Emerging drugs for the treatment of myasthenia gravis

Menon, Deepak; Pincheira, Alejandra Urra; Bril, Vera

doi:10.1080/14728214.2021.1952982

Cited by 12 publications

(12 citation statements)

References 90 publications

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“…The benign safety profiles of these novel agents have supported their use. Despite these advances, many challenging questions remain such as the long-term safety, efficacy in seronegative MG, potential use as first-line agents in treatment-naïve patients and the method and timing of switching from one agent to another [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

“…These considerations coupled with the decidedly high cost of novel agents are likely to prevent access for many patients, especially those in resource-limited countries. Factors such as patent protection, orphan drug status, relatively small numbers of patients and the high cost of research and development all play a role in escalating prices that are likely to remain high until biosimilar agents are available [ 13 ]. Hence, despite many positive advances, it is probable that conventional agents will remain in use in many parts of the world.…”

Section: Discussionmentioning

confidence: 99%

“…Despite all these instruments, a single gold standard trial design for MG is still not feasible. Furthermore, current trial designs fail to address multiple relevant questions concerning initiation and discontinuation of novel agents, inter-class and intra-class switching, synergistic or antagonistic actions and application in vulnerable populations such as pregnant women and the paediatric age group [ 13 ]. Other considerations are cost effectiveness of novel therapies, access to care and equity of care.…”

Section: Clinical Trial Considerations In Myasthenia Gravismentioning

confidence: 99%

“…The treatment of MG is firmly based on immunosuppressive or immunomodulatory mechanisms, which range in the case of conventional agents from having a wide and non-targeted action to recent highly selective target-specific biologicals [ 12 ]. The latter have several potential advantages in offering minimal adverse effects, rapid response and patient- and disease-specific personalized treatment [ 13 ]. In this review, we elaborate on the various pharmacotherapeutic agents, with special emphasis on novel and investigational biological agents employed in the treatment of generalized MG, and examine their mechanisms of action and the existing efficacy, safety and tolerability data.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacotherapy of Generalized Myasthenia Gravis with Special Emphasis on Newer Biologicals

Menon

Bril

2022

Drugs

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Myasthenia gravis (MG) is a chronic, fluctuating, antibody-mediated autoimmune disorder directed against the post-synaptic neuromuscular junctions of skeletal muscles, resulting in a wide spectrum of manifestations ranging from mild to potentially fatal. Given its unique natural course, designing an ideal trial design for MG has been wrought with difficulties and evidence in favour of several of the conventional agents is weak as per current standards. Despite this, acetylcholinesterases and corticosteroids have remained the cornerstones of treatment for several decades with intravenous immunoglobulins (IVIG) and therapeutic plasma exchange (PLEX) offering rapid treatment response, especially in crises. However, the treatment of MG entails long-term immunosuppression and conventional agents are viable options but take longer to act and have a number of class-specific adverse effects. Advances in immunology, translational medicine and drug development have seen the emergence of several newer biological agents which offer selective, target-specific immunotherapy with fewer side effects and rapid onset of action. Eculizumab is one of the newer agents that belong to the class of complement inhibitors and has been approved for the treatment of refractory general MG. Zilucoplan and ravulizumab are other agents in this group in clinical trials. Neisseria meningitis is a concern with all complement inhibitors, mandating vaccination. Neonatal Fc receptor (FcRn) inhibitors prevent immunoglobulin recycling and cause rapid reduction in antibody levels. Efgartigimod is an FcRn inhibitor recently approved for MG treatment, and rozanolixizumab, nipocalimab and batoclimab are other agents in clinical trial development. Although lacking high quality evidence from randomized clinical trials, clinical experience with the use of anti-CD20 rituximab has led to its use in refractory MG. Among novel targets, interleukin 6 (IL6) inhibitors such as satralizumab are promising and currently undergoing evaluation. Cutting-edge therapies include genetically modifying T cells to recognise chimeric antigen receptors (CAR) and chimeric autoantibody receptors (CAAR). These may offer sustained and long-term remissions, but are still in very early stages of evaluation. Hematopoietic stem cell transplantation (HSCT) allows immune resetting and offers sustained remission, but the induction regimens often involve serious systemic toxicity. While MG treatment is moving beyond conventional agents towards target-specific biologicals, lack of knowledge as to the initiation, maintenance, switching, tapering and long-term safety profile necessitates further research. These concerns and the high financial burden of novel agents may hamper widespread clinical use in the near future.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Clinical Trial Considerations In Myasthenia Gravismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacotherapy of Generalized Myasthenia Gravis with Special Emphasis on Newer Biologicals

