Complement inhibition in Myasthenia – from basics to RCT data

Myasthenia gravis (MG) is the prototypic autoimmune neurological disorder causing fatiguable muscle weakness either limited to the ocular muscles or becoming generalised involving the limb and bulbar muscles. Nine out of 10 generalised MG patients have IgG1 or IgG3 antibodies against the acetylcholine receptor (AChR). AChR antibodies cause neuromuscular weakness by internalisation of AChR, receptor blockade and by activating the complement pathway. Complement activation causes formation of the membrane attack complex (MAC) leading to degradation of the neuromuscular junction (NMJ). Several animal models have confirmed the role of complement in the pathogenesis of MG, with the experimental models (EAMG) often needing complement inhibitory therapies to prevent or reverse the disease. Various molecules that target the complement system have now been developed to treat myasthenia gravis. The vast majority of the currently studied molecules target the C5 protein, thereby preventing the formation of MAC and subsequent NMJ destruction. The currently studied anti-complement therapies for MG include Eculizumab, Zilucoplan, Ravulizumab, Pozelimab, Cemdisiran, Gefurilimab, Danicopan and few others in the pipeline.  Eculizumab has been shown in clinical trials to be effective in the treatment of refractory MG, but further sub-group analysis and real-life experience have shown that this can be beneficial in various patients including those receiving regular IVIG, plasma exchange or Rituximab. It was approved for use by FDA in Oct 2017. Ravulizumab is a long-acting monoclonal antibody which has similar mechanism of action to Eculizumab and was approved for use in MG by FDA in April 2022. Zilucoplan is a macrocyclic peptide which binds to C5 and C5b thus preventing terminal complement activation, which can be given subcutaneously (FDA new drug application accepted in Nov 2022). Many of these have also been shown to have long term benefit in different sub-groups of patients with MG. Patients would need to be vaccinated against Neisseria meningitidis because of the risk of Gram-negative septicaemia, although no major safety signatures have been noted in the studies so far. Future studies may be able to identify specific biomarkers which might aid in selecting the most appropriate patients who might respond to these therapies.