Generalized Myasthenia Gravis (gMG)

Myasthenia gravis, or MG, is a rare, complement-mediated, autoimmune disease that causes weakness in the skeletal muscles. Patients with MG present with muscle weakness that characteristically becomes increasingly severe with repeated use and recovers with rest. Muscle weakness can be localized to specific muscles, such as those responsible for eye movements, but often progresses to affect a broader range, including head, limb, and respiratory muscles. This is often described as the generalized, or severe, form of the disease. Generalized MG is estimated to affect 30,000 to 50,000 individuals in the United States.

Generalized MG symptoms may become life-threatening when muscle weakness involves the diaphragm and intercostal muscles in the chest wall that are responsible for breathing. The most severe complication of gMG, known as myasthenic crisis, requires hospitalization, intubation, and mechanical ventilation.

There is currently no known cure for MG, and typical treatments include corticosteroids, immunosuppressants, or cholinesterase inhibitors.

MG is characterized by the production of autoantibodies that interfere with the normal transmission of electrical signals from nerves to muscles. The most common target of autoantibodies in MG is the acetylcholine receptor, or AChR, which is located at the site at which a motor neuron transmits signals to a skeletal muscle fiber, known as the neuromuscular junction. Binding of anti-AChR autoantibodies to the AChR results in activation of the classical complement cascade and assembly of the membrane attack complex (MAC). Influx of calcium through the MAC causes local damage to the postsynaptic membrane, local inflammation, diminished response to acetylcholine, and reduced responsiveness of the muscle.

Inhibition of terminal complement activity at the level of C5 or C6 has been demonstrated to prevent development of disease pathology in experimental animal models of MG. Furthermore, a therapeutic monoclonal antibody to C5 has been clinically validated in a rare segment of patients with refractory generalized myasthenia gravis (i.e. generalized MG in which patients have previously failed at least two immunosuppressant therapies and are considered “refractory” to treatment).

Ra Pharma is conducting a Phase 2 study to evaluate the safety and efficacy of RA101495 in patients with gMG. To learn more about this study, please click here, email or call 617-401-4060.