Spleen tyrosine kinase (Syk) is a cytoplasmic tyrosine kinase involved in 
signalling in many of the cells that drive immune inflammation. The development 
of small molecules that inhibit Syk kinase may change the way we treat disorders 
such as rheumatoid arthritis (RA), as well as a range of other inflammatory 
diseases. Fostamatinib (R-788) is an orally bioavailable small molecule. It is 
the prodrug of R406, which is a potent Syk inhibitor. Fostamatinib was developed 
because it has more favourable physiochemical properties. It is rapidly 
converted to R406 by intestinal enterocytes. It has been evaluated in 
experimental models of RA, such as collagen-induced arthritis. In these models, 
fostamatinib suppressed clinical arthritis, bone erosions, pannus formation and 
synovitis. A phase II programme with fostamatinib has largely been completed. 
Three key trials have been published, lasting 12-26 weeks and each enrolling 
189-457 patients (875 in total). All these trials involved placebo therapy and 
patients continued to receive methotrexate in addition to active treatment with 
fostamatinib. The first dose-ranging trial evaluated three treatment doses in RA 
patients who had not fully responded to methotrexate therapy. The second trial 
compared two treatment doses in patients who had not responded to methotrexate 
therapy. The third trial compared a single treatment dose with placebo in 
patients who had not responded to biological therapy. The primary outcome 
measure was the number of patients achieving American College of Rheumatology 
(ACR) 20% (ACR20) responses. Placebo ACR20 response rates in all three trials 
were similar (35-38%). All three trials involved one treatment arm receiving 
fostamatinib 100 mg twice daily; ACR20 responses with this active treatment 
ranged from 38% to 67%. A meta-analysis of ACR responses in these trials, using 
responses to the highest dose in each trial for comparisons with placebo therapy 
in a random effects model, showed a borderline benefit with ACR20 responses. 
There were more significant differences with ACR50 and ACR70 responses. The 
reason that this meta-analysis was not more strongly positive is that the third 
trial, which evaluated patients who had failed to respond to biological 
treatments, gave negative results. Individual ACR response components, such as 
changes in swollen joint counts, showed significant differences in the first two 
trials, but there were no definite treatment benefits in the third trial. 
Overall, the differences were significant in a meta-analysis of all three 
trials. The most important adverse reactions were diarrhoea, neutropenia and 
raised ALT levels, which all showed significant excesses with active treatment 
compared with placebo. Too few patients have been studied for a definitive 
safety profile to be known. Overall, the results of the phase II trials were 
sufficiently encouraging for a phase III programme to be initiated. It will be 
some years before their definitive results are available.