Background GLPG0634 is an orally-available, selective inhibitor of Janus kinase 1 (JAK1). JAKs are critical in signaling for cytokines and growth factors, including those involved in rheumatoid arthritis (RA). Non-selective JAK inhibitors have demonstrated efficacy in patients with RA, but also dose-limiting toxicity. GLPG0634 has demonstrated encouraging efficacy and safety in a previous 4-week trial.
Objectives Evaluate short-term safety and efficacy of a dose range of GLPG0634 in RA patients with insufficient response to methotrexate (MTX) alone.
Methods A 4-week, double-blind, placebo-controlled Phase IIA dose-ranging trial in patients with active RA showing an insufficient response to MTX and naïve to biologicals was conducted to evaluate the safety and efficacy of GLPG0634 at doses of 30, 75, 150 and 300 mg or placebo (pbo), all once-daily (QD). All patients continued to take their stable background therapy of MTX.
Results 91 patients initiated treatment. Some variation in patient and disease characteristics was apparent for the dose groups at baseline, e.g., the average duration of RA was 4.4 years for pbo vs. ≥8 years of RA for all treatment groups, correlating with a younger age in the pbo group. DAS28 scores ranged from 5.7 to 6.4. The 150 mg dose group had consistently worse disease than other groups (10 years of RA, DAS28 6.4, highest scores for HAQ-DI, TJC and SJC). Overall, patients were 51 y of age and 78% were female.
GLPG0634 was generally well tolerated. Most adverse events (AEs) were mild and no serious AEs were reported. No patient discontinued due to AEs. In contrast to observations with JAK inhibitors with other selectivity profiles, no anemia but rather a modest improvement in hemoglobin was induced by GLPG0634. There was a limited decrease in absolute neutrophil count, no neutropenia, and no impact on lymphocyte differentials. Likewise, no increases in LDL-C and no elevations in liver transaminases (ALT/AST) were observed in this trial.
Within 4 weeks, GLPG0634 showed encouraging dose-dependent trends in efficacy with little improvement seen for the 30 mg dose and the best results being achieved at the 300 mg dose. Compared to other studies in RA, there was a relatively high pbo response, potentially related to a lower level of disease activity in this group. In spite of the short duration and small size of the study, several efficacy read-outs showed statistical significance: for 75 mg through 300 mg, changes in endpoints such as reductions in serum CRP (-15 to -21 mg/L, p<0.01 vs pbo, all 3 doses), in DAS28 (-1.7 to -2.3, p<0.01 at 300mg) and in HAQ-DI (-0.47 to -0.57, p<0.05 at 300 mg). This was not the case for ACR20 (41% of patients on placebo vs. 65% on 300 mg), but it was for ACR50 (6% for placebo vs. 45% on 300mg). Consistent improvements were observed for tender and swollen joint counts, but the 4-week duration was insufficient to yield statistical significance.
Conclusions These early clinical results demonstrate that selective inhibition of JAK1 by once-daily dosing of GLPG0634 from 75 mg to 300 mg is efficacious and generally well tolerated for 4-weeks treatment of RA, and confirm data from a previous study at a 200 mg daily dose. A dose of 30 mg QD was sub-optimal for efficacy. Larger, longer term studies in RA are being initiated to evaluate optimal doses for efficacy and safety.
Disclosure of Interest F. Vanhoutte Employee of: Galapagos NV, A. Van der Aa Employee of: Galapagos NV, L. Meuleners Employee of: Galapagos NV, G. van ’t Klooster Employee of: Galapagos NV