The IRAK4 kinase inhibitor PF-06650833 blocks inflammation in preclinical models of rheumatologic disease and in humans enrolled in a randomized clinical trial.

Abstract

OBJECTIVE\nUse a highly potent and selective small molecule inhibitor of interleukin-1 associated kinase (IRAK) 4, PF-06650833, to demonstrate its role in autoimmune pathophysiology in vitro, in vivo and in the clinic.\n\n\nMETHODS\nRheumatoid arthritis (RA) inflammatory pathophysiology was modeled in vitro through stimulation of primary human macrophages (MΦ) with anti-citrullinated protein antibody (ACPA) immune complexes (IC), RA fibroblast-like synoviocyte (-FLS) cultures stimulated with toll-like receptor (TLR) ligands, as well as additional human primary cell co-cultures. Systemic lupus erythematosus (SLE) pathophysiology was simulated in human neutrophils, dendritic cells (DC), B cells and PBMC stimulated with TLR ligands and SLE patient IC. PF-06650833 was evaluated in vivo in the rat collagen-induced arthritis (CIA) model and the mouse pristane-induced and MRL/lpr models of lupus. Finally, RNASeq data generated with whole blood samples from a Phase 1 multiple ascending dose clinical trial of PF-06650833 were used to test in vivo human pharmacology.\n\n\nRESULTS\nIn vitro, PF-06650833 inhibited human primary cell inflammatory responses to physiologically relevant stimuli generated with RA and SLE patient plasma. In vivo, PF-06650833 reduced circulating autoantibody levels in the pristane-induced and MRL/lpr murine models of lupus and protected rats from CIA. In a phase 1 clinical trial (NCT02485769), PF-06650833 demonstrated in vivo pharmacology pertinent to SLE by reducing whole blood interferon (IFN) gene signature expression in healthy volunteers.\n\n\nCONCLUSION\nThese data demonstrate that inhibition of IRAK4 kinase activity can reduce markers of inflammation in humans and provide confidence in the rationale for clinical development of IRAK4 inhibitors for rheumatologic indications.