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 approximately 60,000 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).

Immune-Mediated Necrotizing Myopathy (IMNM)

Immune-mediated necrotizing myopathy, or IMNM, is an autoimmune myopathy characterized by skeletal muscle necrosis, severe proximal limb weakness, and elevated creatine kinase (CK) levels. IMNM is categorized into two subtypes defined by the presence of distinct autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) or signal recognition particle (SRP). In IMNM, these autoantibodies drive complement-mediated necrosis of muscle fibers, resulting in severe, progressive, and debilitating proximal muscle weakness. IMNM affects more than 15,000 patients in the United States, European Union, and Japan.

There are currently no approved therapies for the treatment of IMNM. Typical treatments include steroids, immunosuppressive therapies (ISTs), rituximab, and intravenous immunoglobulin therapy.

As is the case with generalized myasthenia gravis (gMG), muscle fiber necrosis in IMNM may be secondary to an antibody-dependent complement attack. Muscle biopsies from patients with IMNM demonstrate strong C5b-9 membrane attack complex (MAC) deposition as compared with other inflammatory myopathies.

Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis, or ALS, is the most prevalent adult-onset progressive motor neuron disease, affecting approximately 30,000 people in the U.S. and an estimated 500,000 people worldwide. ALS causes the progressive degeneration of motor neurons, resulting in progressive muscle weakness and atrophy that eventually leads to partial or total paralysis. Therapeutic options for ALS are currently limited to two approved products.

Robust experimental data supports a role for complement activation and deposition in both the peripheral and central nervous systems in ALS.