Introduction: 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. Methods: purified immunoglobulin G (IgG) from an anti-HMGCR⁺ IMNM patient was co-injected intraperitoneally with human complement in C57BL/6, C5-deficient B10 (C5^def) 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^def mice or 8 days after disease induction in Rag2^-/- mice. Results: prophylactic administration of zilucoplan prevented muscle strength loss in C5^def mice (anti-HMGCR⁺ vs. anti-HMGCR⁺ + zilucoplan: p = 0.0289; control vs. anti-HMGCR⁺ + zilucoplan: p = 0.4634) and wild-type C57BL/6 (anti-HMGCR⁺ vs. anti-HMGCR⁺ + zilucoplan: p = 0.0002; control vs. anti-HMGCR⁺ + zilucoplan: p = 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. Conclusion: Early administration of zilucoplan prevents the onset of myopathy at the clinical and histological level in a humanized mouse model of IMNM.

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