Background Janus kinase 3 (JAK3) plays a critical role in intracellular signal transduction and is required for activation of lymphocytes. Oral VX-509 selectively inhibits JAK3 and improves signs and symptoms in patients with active RA.
Objectives To evaluate the pharmacodynamic effect of VX-509 on inflammatory biomarkers of RA disease activity including interleukin 6 (IL-6), IL-2 receptor alpha (CD25), and chemokine ligand 18 (CCL18), and markers of bone erosion (matrix metalloproteinase, MMP-3). These analyses advance our understanding of the response to VX-509 treatment in RA patients.
Methods Two hundred and four RA patients with inadequate response to DMARDs were enrolled in a 12-week, phase 2a, double-blind, randomized, placebo-controlled study of oral VX-509 monotherapy with 25 mg, 50 mg, 100 mg, 150 mg bid, or placebo. Plasma was collected at baseline, week 6, and week 12. Samples from 93 study completers were stratified to represent the non-responder, ACR20, ACR50, and ACR70 responses observed within each dosage group. Markers of RA associated with inflammation were analyzed by Luminex multiplex technology. The mean, median, and change from baseline were calculated; the 25 mg bid group was not included.
Results Patients treated with VX-509 at dosages of 50 mg, 100 mg, and 150 mg bid had decreases from baseline in levels of IL-6, CD25, CCL18, and MMP-3 at week 12 that were dose-related (Table 1).
Conclusions VX-509 treatment modulated biomarkers of RA associated with inflammation (IL-6, CD25, and CCL18) and bone erosion (MMP-3). These changes are consistent with the efficacy of VX-509 in improving RA signs and symptoms.
Disclosure of Interest I. Catlett Shareholder of: Vertex Pharmaceuticals Incorporated, Employee of: Vertex Pharmaceuticals Incorporated, A. Legedza Shareholder of: Vertex Pharmaceuticals Incorporated, Employee of: Vertex Pharmaceuticals Incorporated, L. Sewell Shareholder of: Vertex Pharmaceuticals Incorporated, Employee of: Vertex Pharmaceuticals Incorporated, T. Hoock Shareholder of: Vertex Pharmaceuticals Incorporated, Employee of: Vertex Pharmaceuticals Incorporated