Background Janus kinase 3 (JAK3) plays a critical role in gamma-chain cytokine signal transduction and is essential for activation of lymphocytes. Interferon signaling is dependent on other Janus kinase family members, but not JAK3, and is an important component of immune response to infectious agents. VX-509 selectively inhibits JAK3 and improves signs and symptoms in patients with rheumatoid arthritis (RA).
Objectives To evaluate the in-vivo pharmacodynamic effects of VX-509 treatment on systemic markers of RA disease state and interferon signaling.
Methods Two hundred and four patients with RA and inadequate response to DMARDs were enrolled in a 12-week, phase 2a, double-blind, randomized, placebo-controlled study of oral VX-509 monotherapy. Primary efficacy endpoints were met and efficacy and safety results have previously been reported. Plasma samples were collected at baseline, week 6 and week 12. Samples from 93 representative study completers were selected and 129 proteins relevant to RA pathophysiology were analyzed with Luminex multiplex technology. Data were analyzed using linear mixed effect models for each protein. Whole-blood samples were also collected at baseline and end of treatment (up to 12 weeks) for transcriptomic profiling using the Affymetrix Primeview microarray. Transcriptomic data for all 104 consenting patients were analyzed using gene set enrichment and weighted gene coexpression network analysis.
Results The expression levels of 36 proteins were significantly associated with VX-509 exposure (q<5%), including chemokines, cytokines and markers for immune activation, bone degradation, adhesion and inflammation. Gene set enrichment analysis revealed decreased expression of genes induced by common-gamma chain cytokines (q<10%). Interferon-induced genes are coexpressed in the dataset and correlate with IP10 protein levels. However, protein and mRNA levels of the interferon-induced genes, including IP10 and MIG, are not associated with VX-509 exposure (Table 1). Finally, co-expressed genes correlating with VX-509 exposure were highly enriched in genes that are differentially expressed between effector memory and naïve CD8 T-cells.
Conclusions VX-509 treatment results in improvement in levels of biomarkers associated with RA pathophysiology. VX-509 reduces the expression of genes induced by common gamma-chain cytokines while interferon signaling remains intact, confirming that selective JAK3 inhibition underlies the efficacy seen in RA patients treated with VX-509.
Disclosure of Interest : B. Hare Shareholder of: Vertex Pharmaceuticals, Employee of: Vertex Pharmaceuticals, E. Haseltine Shareholder of: Vertex Pharmaceuticals, Employee of: Vertex Pharmaceuticals, D. Takemoto Shareholder of: Vertex Pharmaceuticals, Employee of: Vertex Pharmaceuticals, J. Sullivan Shareholder of: Vertex Pharmaceuticals, Employee of: Vertex Pharmaceuticals, I. Catlett Shareholder of: Vertex Pharmaceuticals, Employee of: Vertex Pharmaceuticals, M. Harding Shareholder of: Vertex Pharmaceuticals, Employee of: Vertex Pharmaceuticals