Therapy For Myasthenia Gravis Research Articles

Correction to: Several more myasthenia gravis therapy options now available

Correction to: Several more myasthenia gravis therapy options now available

Registered trials on novel therapies for myasthenia gravis: a cross-sectional study on ClinicalTrials.gov

Novel biologics in MG therapy research is on the rise. This research aimed to investigate the characteristics of registered trials on novel therapies for myasthenia gravis on ClinicalTrials.gov. This cross-sectional study used a descriptive approach to assess the features of the included trials on ClinicalTrials.gov. We found 62 registered trials from 2007 to 2023 on ClinicalTrials.gov. The results showed a yearly rise in the number of registered trials (r = 0.76, p < 0.001). Following 2017, more industry-sponsored trials were conducted (91.5% [43] vs. 60% [9], p = 0.009), fewer results were released (10.6% [5] vs. 60% [9], p = 0.001), and more trials entered phase 3 (67.4% [31] vs. 20% [2], p = 0.001). The most researched novel medications were neonatal Fc receptor inhibitors (51.2% [21]), complement inhibitors (39.0% [16]), and B cell depletors (14.6% [6]). According to the website’s data, the neonatal Fc receptor inhibitors and complement inhibitors were effective in treating myasthenia gravis patients in three trials (NCT03315130, NCT03669588, and NCT00727194). This study provides valuable insights into the profile of registered trials on novel therapies for myasthenia gravis. More clinical studies are needed in the future to prove the value of its application.

Update on new and emerging therapies for myasthenia gravis

Update on new and emerging therapies for myasthenia gravis

Pharmacological treatment of Lambert-Eaton Myasthenic Syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is a very rare antibody-mediated autoimmune disease of the neuromuscular junction. Therapy can be divided in symptomatic treatment and immunosuppressive treatment. Symptomatic treatment with amifampridine is the only therapy currently authorized for use in LEMS patients. In the Netherlands the first choice drug is amifampridine base in an extended release formulation instead of the currently authorized amifampridine phosphate. This formulation has lower costs and is possibly safer due to lower peak concentrations. Other therapy used in LEMS patients is prescribed off-label and is based on experience in patients with myasthenia gravis. In many cases pyridostigmine is added as symptomatic treatment. In almost half of patients immunosuppressive therapy is started, mostly corticosteroids with or without azathioprine. Intravenous immunoglobulins and plasma exchange are used as emergency treatment.&#x0D; Currently no randomized clinical trials with new therapies are ongoing or announced in patients with LEMS, although multiple new therapies for myasthenia gravis are being investigated. These future therapies can be differentiated in symptomatic and immunomodulating drugs. The immunomodulating drugs can be further differentiated in early stage drugs which target the B-cell, later stage drugs which target the circulating antibodies and targeted therapy which have a disease-specific target. Some early and later stage immunomodulating drugs show promising results in myasthenia gravis although high cost and uncertain long term safety may be limiting for incorporating these drugs in LEMS treatment guidelines.&#x0D; Clinical trials in LEMS patients are lacking due to the rarity of the disease and we suggest the following requirements for future trials of potential new treatments: Sufficient power by performing multicenter or n-of-1 trials when appropriate, a cross-over design to reduce the number of patients and using a LEMS-specific quantitative primary outcome measure like the 3TUG score.

Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study

Chimeric antigen receptor (CAR) T cells are highly effective in treating haematological malignancies, but associated toxicities and the need for lymphodepletion limit their use in people with autoimmune disease. To explore the use of CAR T cells for the treatment of people with autoimmune disease, and to improve their safety, we engineered them with RNA (rCAR-T)-rather than the conventional DNA approach-to target B-cell maturation antigen (BCMA) expressed on plasma cells. To test the suitability of our approach, we used rCAR-T to treat individuals with myasthenia gravis, a prototypical autoantibody disease mediated partly by pathogenic plasma cells. MG-001 was a prospective, multicentre, open-label, phase 1b/2a study of Descartes-08, an autologous anti-BCMA rCAR-T therapy, in adults (ie, aged ≥18 years) with generalised myasthenia gravis and a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 6 or higher. The study was done at eight sites (ie, academic medical centres or community neurology clinics) in the USA. Lymphodepletion chemotherapy was not used. In part 1 (phase 1b), participants with Myasthenia Gravis Foundation of America (MGFA) disease class III-IV generalised myasthenia gravis received three ascending doses of Descartes-08 to determine a maximum tolerated dose. In part 2 (phase 2a), participants with generalised myasthenia gravis with MGFA disease class II-IV received six doses at the maximum tolerated dose in an outpatient setting. The primary objective was to establish safety and tolerability of Descartes-08; secondary objectives were to assess myasthenia gravis disease severity and biomarkers in participants who received Descartes-08. This trial is registered with clinicaltrials.gov, NCT04146051. We recruited 16 individuals for screening between Jan 7, 2020 and Aug 3, 2022. 14 participants were enrolled (n=3 in part 1, n=11 in part 2). Ten participants were women and four were men. Two individuals did not qualify due to low baseline MG-ADL score (n=1) or lack of generalised disease (n=1). Median follow-up in part 2 was 5 months (range 3-9 months). There was no dose-limiting toxicity, cytokine release syndrome, or neurotoxicity. Common adverse events were headache (six of 14 participants), nausea (five of 14), vomiting (three of 14), and fever (four of 14), which resolved within 24 h of infusion. Fevers were not associated with increased markers of cytokine release syndrome (IL-6, IL-2, and TNF). Mean improvements from baseline to week 12 were -6 (95% CI -9 to -3) for MG-ADL score, -7 (-11 to -3) for Quantitative Myasthenia Gravis score, -14 (-19 to -9) for Myasthenia Gravis Composite score, and -9 (-15 to -3) for Myasthenia Gravis Quality of Life 15-revised score. In this first study of an rCAR-T therapy in individuals with an autoimmune disease, Descartes-08 appeared to be safe and was well tolerated. Descartes-08 infusions were followed by clinically meaningful decreases on myasthenia gravis severity scales at up to 9 months of follow-up. rCAR-T therapy warrants further investigation as a potential new treatment approach for individuals with myasthenia gravis and other autoimmune diseases. Cartesian Therapeutics and National Institute of Neurological Disorders and Stroke of the National Institutes of Health.

Are CAR T cells the answer to myasthenia gravis therapy?

Are CAR T cells the answer to myasthenia gravis therapy?

Efficacy of innovative therapies in myasthenia gravis: A systematic review, meta-analysis and network meta-analysis.

Therapy for myasthenia gravis (MG) is undergoing a profound change, with new treatments being tested. These include complement inhibitors and neonatal Fc receptor (FcRn) blockers. The aim of this study was to perform a meta-analysis and network meta-analysis of randomized and placebo-controlled trials of innovative therapies in MG with available efficacy data. We assessed statistical heterogeneity across trials based on the Cochrane Q test and I2 values, and mean differences were pooled using the random-effects model. Treatment efficacy was assessed after 26 weeks of eculizumab and ravulizumab, 28 days of efgartigimod, 43 days of rozanolixizumab, 12 weeks of zilucoplan, and 16, 24 or 52 weeks of rituximab treatment. We observed an overall mean Myasthenia Gravis-Activities of Daily Living scale (MG-ADL) score change of -2.17 points (95% confidence interval [CI] -2.67, -1.67; p < 0.001) as compared to placebo. No significant difference emerged between complement inhibitors and anti-FcRn treatment (p = 0.16). The change in Quantitative Myasthenia Gravis scale (QMG) score was -3.46 (95% CI -4.53, -2.39; p < 0.001), with a higher reduction with FcRns (-4.78 vs. -2.60; p < 0.001). Rituximab did not significantly improve the MG-ADL (-0.92 [95% CI -2.24, 0.39]; p = 0.17) or QMG scores (-1.9 [95% CI -3.97, 0.18]; p = 0.07). In the network meta-analysis, efgartigimod had the highest probability of being the best treatment, followed by rozanolixizumab. Anti-complement and FcRn treatments both proved to be effective in MG patients, whereas rituximab did not show a significant benefit for patients. Within the limitations of this meta-analysis, including efficacy time points, FcRn treatments showed a greater effect on QMG score in the short term. Real-life studies with long-term measurements are needed to confirm our results.

