Cemdisiran

Nearly 90 % of generalized myasthenia gravis (MG) patients have IgG1 or IgG3 antibodies against the acetylcholine receptor (AChR). Acetylcholine receptor antibodies induce neuromuscular transmission defect by various potential mechanisms including internalisation of AChR, receptor blockade and by activation of the classical complement pathway. Membrane attack complex (MAC) which is the final end product of complement activation leads to architectural destruction of the neuromuscular junction (NMJ). Several experimental models (EAMG) have shown evidence for complement in the pathogenesis of MG, with demonstration of prevention or reversal of the disease using complement inhibitory therapies. Various molecules that target the complement system have been developed to treat myasthenia gravis. Most of the currently studied molecules inhibit complement protein 5 (C5), which prevents 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. Many of these have also been shown to have long term benefit in different sub-groups of patients with MG. Given the risk of Gram-negative septicaemia (especially by meningococcus), patients would need vaccination prior to initiation of treatment and in some countries prophylactic antibiotics during treatment is recommended, although no major safety signatures have been noted in the studies so far. Future studies identifying specific biomarkers might help clinicians select the most appropriate patients who are more likely to respond to complement inhibitory therapies.

Complement inhibitors are the mainstay of paroxysmal nocturnal hemoglobinuria (PNH) treatment. The anti‐C5 monoclonal antibody eculizumab was the first treatment to improve hemolysis, thrombotic risk, and survival in PNH although at the price of a life‐long intravenous fortnightly drug. Additionally, suboptimal response may occur in up to 2/3 of patients with persistent anemia due to incomplete control of intravascular hemolysis, development of upstream C3‐mediated extravascular hemolysis (EVH), or concomitant bone marrow failure. Ravulizumab, a longer half‐life anti‐C5 developed from eculizumab, administered every 8 weeks, improved patient convenience, and reduced pharmacokinetic breakthrough hemolysis (BTH) by establishing more stable anti‐C5 concentrations. More recently, several other anti‐C5 compounds (crovalimab, pozelimab, tesidolumab, cemdisiran, zilucoplan, and coversin) are on study in clinical trials. Upstream inhibition of complement cascade was also explored with the anti‐C3 pegcetacoplan, and with the alternative pathway inhibitors iptacopan (anti‐factor B) and danicopan (anti‐factor D). These drugs efficiently target EVH and are able to improve anemia and transfusion need in suboptimal responders to anti‐C5. The route and schedule of administration (twice weekly subcutaneously for pegcetacoplan and twice or thrice oral daily dosing for iptacopan and danicopan, respectively) are very convenient but pose novel issues regarding adherence. Additionally, both anti‐C5 and upstream inhibitors do not resolve the unmet need of pharmacodynamic BTH events due to complement amplifying conditions such as infections, traumas, and surgery. In this review, we will recapitulate PNH physiopathology, clinical presentation, and diagnosis and describe available and developing drugs that will lead to a precision medicine approach for this rare though heterogenous disease.