VTP-43742 is a potent and selective RORγt blocker that demonstrates oral efficacy in a mouse model of autoimmunity through suppression of IL-17A production (THER7P.945)

Abstract Increased production of the inflammatory cytokine IL-17A by Th17 cells is a driver of multiple autoimmune disorders, including psoriasis, ankylosing spondylitis (AS) and psoriatic arthritis (PsA). The nuclear receptor RORγt, IL-23 and TGFb are required for the differentiation of Th17 cells. RORγt stabilizes the Th17 phenotype by increasing the expression of IL-23R and inducing the synthesis of IL-17A in Th17 cells. Antibodies targeting IL-23 or IL-17A are highly effective in the treatment of psoriasis, AS and PsA, validating the RORγt /Th17 pathway in human disease. VTP-43742 is an orally active inhibitor of RORgt that is being pursued for the treatment of autoimmune disorders. VTP-43742 binds to RORγt with high affinity (Ki=3.5 nM) and exhibits >1000-fold selectivity versus the RORa and RORβ isotypes. VTP-43742 inhibits Th17 differentiation and IL-17A secretion from mouse splenocytes (IC50=57 nM) without affecting Th1, Th2, or Treg cell differentiation. In the MOG35-55/CFA immunized mouse EAE model, orally dosed VTP-43742 significantly suppressed clinical symptoms, demyelination and mRNA expression of multiple inflammatory markers in the spinal cord. Importantly, VTP-43742 inhibits the secretion of IL-17A from activated hPBMCs (IC50=18 nM) and human whole blood (IC50=192 nM) from healthy and psoriatic donors. Further, VTP-43742 is well absorbed after oral administration in multiple animal species and has pharmacokinetics consistent with once-a-day dosing in humans.