THYMECTOMY IN SEVERE (MGFA CLASS IV-V) GENERALIZED MYASTHENIA GRAVIS: IS THE GAME REALLY WORTH THE CANDLE?

Total thymectomy in addition to medical treatment is an accepted standard therapy for myasthenia gravis. Patients with severe generalized myasthenia gravis present life-threatening events, poor prognosis and higher risk of postoperative myasthenic crisis. Aim of our study is to investigate neurological and surgical results in patients with MGFA class IV and V MG following thymectomy. Data on 76 myasthenia gravis patients with preoperative MGFA class IV and V who underwent thymectomy were retrospectively collected. Primary end-points included short-term surgical outcomes and long-term neurological results including the achievement of complete stable remission and any improvement as defined by MGFA postintervention status criteria. There were 27(35.5%) males and 49(64.5%) females; 53(69.7%) were classified as MGFA class IV and 23(30.3%) as class V. Thymectomy was performed through sternotomy in 25(32.9%) patients, by VATS in 5(6.6%) and RATS in 46(60.5%). Median operative time was 120(IQR 95; 148) min. In-hospital mortality was observed in 1(1.3%) patient, postoperative complications in 14 (18.4%). Median postoperative hospital stay was 4(IQR 3; 6) days. Pathological examination revealed 31(40.8%) thymic hyperplasia/other benign and 45(59.2%) thymomas. Cumulative complete stable remission and improvement probabilities were 20.6% and 83.7% at 5-year, and 66.9% and 97.6% at 10-year, respectively. A significant improvement rate was found in patients with age at time of thymectomy of ≤ 50 years(p = 0.0236), MGFA class V(p = 0.0154), and AchR-antibodies positivity(p = 0.0152). Thymectomy in patients with severe myasthenia gravis yields good perioperative outcomes and satisfactory long-term neurological improvement, especially for patients younger than 50 years, with MGFA class V and anti-AChR+ myasthenia gravis.

Efficacy of Rozanolixizumab in Generalized Myasthenia Gravis: Subgroup Analyses from the Randomized Phase 3 MycarinG Study (S5.007)

Efficacy of Rozanolixizumab in Generalized Myasthenia Gravis: Subgroup Analyses from the Randomized Phase 3 MycarinG Study (S5.007)

Myasthenia in adults, children, and adolescents: what's new?

Therapy of myasthenia gravis (MG) is increasingly oriented to the patient's antibody status. In addition to symptomatic therapy, steroids, classic long-term immunosuppressive therapies and thymectomy are regularly used. In recent years, new therapeutic approaches have been developed that particularly benefit acetylcholine receptor (AChR) antibody (Abs) positive patients with highly active disease. While the C5 complement inhibitor eculizumab was reserved for treatment-refractory generalized courses of AChR-Abs positive MG, two new drugs, the neonatal Fc receptor inhibitor efgartigimod and the more advanced C5 complement inhibitor ravulizumab, have recently been approved as add-on therapy for AChR-Abs positive generalized MG (gMG). In highly active courses of MG with Abs against the muscle-specific receptor tyrosine kinase (MuSK), the use of rituximab should be considered early in the course of the disease. The efficacy of the new drugs in children and adolescents with juvenile MG (JMG) is currently being tested in clinical trials. The new guideline recommends the use of modern immunomodulators based on astep-by-step approach depending on disease activity. With the German Myasthenia Register (MyaReg), the changing therapeutic landscape and quality of life of patients with myasthenic syndromes can be assessed, thus providing real-world data on the care of MG patients. Despite treatment based on the previous guideline, many MG patients suffer considerable impairment to their quality of life. With the new immunomodulators, there is the possibility of early intensified immunotherapy, which, in contrast to long-term immunosuppressants, can lead to arapid improvement in the course of the disease.

