Background/Purpose: VX-509 is an oral selective JAK3 inhibitor being evaluated for the treatment of rheumatoid arthritis (RA). The objective of this 24-week, randomized, placebo-controlled, double-blind, phase 2 study is to assess the efficacy, tolerability, and safety of four dosing regimens of VX-509, administered to patients with RA on stable background methotrexate therapy (MTX).

Methods: Patients with active RA (defined as 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 doses of VX-509 (100 mg QD, 150 mg QD, 200 mg QD, or 100 mg BID) for a duration of 24 weeks. Primary efficacy measures were the proportion of patients achieving ACR20 and the mean change from baseline in DAS28(CRP) at week 12.  

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 15, the mean swollen joint count was 11, and the average disease duration was 7.3 years. A significant clinical response was observed at 12 weeks; the proportion of patients achieving ACR20 and the decrease from baseline in DAS28(CRP) were significantly greater in each of the VX-509 dose groups than in placebo (Table). Significant improvements versus placebo in ACR50, ACR70, HAQ-DI, and CDAI were also noted in VX-509-treated groups.

Over 12 weeks, adverse event (AE) rates were higher in the VX-509 group (all VX-509 dose groups combined) (51.2%) relative to placebo (38.0%) and led to study discontinuation in 6.6% 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%), hypercholesterolemia (3.8%), and nasopharyngitis (3.5%). Infections occurred at slightly higher rates in the VX-509 group (22.0%) than in the placebo group (15.5%). Serious AEs occurred in equal proportions of VX-509 and placebo patients (5.6%), but there was a higher rate of serious infections in the VX-509 group (2.8%) compared with placebo (1.4%). One unrelated death due to cardiac failure occurred in the VX-509 100 mg BID 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 all groups receiving VX-509.

Conclusion: VX-509 improved the signs and symptoms of RA when administered in combination with stable background methotrexate therapy for 12 weeks. VX-509 was associated with small increases in AE rates, (serious) infections, and mostly minor laboratory abnormalities. Efficacy and safety were comparable for VX-509 at 150-200 mg QD and 100 mg BID. These results support the further development of VX-509, at a once-daily dose.