Clinical trials for myasthenia gravis: a historical perspective

Kaminski, Henry J.; Alnosair, Eman; Algahtani, Rami

doi:10.1111/nyas.13545

Cited by 5 publications

(4 citation statements)

References 58 publications

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“…For MG, treatment response has been assessed from various perspectives. Clinical outcome measures for MG have evolved from simple physician-centric determination of improvement to standardized strength assessment performed by trained individuals to patient reported outcomes ( 24 , 25 ). Primary outcome measures for randomized trials in MG have included the total dose of GC over time, the quantitative MG Score, and the MG-Activities of Daily Living with the last of which has become the primary measure recommended by the FDA for drug approval.…”

Section: The Challenge Of Defining Treatment Responsementioning

confidence: 99%

Corticosteroid Treatment-Resistance in Myasthenia Gravis

Kaminski

Denk

2022

Front. Neurol.

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Chronic, high-dose, oral prednisone has been the mainstay of myasthenia gravis treatment for decades and has proven to be highly beneficial in many, toxic in some way to all, and not effective in a significant minority. No patient characteristics or biomarkers are predictive of treatment response leading to many patients suffering adverse effects with no benefit. Presently, measurements of treatment response, whether taken from clinician or patient perspective, are appreciated to be limited by lack of good correlation, which then complicates correlation to biological measures. Treatment response may be limited because disease mechanisms are not influenced by corticosteroids, limits on dosage because of adverse effects, or individual differences in corticosteroids. This review evaluates potential mechanisms that underlie lack of response to glucocorticoids in patients with myasthenia gravis.

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Section: The Challenge Of Defining Treatment Responsementioning

confidence: 99%

Corticosteroid Treatment-Resistance in Myasthenia Gravis

Kaminski

Denk

2022

Front. Neurol.

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“…A discussion of clinical trials in MG cannot be provided in the absence of some understanding of clinical outcome measures. For a thorough discussion of outcome measures and trial design please see Kaminski and Kusner [3] and Kaminski et al [15]. Common to all areas in medicine, the rigor of trial performance for MG has increased over the last two decades.…”

Section: Clinical Trials In Myasthenia Gravismentioning

confidence: 99%

Monoclonal Antibody-Based Therapies for Myasthenia Gravis

et al. 2020

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Myasthenia gravis (MG) is an autoimmune, neuromuscular disorder that produces disabling weakness through a compromise of neuromuscular transmission. The disease fulfills strict criteria of an antibody-mediated disease. Close to 90% of patients have antibodies directed towards the nicotinic acetylcholine receptor (AChR) on the post-synaptic surface of skeletal muscle and another 5% to the muscle-specific kinase, which is involved in concentrating the AChR to the muscle surface of the neuromuscular junction. Conventional treatments of intravenous immunoglobulin and plasma exchange reduce autoantibody levels to produce their therapeutic effect, while prednisone and immunosuppressives do so by moderating autoantibody production. None of these treatments were specifically developed for MG and have a range of adverse effects. The extensive advances in monoclonal antibody technology allowing specific modulation of biological pathways has led to a tremendous increase in the potential treatment options. For MG, monoclonal antibody therapeutics target the effector mechanism of complement inhibition and the reduction of antibody levels by FcRn inhibition. Antibodies directed against CD20 and signaling pathways, which support lymphocyte activity, have been used to reduce autoantibody production. Thus far, only eculizumab, an antibody against C5, has reached the clinic. We review the present status of monoclonal antibody-based treatments for MG that have entered human testing and offer the promise to transform treatment of MG.

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“…Azathioprine (AZA) was the first immunosuppressive used for MG either alone or as an agent to limit corticosteroid use [108]. A single, randomized trial indicated that efficacy takes 12–18 months as assessed by a reduction of corticosteroid requirement [109].…”

Section: Standard Treatmentsmentioning

confidence: 99%

“…A tremendous amount of late stage preclinical work and clinical trials at various stages is being done for MG. This is surprising given the slow pace of therapeutic development in the late 1900’s and first decade of this century [108]. We suspect the reasons for this are a combination of its relatively well-defined pathophysiology, advances in understanding of autoimmunity, and financial advantages that exist for drug development for rare diseases.…”

Section: Five-year Viewmentioning

confidence: 99%

Advances in autoimmune myasthenia gravis management

Wang

Breskovska

Gandhy

et al. 2018

Expert Review of Neurotherapeutics

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Myasthenia gravis (MG) is an autoimmune neuromuscular disorder with no cure and conventional treatments limited by significant adverse effects and variable benefit. In the last decade, therapeutic development has expanded based on improved understanding of autoimmunity and financial incentives for drug development in rare disease. Clinical subtypes exist based on age, gender, thymic pathology, autoantibody profile, and other poorly defined factors, such as genetics, complicate development of specific therapies. Areas covered: Clinical presentation and pathology vary considerably among patients with some having weakness limited to the ocular muscles and others having profound generalized weakness leading to respiratory insufficiency. MG is an antibody-mediated disorder dependent on autoreactive B cells which require T-cell support. Treatments focus on elimination of circulating autoantibodies or inhibition of effector mechanisms by a broad spectrum of approaches from plasmapheresis to B-cell elimination to complement inhibition. Expert commentary: Standard therapies and those under development are disease modifying and not curative. As a rare disease, clinical trials are challenged in patient recruitment. The great interest in development of treatments specific for MG is welcome, but decisions will need to be made to focus on those that offer significant benefits to patients.

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Clinical trials for myasthenia gravis: a historical perspective

Cited by 5 publications

References 58 publications

Corticosteroid Treatment-Resistance in Myasthenia Gravis

Corticosteroid Treatment-Resistance in Myasthenia Gravis

Monoclonal Antibody-Based Therapies for Myasthenia Gravis

Advances in autoimmune myasthenia gravis management

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