Background/Purpose: Polymyositis (PM) is a chronic autoimmune inflammatory myopathy affecting striated muscles and resulting in muscle weakness. PM is a rare disease, and there are limited approved therapies available. High-dose corticosteroids or IV immunoglobulin are commonly used to treat PM, however response is poor and both treatments contribute to comorbidity. Here we have investigated KZR-616, a first-in-class selective inhibitor of the immunoproteasome in C protein-induced myositis (CIM), a mouse model of PM that closely resembles the human disease. Positive results from this study support the rationale for PRESIDIO (KZR-616-003, NCT: NCT04033926), an ongoing Phase 2 clinical trial of KZR-616 in patients with PM and dermatomyositis (DM).

Methods: CIM was induced in female C57BL/6 mice (5/treatment group) immunized subcutaneously (SC) with 200 µg of fragment 2 (amino acids 284-580) of recombinant skeletal muscle fast-type C protein in complete Freund’s adjuvant combined with intraperitoneal (IP) administration of 2 µg of pertussis toxin. Diseased mice (Day 13 post immunization) were treated with 10 mg/kg KZR-616 or ONX 0914 (a structural analog of KZR-616) or vehicle three times per week until Day 28. Endpoints included muscle strength assessed by a grip strength meter, serum creatine kinase activity and immunohistology and immunohistochemistry of the triceps brachii muscle.

Results: Treatment with KZR-616 or ONX 0914 completely blocked the loss of grip strength in mice after vaccination for CIM induction while vehicle treated animals displayed progressive muscle weakness.  Compared to vehicle, immunoproteasome inhibition resulted in lowered PM-associated leukocyte infiltration of the triceps brachii muscle, including CD8⁺ T-cells and F4-80⁺ macrophages, and prevented an increase in serum creatine kinase.

Conclusion: Selective immunoproteasome inhibition shows therapeutic efficacy in a preclinical mouse model of PM with suppression of muscle inflammation and prevention of muscle weakness. These results strengthen the hypothesis that KZR-616, currently under evaluation in PRESIDIO (KZR-616-003, NCT: NCT04033926), a Phase 2 placebo-controlled, cross-over study of KZR-616 for patients with PM and DM evaluating safety, tolerability, and exploratory efficacy such as muscle function and disease activity over a 32 week treatment period, will elicit similar results.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/kzr-616-a-first-in-class-selective-inhibitor-of-the-immunoproteasome-ameliorates-polymyositis-in-a-murine-model/