Targeting the MK2 Pathway Reduces Tachyphylaxis Related to Rheumatoid Arthritis Therapy

David Gordon, MB ChB

In the first clinical study evaluating ATI-450 (Zunsemetinib), an investigational MK2 pathway inhibitor, investigators observed reduced tachyphylaxis in patients with rheumatoid arthritis (RA). In rheumatoid arthritis treatment, p38 mitogen-activated protein kinase (p38 MAPK) inhibitors have been a focal point for immunoinflammatory research, as well as a therapeutic target for any relative inflammatory diseases.

However, investigators noted that the practice of inhibiting p38 MAPK hasn't yielded full efficacy for treating rheumatoid arthritis, which has led to further examination on the MK2 pathway and promising findings.

David Gordon, MB, ChB, Head of Clinical Development, Immunology, Johnson & Johnson, and a team of investigators aimed to evaluate the safety, tolerability, pharmacodynamics, and preliminary efficacy of ATI-450 with methotrexate in this patient population.

"Understanding the reasons for the failure of p38 MAPK inhibitors may lead to the development of therapies that optimally target the pathway and lead to new therapeutic approaches to treat inflammatory diseases," the team wrote.

Investigating the MK2 Pathway

The primary objective of the study was to look at the safety and tolerability of ATI-450 in adults, 18-70 years, with moderate-to-severe rheumatoid arthritis. The change from baseline in endogenous and ex-vivo-stimulated cytokine levels were exploratory outcomes. Secondary objectives included assessment of:

• Median percentage change from baseline high-sensititivity C-reactive protein (hs-CRP) levels
• Mean change in Disease Activity Score in 28 joints from baseline, measured by high-sensitivity C-reactive protein (hs-CRP) levels
• 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
• 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

Patients that met inclusion criteria for the parallel-assignment, placebo-controlled, blinded multicenter study were randomized (1:1) to receive 50-mg oral tablets of ATI-450 50-mg twice daily, or placebo with a stable weekly dose of methotrexate for 12 weeks.

The Results

Results showed that ATI-450 was well tolerated and no severe adverse events were reported. Those who received the intervention had reduced median hs-CRP levels by 42% or higher at all post-treatment follow-ups. A mean (median) decrease in DAS28-CRP score of 2.0 (2.1) was observed at week 12 in the intervention group.

In patients with with an ACR 20/50/70, investigators observed a response of 60%, 33%, and 20%, respectively, at week 12. When evaluating key inflammatory cytokines, including tumor necrosis factor α, macrophage inflammatory protein 1β, interleukin 6, interleukin 8, endogenous plasma levels of key inflammatory cytokines were reduced across the 12 treatment weeks.

"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," investigators concluded. "This suggests that targeting the MK2 pathway mitigates the tachyphylaxis observed with p38 MAPK inhibitors in RA and supports further exploration."

The study "Selective Inhibition of the MK2 Pathway: Data From a Phase IIa Randomized Clinical Trial in Rheumatoid Arthritis" was published in ACR Open Rheumatology.