Plonmarlimab, a GM-CSF-neutralizing antibody, for macrophage activation syndrome

Macrophage activation syndrome (MAS) is a subtype of secondary hemophagocytic lymphohistiocytosis (sHLH) and a rare, life-threatening complication of uncontrolled rheumatic diseases, characterized by systemic inflammation driven by aberrant activation of macrophages. We aimed to assess the efficacy and safety of plonmarlimab, a high-affinity neutralizing monoclonal antibody targeting granulocyte-macrophage colony-stimulating factor (GM-CSF), for the treatment of MAS. In this phase 2, multicenter, open-label, single-arm clinical trial (NCT07034209 and CTR20230579), 18 patients with MAS secondary to systemic autoimmune rheumatic disease who were refractory to or had relapsed after high-dose glucocorticoid therapy were enrolled. Patients received plonmarlimab once weekly for 8 weeks at 6 mg/kg as the starting in the accelerated titration stage, and then at 10 mg/kg for the first two doses followed by dose adjustments at the investigator's discretion. The primary endpoint, overall response rate at week 8, was 83.3% (15/18) among all treated patients. The median time to response was 2.1 weeks (95% confidence interval [CI], 1.0-3.1), and the median time to remission of MAS symptoms was 1.1 weeks (95% CI, 1.0-2.3). The least-squares mean percentage reduction in glucocorticoid dose from baseline to week 8 was 79.3% (95% CI, 76.3-82.3), and 83.3% of patients (15/18) achieved a ≥ 50% reduction. No grade ≥ 3 infections were observed. Biomarker analysis showed rapid reductions in ferritin and interleukin (IL)-18 levels. Plonmarlimab showed promising clinical activity and was generally well tolerated in patients with MAS, and IL-18 may serve as a potential pharmacodynamic marker for GM-CSF antibody therapy.