Myasthenia Gravis Is the Disease. FcRn Is the Target

Myasthenia gravis is a rare, B cell-mediated autoimmune disease that manifests as weakened voluntary muscles, particularly

those of the eyes, face, throat, limbs and diaphragm. “Myasthenia” means “muscle weakness” in Greek, and “gravis” is “severe” in Latin. The condition affects approximately 14 to 20 of every 100,000 people in the United States. Although myasthenia gravis can occur at any age, it is more common among women younger than 40 and men older than 60.

Symptoms can range from mild to debilitating, including drooping eyelids, blurred or double vision and impaired speech. Some people may have more serious symptoms, such as difficulty swallowing, shortness of breath or weakness of the limbs, hands, fingers and neck. Approximately 1 in 5 people living with the disease experiences life-threatening symptoms, such as swallowing problems that may lead to choking and breathing difficulties requiring mechanical ventilation (myasthenic crisis).

The pathology of the condition stems from a disruption in the signaling between nerve endings and muscle fibers in the neuromuscular junction caused by autoantibodies directed against the acetylcholine receptor (AChR), muscle-specific tyrosine kinase (MuSK) or low-density lipoprotein-related protein 4 (LRP4). Approximately 85% of people with myasthenia gravis have autoantibodies against AChR (AChR+ myasthenia gravis). Up to 10% of myasthenia gravis cases are MuSK antibody positive (MuSK+ myasthenia gravis). Another 5% are LRP4 antibody positive. These differences in antibody types come into play when determining treatment choice.

Standard treatments for myasthenia gravis include the acetylcholinesterase inhibitor pyridostigmine, corticosteroids, and immunosuppressants, such as azathioprine, which is sold under the brand names Imuran and Azasan, and mycophenolate mofetil, sold under the brand names CellCept, Myfortic and Myhibbin.

In 2017, the landscape for managing myasthenia gravis changed dramatically when the FDA approved Alexion’s Soliris (eculizumab), the first medication specifically indicated to treat myasthenia gravis. Four more biologics were approved from 2021 through 2023, including UCB’s Rys- tiggo (rozanolixizumab), the only agent approved to treat both AChR+ and MuSk+ myasthenia gravis.

Symptoms of myasthenia gravis can range from mild to debilitating, including drooping eyelids, blurred or double vision, impaired speech, difficulty swallowing, shortness of breath and more.

Most currently available myasthenia gravis treatments are complement C5 inhibitors that target antibodies associated with AChR+ myasthenia gravis. Rystiggo is a neonatal fragment crystallizable receptor (FcRn) blocker that helps break down immunoglobulin G, the protein responsible for releasing pathogenic antibodies associated with AChR+ and MuSK+ myasthenia gravis.

Several agents targeting FcRn are in late stages of development. They could potentially address the dearth of treatments available for the MuSK+ form of myasthenia gravis.

Nipocalimab

In 2020, Johnson & Johnson secured nipocalimab in a $6.5 billion acquisition of Momenta Pharmaceuticals. The investigational FcRn blocker is being developed for the treatment of myasthenia gravis in patients with antibodies against AChR, MuSK or LRP4.

The company recently announced positive results from the Vivacity-MG3 phase 3 trial measuring sustained efficacy and safety of nipocalimab in the treatment of AChR+, MuSK+ or LRP4+ myasthenia gravis. Participants taking nipocalimab plus standard of care showed a significantly greater reduction in the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale versus those who received placebo plus standard of care. Based on the trial results, the company filed for FDA approval and was granted priority review of the application in January 2025.

Batoclimab

New York-based Immunovant is developing batoclimab, a fully human anti-FcRn monoclonal antibody, for the potential treatment of AChR+, MuSK+ or LRP4+ myasthenia gravis. The investigational agent is in the FLEX phase 3 trial, which is assessing its safety and efficacy as induction and maintenance therapy in adults with myasthenia gravis.

The trial is designed to test an induction-maintenance mode of treatment in which a high dose is given initially to reduce disease symptoms and prevent myasthenic crisis, followed by a period of lower dosing to maintain remission. Batoclimab is being developed as a low-volume subcutaneous injection with the potential for self-administration at home. The study is anticipated to be completed in April 2025, and the company plans to file for FDA approval based on the results from this pivotal trial.

Uplizna

Uplizna (inebilizumab), marketed by Amgen, is an anti-CD19 monoclonal antibody approved by the FDA to treat neuromyelitis optica spectrum disorder (NMOSD), an autoimmune disease that typically affects the optic nerve and spinal cord. Patients receiving Uplizna for NMOSD are given two initial doses two weeks apart and then receive an infusion every six months.

In October 2024, the company announced positive results from the phase 3 MINT trial investigating the safety and efficacy of Uplizna for the treatment of adults with AChR+ or MuSK+ myasthenia gravis. The trial met the primary end points of a statistically significant change from baseline in MG-ADL score compared with placebo (-4.2 versus -2.2) at 26 weeks.

The study results were presented at the 2025 Muscular Dystrophy Association Clinical and Scientific Conference in March. Based on these findings, Amgen plans to file for approval of Uplizna to treat myasthenia gravis in the U.S. and other key markets.

Alternative mechanisms

FcRn blockers are the leading candidates and treatments available for people with MuSK+ myasthenia gravis. However, ongoing research is exploring other mechanisms to treat this version of the disease.

Chimeric antigen receptor T cell (CAR-T cell) therapy is an emerging treatment currently approved to treat several types of blood cancers, such as multiple myeloma and various types of lymphomas and leukemia. With CAR-T cell therapy, T cells are collected from a donor’s (allogeneic) or patient’s (autologous) blood and reengineered to express CARs on their surfaces that recognize and attach to CD19 or B cell maturation antigens on cancer cells. The modified T cells are infused back into the patient, where they target and kill malignant cells.

Cartesian Therapeutics, based in Gaithersburg, Maryland, is developing Descartes-08, an autologous CAR-T cell therapy directed against B cell maturation antigen. The investigational treatment is currently in a phase 2 trial of patients with any type of generalized myasthenia gravis, including the MuSK+ form. The trial has an expected completion date of March 2026.

Rituximab, which is sold as Rituxan and as several biosimilars (Riabni, Ruxience, and Truxima), is a CD20-directed antibody approved by the FDA to treat non-Hodgkin lymphoma, chronic lymphocytic leukemia, and various autoimmune conditions. With a mechanism that depletes circulating B cells, several studies have found rituximab effective in treating MuSK+ myasthenia gravis. Although clinical guidelines now recommend rituximab as early treatment for patients with MuSK+ myasthenia gravis, its use remains off-label.