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 once daily ASP015K  in patients (pts) with moderate to severe rheumatoid arthritis (RA) with an inadequate response/intolerance to DMARDs and not currently on concomitant methotrexate (MTX) (Clinical Trials Registration: NCT01565655).

Methods

In this 12-week, double-blind, placebo (PBO)-controlled study, pts 18 years or older who met ACR criteria for RA, were not on concomitant MTX, and had active RA (defined as either CRP ≥ 0.8 mg/dL or ESR ≥ 28 mm/hr and ≥ 6 tender and swollen joints) were randomized 1:1:1:1:1 to ASP015K 25 mg, 50 mg, 100 mg, 150 mg or PBO. Allowed concomitant DMARD therapies were anti-malarials and/or sulfasalazine. The primary endpoint was ACR20 response at week 12.

Results

289 pts (82% female; mean age 53.9 years) were randomized and dosed. Approximately half  the subjects (48%) were enrolled in the U.S. and the remainder from Europe (41%) and Mexico (11%). 48% had used a biologic, with 36% exposed to  ≥ 2. Mean baseline values: disease duration, 10.4 y, tender joint count 25.7 (of 68), swollen joint count 16.3 (of 66), CRP 1.69 mg/dL, ESR 44.36 mm/hr,  DAS28-CRP 5.83, and DAS28-ESR 6.64 . A statistically significant dose-response at week 12 was seen for ACR20 with the highest response seen in the ASP015K 100 mg and 150 mg groups. ACR50/70 response and DAS28-CRP remission were also higher in the 2 highest ASP015K dose groups as compared to PBO. Dose-dependent improvement in DAS28-CRP was seen, with statistically significant differences shown in the two highest dose groups as early as week 4. The incidence of adverse events (AEs) was similar between combined ASP015K groups and PBO (41.6% vs 43.1%). The most frequently reported AEs in the combined ASP015K groups as compared to PBO were upper respiratory tract infection (5.5% vs 3.9%), nausea (5.0% vs 0%), and diarrhea (3.8% vs 2.0%). The overall incidence of infections and serious adverse events was similar between ASP015K and PBO (13.4% vs 13.7% and 4.2% vs 3.9%, respectively). No meaningful differences in absolute neutrophil and lymphocyte counts or hemoglobin were seen between ASP015K and PBO.  The safety profile was generally comparable among the ASP015K dose groups, except for a higher incidence of dyspepsia, headache, and blood creatinine phosphokinase increased (transient without associated symptoms) in the 100 mg and/or 150 mg groups.

Conclusion

In a population of RA pts with long-standing disease and previous treatment with multiple DMARDs, 12 weeks of treatment with ASP015K was well tolerated and efficacious, with the highest response seen at the 100 and 150 mg doses. These data support further development of ASP015K for the treatment of RA.