Background/Purpose:   Novel, targeted small-molecular medications are needed in the treatment of rheumatoid arthritis (RA).  MK-8457 is a novel inhibitor of spleen tyrosine kinase (SYK) and zeta-chain-associated protein kinase 70 (ZAP70) that is being investigated as an RA treatment.

Methods:   Two Phase 2, multicenter, double-blind, placebo-controlled trials were conducted in RA subjects (≥ 18 years old) .  Study 1 was an adaptive study in subjects with active RA despite treatment with methotrexate (MTX) and included MRI; Study 2 included subjects with active RA and an inadequate response or intolerance to anti-TNF-α therapy.  Subjects in both studies were randomized to MK-8457 100 mg BID + MTX or placebo + MTX for 24 weeks, this dose has 99% inhibition of basophil CD63 biomarker. The primary endpoints were the American College of Rheumatology 20 (ACR20) response at Week 12 in Study 1 and change from baseline in the Disease Activity Score 28 (DAS28) based on C-reactive protein (CRP) at Week 12 in Study 2.  ACR 50 and ACR70 were also evaluated.  Subjects were eligible to continue open-label safety extensions for up to 100 weeks upon completion of the initial 24-week treatment period.  Safety was monitored by physical examination, vital signs, safety labs, and adverse event (AE) reporting. 

Results:   Both studies were discontinued early due to serious infections.  At the time of study discontinuation, there were 82 subjects (mean age 55 years; 77% female; baseline mean DAS28^CRP 5.98) randomized to MK-8457 (n=41) and placebo (n=41) in Study 1.  In Study 2, 56 subjects (mean age 59 years; 77% female; baseline mean DAS28^CRP 6.12) were randomized to MK-8457 (n=30) and placebo (n=26).  Statistically significant efficacy improvement was observed with MK-8457 in Study 1 (MTX-IR), but not in Study 2 (TNF-IR) (Table).  Study 1 also showed efficacy on osteitis and synovitis on MRI.  At termination, Study 2 only had 31 subjects with Week 12 data; therefore, there was little power to assess efficacy endpoints.  There were 27% (MK-8457) vs 10% (placebo) with non-infection gastrointestinal (GI) AEs in Study 1, and; 27% (MK-8457) vs 4% (placebo) with GI AEs in Study 2.    In Studies 1 and 2, there were 6 serious respiratory infections (5 pneumonia and 1 bronchitis) and 1 serious case of enterocolitis; 1 subject with presumed opportunistic infection died during the Study 1 extension.  The combined serious infection rate per 100 patient-years was 16.3.  There were no significant changes in blood pressure in the MK-8547 treated groups.  

Conclusion:   MK-8457 improved efficacy in subjects with an inadequate response to MTX (Study 1), but not in subjects who failed anti-TNF-α therapy (Study 2), although Study 2 was limited to a small sample size.  A high rate of serious infections was observed leading to the termination of both studies suggesting a potential increased infection risk with high degree of SYK and/or ZAP70 inhibition.

Table:  Efficacy Endpoints at Week 12