Background The IL-2 cytokine receptor family plays an important role in lymphocyte development, survival, and T cell-mediated immune response. Janus kinase 3 (JAK3) is an integral mediator of this signaling pathway and downstream physiology through the phosphorylation of multiple substrates, including the STAT family. VX-509 is a potent, small-molecule, investigational selective inhibitor of JAK3. VX-509 is active in animal models of inflammation, including collagen-induced arthritis.
Objectives To evaluate exploratory biomarkers of JAK3 or JAK2 activity and their relationship with pharmacokinetic parameters in healthy volunteers dosed with VX-509.
Methods This was a Phase 1, double-blind, dose-escalation, placebo-controlled study. Volunteers were administered single or multiple ascending doses of VX-509 (maximum 400 mg single-dose and 150 mg q12h). Blood samples were collected to quantify VX-509 concentrations and assess experimental biomarkers of JAK activity. Blood samples were stimulated with IL-7, a JAK1/3 activator, or IL-6, a JAK1/2 activator. Phospho(p)-STAT5 or pSTAT3 respectively were measured in T cell subsets by flow cytometry. PK and PD parameters were studied using non-compartmental analysis (NCA) and PK/PD relationships were explored using an inhibitory, sigmoid effect PD model.
Results Inhibition of the JAK3-biomarker, IL-7 induced pSTAT5, was dose dependent and correlated with the concentration of VX-509. Peak pSTAT5 inhibition was reached at approximately 1 to 2 h post dose. This was consistent with the PK of VX-509, with a median tmax of approximately 1 h. Inhibition of pSTAT5 increased from Day 1 to Day 14 consistent with VX-509 exposure, and pSTAT5 inhibition was reversible. Inhibition of the JAK3 biomarker pSTAT5 was observed across the dose range, with a maximal inhibition of 89%. In contrast, measurement of IL-6-mediated pSTAT3, a JAK1/2 biomarker, was inhibited only at the highest dose, with a maximal inhibition of 54%. Inhibition of the JAK1/2-biomarker was of short duration and was also reversible. The pSTAT5 and VX-509 relationship can be well described using a simple direct sigmoid inhibitory PD model. However, pSTAT3 and VX-509 showed only weak correlation, likely due to the weak inhibitory effect of VX-509 against JAK2.
Conclusions The PK/PD correlations of the experimental biomarkers demonstrated that VX-509 is a selective, reversible inhibitor of JAK3 signaling in humans. VX-509 warrants further clinical investigation in patients with chronic, immune-mediated inflammatory disorders, including rheumatoid arthritis.
Disclosure of Interest I. Catlett Shareholder of: Vertex Pharmaceuticals, Employee of: Vertex Pharmaceuticals, X. Luo Shareholder of: Vertex Pharmaceuticals, Employee of: Vertex Pharmaceuticals, M. Penney Shareholder of: Vertex Pharmaceuticals, Employee of: Vertex Pharmaceuticals, M. Pray Shareholder of: Vertex Pharmaceuticals, Employee of: Vertex Pharmaceuticals, G. Spencer-Green Shareholder of: Vertex Pharmaceuticals, Employee of: Vertex Pharmaceuticals, M. Botfield Shareholder of: Vertex Pharmaceuticals, Employee of: Vertex Pharmaceuticals, T. Hoock Shareholder of: Vertex Pharmaceuticals, Employee of: Vertex Pharmaceuticals