Selective Inhibition of the MK2 Pathway: Data From a Phase IIa Randomized Clinical Trial in Rheumatoid Arthritis.

Objective: The study objective was to evaluate the safety, tolerability, pharmacodynamics, and preliminary efficacy of ATI-450 with methotrexate in patients with rheumatoid arthritis (RA).

Methods: A parallel-assignment, placebo-controlled, investigator-blinded/patient-blinded multicenter study evaluated patients with moderate-to-severe RA aged 18 to 70 years. Eligible patients were randomized (1:1) to ATI-450 50-mg oral tablets twice daily or placebo with a stable weekly dose of methotrexate for 12 weeks. The primary objective was to assess ATI-450 safety and tolerability. The secondary objectives were to assess the median percentage change from baseline high-sensitivity C-reactive protein (hs-CRP) levels, the mean change from baseline in Disease Activity Score in 28 joints based on CRP level (DAS28-CRP) and Rheumatoid Arthritis Magnetic Resonance Imaging Score hand-wrist assessments of synovitis or bone erosion at week 12, and the proportion of patients with American College of Rheumatology 20/50/70 (ACR 20/50/70) and with DAS28-CRP scores of less than 2.6. The exploratory outcomes were change from baseline in endogenous and ex vivo-stimulated cytokine levels.

Results: ATI-450 was well tolerated with no severe adverse events reported. ATI-450 reduced median hs-CRP levels by 42% or more at all posttreatment timepoints. In the ATI-450 group, a mean (median) decrease in DAS28-CRP score of 2.0 (2.1) was observed at week 12; proportions of patients with an ACR 20/50/70 response in the per-protocol population were 60%, 33%, and 20%, respectively, at week 12. Endogenous plasma levels of key inflammatory cytokines (tumor necrosis factor α, macrophage inflammatory protein 1β, interleukin 6, interleukin 8) were reduced across the 12 treatment weeks.

Conclusion: This is the first clinical study demonstrating that selective mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2) pathway blockade leads to a sustained antiinflammatory effect. This suggests that targeting the MK2 pathway mitigates the tachyphylaxis observed with p38 MAPK inhibitors in RA and supports further exploration.