Background/Purpose

ASP015K is a novel oral Janus kinase (JAK) inhibitor in development for the treatment of rheumatoid arthritis (RA). ASP015K inhibits JAK 1/3 with relative selectivity over JAK2 and can be dosed once daily (QD). This study evaluated the efficacy, safety and dose response of ASP015K QD  in patients (pts) with moderate to severe rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX) (Clinical Trials Registration: NCT01554696).

Methods

In a 12-week, double-blind, placebo (PBO)-controlled study, pts 18 years or older who met ACR criteria for RA, were on MTX ≥ 90 days, and had active RA (CRP ≥ 0.8 mg/dL or ESR ≥ 28 mm/hr and ≥ 6 tender/swollen joints on a stable dose of MTX) were randomized 1:1:1:1:1 to ASP015K 25 mg, 50 mg, 100 mg, 150 mg or PBO, stratified by prior anti-TNF use and geographic region. Pts continued stable MTX therapy during the study. The primary endpoint was ACR20 response at week 12.

Results

378 pts (83% female; mean age 53 years) were randomized and dosed. 43% of subjects were enrolled in Europe, 39% in U.S., and 18% in Latin America.  26% had used a TNF-inhibitor. Mean baseline values: tender joint count 23.0 (of 68), swollen joint count 13.6 (of 66), CRP 1.17 mg/dL, ESR 39.86 mm/hr, DAS28-CRP 5.54, and DAS28-ESR 6.36. Concomitant MTX dose was similar among groups. Dose-response on ACR20 was not shown. Numerically greater ACR20 responses than PBO were seen in the ASP015K 50 mg and 150 mg groups, with statistical significance shown in the 50 mg group. A statistically significant dose response was demonstrated in change in DAS28-CRP and DAS28-ESR, with effects seen as early as week 1. Pre-specified analyses by geographic region showed significant responses in ACR20 in the ASP015K 100 mg and 150 mg dose groups as compared to PBO in Europe but not in the other regions (Table). The incidence of adverse events (AEs) was similar between combined ASP015K groups and PBO (47.7% vs 47.2%). The most frequently reported AEs in the combined ASP015K groups vs PBO were headache (2.9% vs 1.4%) and hypercholesterolemia (2.0% vs 1.4%). The overall incidence of infections and serious adverse events (SAEs) were similar between ASP015K and placebo (18.3% vs 26.4% and 1.0% vs 0%, respectively). No meaningful differences in absolute neutrophil and lymphocyte counts and hemoglobin were seen between ASP015K and PBO.  The safety profile was comparable among the ASP015K dose groups, although more AEs leading to study drug discontinuation and all 3 SAEs occurred in the 100 mg and 150 mg groups.

Conclusion

In this study of active RA subjects with an inadequate response to MTX, ASP015K did not demonstrate a dose-response on the primary endpoint of ACR20, with differential placebo response rates seen by region. Significant effects on inflammatory markers and DAS28 were shown, warranting further evaluation. ASP015K was well tolerated with no meaningful differences in safety measures from placebo noted.