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).

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.

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).