An oral Syk kinase inhibitor in the treatment of rheumatoid arthritis (RA): a 3 month randomized placebo controlled phase 2 study in patients with active RA who had failed biologic agents

PURPOSE: R788, an oral, relatively selective inhibitor of Syk kinase, demonstrated significant clinical efficacy in a 3 month trial in RA pts on methotrexate (Arth Rheum 2008.58:3309). The objectives of this study were to assess the efficacy, radiologic response, and safety of R788 in pts with active disease who had failed biologic agents. METHOD: 219 pts with active RA who had failed biologic agents enrolled in a 3 month randomized double‐blind study in which they received either 100 mg bid of R788 or placebo. The principal endpoint was the ACR 20 response rate at Month 3. R788 was also compared with placebo using MRI (modified RAMRIS) of hand and wrist at Baseline and Month 3. RESULTS: Demographic and baseline clinical characteristics were similar between groups with the exception of 21% of the R788 pts having failed three or more biologics versus 12% of the placebo pts. At Month 3, no significant difference in ACR responses was achieved between the R788 and the placebo group. Although differences in ACR20 responses were noted at Week 6 (p=0.003), this response difference was not seen at Months 2 or 3, primarily because of an increasing placebo response. Significant changes from baseline in CRP and ESR at all time points were achieved in the R788 group versus the placebo group. At Month 3, significant differences in change from baseline between the R788 and placebo groups were observed in RAMRIS osteitis scores (‐0.19 in R788 vs +1.17 in placebo [p=0.058]) and synovitis scores (‐0.52 in R788 vs. +0.35 in placebo [p=0.038]). A post hoc analysis of ACR response according to whether the patient qualified for entry into the study by an elevated CRP or ESR was conducted. Although the proportion of patients who had an elevated CRP at baseline was balanced between the R788 and placebo groups (69% vs. 70%), the ACR responses in the R788 and placebo groups of those pts who had an elevated CRP at baseline and those with only an elevated ESR were quite different: CONCLUSION: Although a significant decrease in ESR and in CRP and improvement in synovitis and osteitis scores on MRI were observed in the R788 group compared to placebo, there were no significant differences in the principle endpoint of ACR responses between the groups in this study of RA patients who had failed biologics. The exceptionally high placebo ACR response appears to have been driven by patients who entered the trial via an elevated ESR but normal CRP.