1770: Brepocitinib Inhibits Key Pathogenic Cytokine Signaling in Dermatomyositis Patients

Background/Purpose: Dermatomyositis (DM) is a rare autoimmune disease of the skin and muscles with significant unmet need and limited treatment options. Brepocitinib is an oral, selective inhibitor of TYK2/JAK1 that suppresses signaling of multiple pathogenic cytokines that have been implicated in the pathogenesis of DM disease activity including Type I and II interferons (IFN) and IL-6. Previous data has suggested that brepocitinib 30 mg may demonstrate superior inhibition of DM-relevant cytokine signaling in vitro compared to tofacitinib, a JAK1/JAK3 inhibitor.¹ The purpose of this study was to evaluate the ability of brepocitinib to inhibit pathogenic cytokine signaling ex vivo in peripheral blood mononuclear cells (PBMCs) from patients with DM and healthy donors.

Methods: PBMCs were isolated from whole blood from six participants with a diagnosis of DM according to the 2017 EULAR/ACR Classification Criteria for Idiopathic Inflammatory Myopathies and screened for baseline responsiveness to cytokine stimulation. PBMCs from responsive DM patients (n=5) and healthy donors (n=3) were separately pooled, pretreated with brepocitinib [0.0192 to 1500 nM] for 2 hours, and then stimulated with IFNα, IFNβ, or IL-6. IC₅₀ curves for both groups were generated for inhibition of downstream STAT1 and STAT3 phosphorylation from each cytokine using flow cytometry.

Results: Brepocitinib potently inhibited STAT1 and STAT3 phosphorylation following IFNα, IFNβ, or IL-6 stimulation. All IC₅₀s were ≤ 30 nM in pooled PBMCs from 5 DM patients, with IC₅₀ values of 4 nM and 2 nM for IFNα- and IFNβ-induced STAT1 and STAT3 phosphorylation, respectively. Brepocitinib demonstrated greater potency in inhibiting signaling in PBMCs from DM patients compared to healthy donors (Figure 1). Daily average unbound plasma concentrations (free C_avg, 123 nM) after administration of 30 mg once daily exceed these IC₅₀s by ≥ 4-fold, resulting in > 96% inhibition of IFNα and IFNβ signaling and > 80% inhibition of IL-6 signaling over a 24-hour dosing interval in the pooled DM patient PBMCs (Figure 2).

Conclusion: Brepocitinib demonstrated potent inhibition of proinflammatory cytokine signaling in PBMCs at exposures achieved with brepocitinib 30 mg QD. This inhibition was more potent in samples from patients with DM than healthy donors, which may reflect pathologic overactivation of JAK-STAT signaling in DM. These results confirm findings from previous work and strongly support the therapeutic rationale for TYK2/JAK1 inhibition with brepocitinib in DM. Results of a global, Phase 3, randomized, placebo-controlled trial are expected in late 2025 (VALOR; NCT05437263).



References:

Pa1. Paiik JJ, et al. Clin Exp Rheumatol. 2025 Feb;43(2):354-363.