A randomized dose-ranging, placebo-controlled study of INCB028050, a selective JAK1 and JAK2 inhibitor in subjects with active Rheumatoid Arthritis

PURPOSE: To characterize safety and efficacy of INCB028050 (050) in RA in subjects who have had an inadequate response to any DMARD therapy including biologics. METHODS: Subjects with active RA(>=6 tender>/4 swollen joints of 28), ESR>=28mm or CRP >= 7mg/L) despite DMARD therapy were randomized to placebo (PBO)or 050 at once daily oral doses of 4mg, 7 mg or 10 mg with background DMARDs (excluding biologics). After 12 weeks subjects randomized to placebo were re-randomized to 7mg or 10mg for an additional 12 weeks (wks). The primary analysis was at the end of the 12-week PBO-controlled period. Subjects remained blinded to treatment assignment during the 24-wk treatment period. Subjects could be on stable doses of methotrexate (MTX), hydroxychloroquine, leflunomide, corticosteroids (<10 mg/day) and/or sulfasalazine. Results below are at Wk 12. The study was not designed to test for statistically significant differences between individual dose groups and placebo; p-values and significance levels are not displayed. RESULTS: The study enrolled 127 subjects, eighty percent women. Two subjects were randomized but not treated. One subject had no post-baseline assessments. Mean ages across treatment groups 54-58yrs. Mean disease duration ranged from 7-9 yrs. The proportion of subjects on background MTX ranged from 72-77%. The proportion of subjects who failed biologics in the past was 13%, 38%, 6% and 20% for the PBO, 4mg, 7mg and 10mg groups respectively. Of the subjects who had failed biologics, 30% failed multiple biologics. (Table presented)Responses were observed as early as the first assessment (Wk2), demonstrating a rapid onset of action. Similar ACR responses were achieved with 050 regardless of background therapy or previous biologic experience. ACR20 responses for biologic experienced subjects was 33% for PBO and 53%, 73% and 43% for 4mg, 7mg and 10mg, respectively. ACR50 responses for biologic experienced subjects was 11% for PBO and 33%, 45% and 29% for 4mg, 7mg and 10mg, respectively. The nature of treatment-emergent adverse events (TEAEs) was similar across groups. The frequency of TEAEs in PBO, 4mg, 7 mg and 10 mg 050 groups was 61.3%, 48.4%, 59.4% and 74.2%, respectively. One subject reported an unrelated serious AE (GI bleed). The most frequently reported TEAEs were headache (active 10.6% vs. 6.5% PBO), URI (active 5.3% vs. 9.7% for PBO) and diarrhea (active 5.3% vs. 6.5% PBO). At Wk 12, two cases of herpes zoster were reported (2.1% active vs. 0% PBO). Increases were observed in HDL and LDL, and hdl:LDL ratios tended to increase with therapy (active 10.06% vs. 0.41% PBO). CONCLUSION: In this study, INCB028050 given once a day over 12 weeks was well tolerated and demonstrated clinically meaningful responses in subjects with inadequate response to DMARDs including biologics over 12 wks of treatment. All three doses tested were effective.