Prevention of Anti-HMGCR Immune-Mediated Necrotising Myopathy by C5 Complement Inhibition in a Humanised Mouse Model.

: immune-mediated necrotising myopathy (IMNM) is associated with pathogenic anti-signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies, at least partly through activation of the classical pathway of the complement. We evaluated zilucoplan, an investigational drug, and a macrocyclic peptide inhibitor of complement component 5 (C5), in humanized mouse models of IMNM. : purified immunoglobulin G (IgG) from an anti-HMGCR IMNM patient was co-injected intraperitoneally with human complement in C57BL/6, C5-deficient B10 (C5) and Rag2 deficient (Rag2) mice. Zilucoplan was administered subcutaneously in a preventive or interventional paradigm, either injected daily throughout the duration of the experiment in C57BL/6 and C5 mice or 8 days after disease induction in Rag2 mice. : prophylactic administration of zilucoplan prevented muscle strength loss in C5 mice (anti-HMGCR vs. anti-HMGCR + zilucoplan: = 0.0289; control vs. anti-HMGCR + zilucoplan: = 0.4634) and wild-type C57BL/6 (anti-HMGCR vs. anti-HMGCR + zilucoplan: = 0.0002; control vs. anti-HMGCR + zilucoplan: = 0.0939) with corresponding reduction in C5b-9 deposits on myofibres and number of regenerated myofibres. Interventional treatment of zilucoplan after disease induction reduced the complement deposits and number of regenerated myofibres in muscles of Rag2 mice, although to a lesser extent. In this latter setting, C5 inhibition did not significantly ameliorate muscle strength. : Early administration of zilucoplan prevents the onset of myopathy at the clinical and histological level in a humanized mouse model of IMNM.