Numbers Needed to Treat and Costs Per Improved Outcome Among Treatments for Myasthenia Gravis

Objective Assess number needed to treat (NNT) and costs required to achieve improvements in symptoms and functional activities with targeted therapies for myasthenia gravis (MG). Background NNT and cost per improved efficacy can help inform comparative clinical efficacy and cost-effectiveness across MG treatments. Design/Methods Relative to conventional therapy (CT), NNTs and annual costs for achieving one point improvement in Quantitative Myasthenia Gravis score (QMG), one additional patient with minimal clinically important difference (MCID) in QMG (i.e., = 3 points improvement), and one additional patient achieving minimal symptom expression (MSE; Myasthenia Gravis-Activities of Daily Living score of 0 or 1) were estimated for efgartigimod (EFG), intravenous immunoglobulin (IVIg), and eculizumab (ECU). All treatments were used in conjunction with CT. Costs per improved outcome (CPR) were compared between EFG, IVIg, and ECU. Efficacy evaluated at week 4 of respective phase 3 randomized trials (ADAPT [NCT03669588], NCT02473952, REGAIN [NCT01997229]. Annual drug acquisition and administration costs (2021 USD) were considered. Results Compared with CT, mean NNTs to achieve one point improvement and MCID in QMG were 0.19 and 2.03 for EFG, 0.52 and 7.14 for IVIg, and 0.56 and 6.25 for ECU. NNTs to achieve an additional patient with MSE was 3.46 for EFG and 8.13 for ECU. Compared to EFG, the mean annual CPR to achieve one point improvement and MCID in QMG were higher for IVIg (Difference [95% confidence interval] = $36,130 [$14,024, $58,237] per point improvement in QMG; $661,561 [$0, $1,546,275] per one patient with MCID in QMG) and ECU ($340,659 [$158,038, $523,280]; $3,838,718 [$1,470,740, $6,206,695]). Cost to achieve one additional patient with MSE was $4,761,649 [$2,859,671, $6,663,626] higher for ECU compared with EFG. Conclusions Evidence indicates more favorable treatment benefit and economic value for EFG with fewer NNT and lower cost required to achieve improved outcomes compared to other treatments.

Pharmacological Management of Myasthenia Gravis: A Century of Expert Opinions in Cecil Textbook of Medicine.

Advances in drug therapy for myasthenia gravis have had a significant impact on the quality of life and work potential of a substantial majority of affected persons and has contributed to a remarkable decrease in the frequency and severity of complications, hospitalizations, and mortality. What are the milestones of the changes in the expert approach to the pharmacological management of myasthenia in the past century? To determine the changes in the experts' approach to the management of myasthenia gravis, as presented in a widely used textbook in the United States. The chapters presenting the management of myasthenia gravis in the 26 editions of Cecil Textbook of Medicine published from 1927 to 2020. Adequate feeding, absolute rest in bed, and "tonics" were the only interventions recommended for the care of patients with myasthenia gravis in 1927. Ephedrine and glycine were used in the early 1930s. Treatment with the anticholinesterases physostigmine and neostigmine was recommended in 1937, 3 years after Mary Walker discovered it in the United Kingdom. Immunosuppressant pharmacological interventions with prednisone and azathioprine have been considered the standard since 1975, and intravenous immune globulin was added to usual care in 1996. The newer immunosuppressant drugs mycophenolate, cyclosporine, and tacrolimus have expanded the arsenal since 2008, and the monoclonal antibodies rituximab and eculizumab have been mentioned in the textbooks published in 2012-2020. The first randomized clinical trial of drug therapy for myasthenia gravis was published in 1987. The pharmacological management of myasthenia gravis was revolutionized by the epiphany of an astute clinician in the 1930s. Immunosuppressant treatment was a logical step once the autoimmune nature of the condition was established. The major therapeutic advances highlight the values of empiricism and persistent attention to detail in treating relatively rare chronic disorders.

