Pharmacodynamic Effects of Litifilimab in Lupus in a Randomized, Placebo-Controlled Phase 2 Study: Rapid and Sustained Reductions in Type I Interferon-Associated Gene Expression and Cytokines.

Abstract

The pharmacodynamic effects of litifilimab on type I interferon (IFN) response and correlations with clinical outcomes were investigated in systemic lupus erythematosus (SLE) and cutaneous lupus erythematosus (CLE). Participants from part A (SLE) or part B (CLE with or without SLE) of the randomized phase 2 LILAC trial who received litifilimab (at 50 mg, 150 mg, or 450 mg) or a placebo were included. IFN gene signature (IFNGS) scores were assessed from whole-blood samples using a 22-gene panel in 120 and 131 participants (parts A and B, respectively). IFNα and other IFN-regulated cytokine concentrations were measured in serum in 112 and 131 participants (parts A and B, respectively). Most participants were IFNGS-high at baseline (79-91%), and no baseline IFNGS-low participant results were reported. In IFNGS-high participants, litifilimab induced rapid, significant (nominal P < 0.05), and sustained reductions in IFNGS scores and IFNα concentrations versus a placebo for litifilimab at 450 mg in part A and for litifilimab at 150 mg and 450 mg in part B. In part A, IFNα reductions with litifilimab were correlated with clinical response measures. In part B, dose-response relationships for IFNGS score and IFNα concentration were observed, similar to those for disease activity measured with the Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity (CLASI-A) score. Administration of litifilimab resulted in reductions in both IFNGS scores and IFNα concentrations, pharmacodynamic effects that correlated with clinical responses. These findings support the mechanism of action of litifilimab and its continued evaluation in larger studies of patients with SLE or CLE.