Menon

Bril

2022

Drugs

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“…The high prices are driven by the cost of research and development, the orphan drug status, patent protection, and the small number of patients for whom they are appropriate. 26 A recent publication revealed that newer-to-market medications are used by a minority of neurological patients, especially in MG, though this study was only conducted through 2019, when solely eculizumab was on the market. 27 Clinical vignette 2 At this point, following a discussion with the patient, we initiated ravulizumab.…”

Section: Commentsmentioning

confidence: 99%

How should newer therapeutic agents be incorporated into the treatment of patients with myasthenia gravis?

Gwathmey,

Ding,

Hehir

et al. 2024

Muscle and Nerve

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Generalized myasthenia gravis (gMG) is a postsynaptic neuromuscular junction disorder that results in fatigable muscle weakness. The traditional treatment approach includes the use of acetylcholinesterase inhibitors, corticosteroids, and steroid‐sparing immunosuppressant therapies (ISTs) for chronic management, whereas exacerbations and crises are managed with intravenous immunoglobulin (IVIg) and plasma exchange (PLEX). Over the past 6 years, four new therapeutic agents with novel immunological mechanisms of action—complement and neonatal Fc receptor (FcRn) inhibition—were approved as a result of clinically significant improvement in gMG symptoms of those treated with these newer agents in Phase 3 clinical trials. At present, it is unclear when and in whom to initiate these therapeutic agents and how to integrate them into the current treatment paradigm. When selecting a newer therapeutic agent, we use a simple equation: Value = Clinical Improvement/(Cost + Side Effects + Treatment Burden), which guides our decision‐making. We consider using these novel therapeutic agents in two specific clinical situations. Firstly, the newer agents are fast‐acting, suggesting they can be used in clinically unstable patients as “bridge therapy,” and secondly, they provide additional options for those patients considered treatment‐refractory. There are downsides, however, including treatment cost, unique side effect profiles, and intravenous and subcutaneous drug administration (though for some, this may be an advantage). As additional drugs enter the marketplace with unique mechanisms of action, routes of administration, and dosing schedules, the placement of the novel therapeutic agents in the gMG treatment algorithm will likely evolve.

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Integrated Applied Clinical Pharmacology in the Advancement of Rare and Ultra‐Rare Disease Therapeutics

Ryder

2024

Clin Pharma and Therapeutics

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The introduction of safe and effective rare/ultra‐rare disease treatments is a focus of many biotherapeutic enterprises. Despite this increased activity, a significant unmet need remains, and the responsibility to meet this need is augmented by enhanced genomic, biologic, medical, analytical, and informatic tools. It is recognized that the development of an effective and safe rare/ultra‐rare disease therapeutic faces a number of challenges with an important role noted for clinical pharmacology. Clinical pharmacology is foundationally an integrative discipline which must be embedded in and is interdependent upon understanding the pathogenic biology, clinical presentation, disease progression, and end‐point assessment of the disease under study. This manuscript presents an overview and two case examples of this integrative approach, the development of C5‐targeted therapeutics for the treatment of generalized myasthenia gravis and asfotase alpha for the treatment of hypophosphatasia. The two presented case examples show the usefulness of understanding the biological drivers and clinical course of a rare disease, having relevant animal models, procuring informative natural history data, importing assessment tools from relevant alternative areas, and using integrated applied clinical pharmacology to inform target engagement, dose, and the cascade of pharmacodynamic and clinical effects that follow. Learnings from these programs include the importance of assuring cross‐validation of assays throughout a development program and continued commitment to understanding the relationship among the array of Pd end points and clinical outcomes. Using an integrative approach, substantive work remains to be done to meet the unmet needs of patients with rare/ultra‐rare disease.

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Emerging drugs for the treatment of myasthenia gravis

Cited by 12 publications

References 90 publications

Pharmacotherapy of Generalized Myasthenia Gravis with Special Emphasis on Newer Biologicals

Pharmacotherapy of Generalized Myasthenia Gravis with Special Emphasis on Newer Biologicals

How should newer therapeutic agents be incorporated into the treatment of patients with myasthenia gravis?

Integrated Applied Clinical Pharmacology in the Advancement of Rare and Ultra‐Rare Disease Therapeutics

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