Targeted molecular therapy for myasthenia gravis

Targeted molecular therapy for myasthenia gravis

Chronic low-dose intravenous immunoglobulins as steroid-sparing therapy in myasthenia gravis

Intravenous immunoglobulin (IVIg) has been proven beneficial in myasthenic crisis, but their role as maintenance therapy is unclear. The aim of this study was to determine if maintenance therapy with low-dose IVIg improves clinical outcome and may be used as a steroid-sparing agent in myasthenia gravis (MG). We retrospectively reviewed charts of all MG patients treated with IVIg from January 2006 to December 2019. Long-term treatment response to IVIg was assessed by improvement in the Myasthenia Gravis Foundation of America (MGFA) clinical classification scale as primary end point, as well as the ability to reduce the time-weighted average required dose of prednisone as secondary end-point, in a follow-up period of 36months. 109 patients were treated with IVIg. The mean follow-up time was 34.03 ± 5.5months. Sixty-seven patients (61.4%) responded to therapy with at least one-point improvement of the MGFA scale. There was no statistical difference in demographic and clinical characteristics between IVIg responders and non-responders. The mean prednisone dose decreased significantly from 33.1 ± 14.5mg at baseline to 7.2 ± 7.8mg after 36months of IVIg treatment (P < 0.0001), with the greatest effect after 6months (33.1 ± 14.5mg Vs. 17.9 ± 11.7mg; P < 0.0001). In the follow-up period of 36months, most patients (92.5%) remained clinically and pharmacologically stable under chronic IVIg treatment. This retrospective study demonstrates that chronic low-dose IVIg treatment in patients with MG improves clinical outcomes and has a prolonged and significant steroid-sparing effect over a period of 3years.

Successful treatment of Mycobacterium chelonae skin infection in a patient on long-term immunosuppressive therapy for myasthenia gravis

Successful treatment of Mycobacterium chelonae skin infection in a patient on long-term immunosuppressive therapy for myasthenia gravis

Immune checkpoint inhibitors for progressive multifocal leukoencephalopathy: a new gold standard?

Progressive multifocal leukoencephalopathy (PML) is a very rare and opportunistic encephalitis caused by JC polyomavirus that is linked to profound immunosuppression and is usually fatal unless immune function can be restored. Immune checkpoint inhibitors (ICI) are monoclonal antibodies (mAbs) that block either CTLA-4 or PD-1 inhibitor receptors, thus enhancing antiviral T-cell activity. Successful treatment of PML by ICI has recently generated some enthusiasm in case reports/small series of patients. However, the initial enthusiasm was mitigated by some individual case reports that did not show any benefit. More data are thus warranted about efficacy of immune checkpoint inhibitors in the specific context of PML. We report here the outcomes of six PML patients treated by ICI between 2017 and 2019. Underlying causes of immunosuppression consisted in hematologic malignancies (n = 4), primary immune deficiency (n = 1) and use of immunosuppressive therapies for myasthenia gravis (n = 1). Three patients were alive with a mean follow-up of 21months (14-33) after first ICI infusion, including one patient with frank clinical response, one with stabilization, and one with initial worsening and further stabilization of PML. The three other patients rapidly died from PML. Our data suggest that ICI may be effective for PML treatment but were less impressive than the ones previously reported. Larger studies are thus warranted to confirm this efficacy and to identify the predictive factors of response.

Update in immunosuppressive therapy of myasthenia gravis

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction. Immunosuppressive treatments are part of the therapeutic armamentarium in MG. Long-term systemic steroid administration carry considerable risks and adverse events. Consequently, steroid-free immunosuppressive therapy is necessary to reduce the dose or discontinue steroids. First immunosuppressive drug trials in MG, were performed in the mid-60s, using standard and nonspecific immunosuppression. Since then, only few randomized controlled clinical trials were developed in MG, showing inconclusive results; and drug efficacy was assessed in terms of its steroid-sparing capacity and the ability to reduce myasthenic signs and symptoms. Treatment strategy in MG is quite challenging, mainly due to the disease heterogeneity in terms of clinical presentation, immunopathogenesis and drug response. To solve this dilemma, emerging treatment are based on biological drugs and use new targets of the immune pathway.

