOSD pathology. The future goal of immunotherapies for NMOSD would be to select suitable therapies for the patient's pathological condition among off‐target and molecular‐target agents.