Background VX-509 is an oral selective JAK3 inhibitor being evaluated for the treatment of rheumatoid arthritis (RA). This was a 24-week, randomized, placebo-controlled, double-blind, phase 2 study of four dosing regimens of VX-509, administered to patients with RA with inadequate response to methotrexate (MTX).
Objectives To assess the efficacy and safety of four dosing regimens of VX-509 administered to patients with RA on stable background methotrexate therapy.
Methods Patients with active RA (C-reactive protein (CRP)>ULN, ≥6 swollen joints (of 66), and ≥6 tender joints (of 68)) taking stable doses of MTX were randomized 1:1:1:1:1 to receive placebo or one of four dosing regimens of VX-509 (100 mg QD, 150 mg QD, 200 mg QD, or 100 mg BID) for a duration of 24 weeks. The primary efficacy endpoints at Week 12 were met and have previously been reported; 24-week efficacy and safety results are reported here.
Results A total of 358 patients were randomized and received ≥1 dose of study drug; 81% of patients were female, with a mean age of 53 years. At baseline, the mean tender joint count was 23.8, the mean swollen joint count was 16.1, and the average disease duration was 7.3 years. After 24 weeks of treatment the proportion of patients achieving ACR20, ACR50, ACR70, DAS28 (CRP) <2.6 and DAS28 (ESR) <2.6 and the decrease from baseline in DAS28 (CRP) were statistically significantly greater in each of the VX-509 dose groups than in the placebo group (Table).
Over 24 weeks, the percentage of patients with any adverse event (AE) was higher in the VX-509 group (all VX-509 dose groups combined) (59.9%) relative to placebo (42.3%) and led to study discontinuation in 9.1% and 8.5% of patients in the VX-509 and placebo groups, respectively. The most common AEs in the VX-509 group were headache (8.7%), hypercholesterolemia (5.2%), and diarrhea (4.5%). Serious AEs occurred in similar proportions of patients receiving VX-509 (7.3%) or placebo (5.6%), but there were more serious infections in the VX-509 group (3.5%) compared with placebo (1.4%). Through 24 weeks there were two SAEs that resulted in death; one was cardiac failure in the VX-509 100 mg BID group (previously reported) and one was pancytopenia in a patient with pneumonia in the VX-509 200 mg QD group. Elevations in transaminase levels and decreases in median neutrophil and lymphocyte counts were observed in the VX-509 groups and were generally mild. Safety profiles were comparable across groups receiving VX-509.
Conclusions All tested doses of VX-509 significantly improved signs and symptoms of RA versus placebo when administered in combination with stable background MTX therapy for 24 weeks. VX-509 was associated with small increases in AE rates, serious infections, and mostly minor laboratory abnormalities. These results support and provide guidance for the further development of VX-509.
Disclosure of Interest R. van Vollenhoven Grant/research support: AbbVie, BMS, GSK, Pfizer, Roche, and UCB, Consultant for: bbVie, Biotest, BMS, GSK, Merck, Pfizer, Roche, UCB, and Vertex Pharmaceuticals Incorporated, M. Genovese Grant/research support: Vertex Pharmaceuticals Incorporated, Consultant for: Vertex Pharmaceuticals Incorporated, Y. Zhang Employee of: Vertex Pharmaceuticals Incorporated, N. Kinnman Employee of: Vertex Pharmaceuticals Incorporated