POLB 001, a p38 MAPK inhibitor, decreases local and systemic inflammatory responses following

Background and aim: POLB 001 is an oral p38 mitogen-activated protein kinase (MAPK) inhibitor in development for the prevention of cancer immunotherapy-induced cytokine release syndrome (CRS). It has previously been shown to be well tolerated and capable of decreasing Methods: Participants received POLB 001 at doses of 30, 70, or 150 mg, or placebo, twice daily for seven consecutive days and were challenged locally with intradermal (ID) LPS on day 4 and systemically with intravenous (IV) LPS on day 6. Following ID LPS administration, skin perfusion and erythema were measured, and skin suction blisters were created to collect blister fluid containing infiltrating immune cells and extracellular fluid. Following IV LPS administration, circulating cytokine levels, leukocyte counts, leukocyte p38 MAPK phosphorylation levels, and vital signs were measured. Results: POLB 001 was well tolerated. It reduced the ID LPS-driven immune cell attraction and cytokine responses measured in blister fluid. The suppression of immune cell recruitment was most pronounced in neutrophils (72.4%-81.5%, Conclusion: POLB 001 was safe and well-tolerated. Pharmacodynamic findings confirm that POLB 001 inhibits LPS-induced local and systemic inflammation Clinical trial registration: https://onderzoekmetmensen.nl/en/trial/51741, identifier NL81214.056.22.