Zilucoplan, a Peptide Inhibitor of Complement Component 5, Prevents Weakness in a Passive Transfer Model of Immune-Mediated Necrotizing Myopathy

Objective: To investigate the role of the terminal complement pathway activation in immune-mediated necrotizing myopathy (IMNM). Background: IMNM is a rare, severe, inflammatory myopathy characterized by necrosis of skeletal muscle fibers. On biopsy, IMNM is associated with prominent complement activation and diffuse deposition of C5b-9 membrane attack complex (MAC) with minimal or no inflammatory cell infiltrate. Three disease subtypes have been identified based on the presence of autoantibodies: anti-SRP (signal recognition particle) myopathy; anti-HMGCR (hydroxy-3-methylglutaryl-CoaA reductase) myopathy; and seronegative IMNM. A recent study established a protective role for C3-deficiency in an IMNM passive transfer model. Ra Pharma is developing zilucoplan, a convenient, subcutaneously self-administered macrocyclic peptide that is designed to bind and inhibit the cleavage of complement component 5 (C5). Zilucoplan is currently in Phase 2 development for IMNM, as well as in Phase 3 development for acetylcholine receptor-positive generalized myasthenia gravis (gMG). Design/Methods: C5-deficient B10.D2/oSn mice were divided into groups receiving daily intraperitoneal injections of 2 mg of IgG purified from an anti-HMGCR+ patient or healthy donor as control for 8 days. Animals were supplemented by daily intraperitoneal injections of 200 μL of IgG-depleted pooled complement human serum. Zilucoplan was administered subcutaneously daily at 10 mg/kg dose. Muscle strength was evaluated by measuring muscle contraction of one gastrocnemius per animal upon electrostimulation of the sciatic nerve at day 8. Finally, muscle tissue sections and sera were assessed for the detection of MAC. Results: Co-administration of human complement-competent serum and anti-HMGCR autoantibodies is sufficient to induce impairment of muscle strength in a passive transfer model of IMNM. Importantly, prophylactic administration of zilucoplan prevents the decrease in muscle strength. Conclusions: Our data provide strong pre-clinical pharmacological proof-of-concept supporting the therapeutic evaluation of zilucoplan for IMNM in an ongoing multicenter Phase 2 clinical trial (NCT04025632). Disclosure: Dr. Boyer has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Inova Diagnostics, and CSL Behring. Dr. Boyer has received research support from CSL Behring, Celogos, Aptar Pharma, Omega Pharma, and Ra Pharma. Dr. Drouot has nothing to disclose. Dr. Ricardo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ra Pharmaceuticals. Dr. Ricardo holds stock and/or stock options in Ra Pharmaceuticals. Dr. Sayegh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ra Pharmaceuticals. Dr. Sayegh holds stock and/or stock options in Ra Pharmaceuticals.