Progress in the therapy of myasthenia gravis: getting closer to effective targeted immunotherapies

To provide an update on immunomodulating and immunosuppressive therapies in myasthenia gravis and highlight newly approved, or pending approval, therapies with new biologics. Preoperative IVIg is not needed to prevent myasthenic crisis in stable myasthenia gravis patients scheduled for surgery under general anesthesia, based on controlled data. Rituximab, if initiated early in new-onset myasthenia gravis, can lead to faster and more sustained remission even without immunotherapies in 35% of patients at 2 years. Biomarkers determining the timing for follow-up infusions in Rituximab-responding AChR-positive patients are discussed. Most patients with MuSK-positive myasthenia gravis treated with Rituximab have sustained long-term remission with persistent reduction of IgG4 anti-MuSK antibodies. Eculizumb in the extension REGAIN study showed sustained long-term pharmacological remissions and reduced exacerbations. Three new biologic agents showed promising results in phase-II controlled myasthenia gravis trials: Zilucoplan, a subcutaneous macrocyclic peptide inhibiting complement C5; Efgartigimod, an IgG1-derived Fc fragment binding to neonatal FcRn receptor; and Rozanolixizumab, a high-affinity anti-FcRn monoclonal antibody. Finally, the safety of ongoing myasthenia gravis immunotherapies during COVID19 pandemic is discussed. New biologics against B cells, complement and FcRn receptor, are bringing us closer to successful targeted immunotherapies in the chronic management of myasthenia gravis promising an exciting future for antibody-mediated neurological diseases.

Update on immune-mediated therapies for myasthenia gravis.

With the exception of thymectomy, immune modulatory treatment strategies and clinical trials in myasthenia gravis over the past 50 y were mainly borrowed from experience in other nonneurologic autoimmune disorders. The current experimental therapy paradigm has significantly changed such that treatments directed against the pathological mechanisms specific to myasthenia gravis are being tested, in some cases as the initial disease indication. Key advances have been made in three areas: (i) the expanded role and long-term benefits of thymectomy, (ii) complement inhibition to prevent antibody-mediated postsynaptic membrane damage, and (iii) neonatal Fc receptor (FcRn) inhibition as in vivo apheresis, removing pathogenic antibodies. Herein, we discuss these advances and the potential for these newer therapies to significantly influence the current treatment paradigms. While these therapies provide exciting new options with rapid efficacy, there are anticipated challenges to their use, especially in terms of a dramatic increase in cost of care for some patients with myasthenia gravis.

New Approaches to Targeting B Cells for Myasthenia Gravis Therapy.

Current therapies for myasthenia gravis (MG) are limited, and many investigations have recently focused on target-specific therapies. B cell-targeting monoclonal antibody (mAb) therapies for MG are increasingly attractive due to their specificity and efficacy. The targeted B cell biomarkers are mainly the cluster of differentiation (CD) proteins that mediate maturation, differentiation, or survival of pathogenic B cells. Additional B cell-directed therapies include non-specific peptide inhibitors that preferentially target specific B cell subsets. The primary goals of such therapies are to intercept autoantibodies and prevent the generation of an inflammatory response that contributes to the pathogenesis of MG. Treatment of patients with MG using B cell-directed mAbs, antibody fragments, or selective inhibitors have exhibited moderate to high efficacy in early studies, and some of these therapies appear to be highly promising for further drug development. Numerous other biologics targeting various B cell surface molecules have been approved for the treatment of other conditions or are either in clinical trials or preclinical development stages. These approaches remain to be tested in patients with MG or animal models of the disease. This review article provides an overview of B cell-targeted treatments for MG, including those already available and those still in preclinical and clinical development. We also discuss the potential benefits as well as the shortcomings of these approaches to development of new therapies for MG and future directions in the field.