The results of this three part, multicenter study show no evidence of efficacy in the repeat dose, powered portion of the study. However, there is evidence of pharmacology and downstream biologic effect with a dose dependent decrease in platelets. The platelet reduction is not con sidered clinically significant table 1 or a safety related issue since in all patients, platelet counts remained within the normal range. OSM stimulates hepatocytes Inhibitors,Modulators,Libraries to release acute phase reactants. Inhibitors,Modulators,Libraries Anti OSM mAb does not bind to IL6, therefore, GSK315234 does not have a direct effect on the acute phase response. Any change in ESR or CRP would be due to inhibition of OSM and indirectly through reduc tion in disease activity. In Part A, the single dose study showed a statistically significant clinical response in the 3 mg kg group on Days 56 and 84 and the 10 mg kg group on Day 84.

One potential explanation is that OSM is not a good thera peutic target in RA and the positive results in the single dose study were false positives. Alternatively, if the ob servations that statistically significant changes in DAS28 compared to placebo occurred in the 3 mg kg group on Days Inhibitors,Modulators,Libraries 56 and 84 and in the 10 mg kg group on Day 84, yet the effect on DAS28 scores at high doses appeared to be worse compared with the low medium doses are true, it would suggest a U shape re sponse curve. Such a response has been observed in some medical conditions but not in clinical trials of musculoskeletal diseases. Inadequate neutralisation of other cytokines due to a protein carrier effect has been reported in the literature and included situations in which there is a high target load, for example, IL 6 in can cer patients.

We conducted an exploratory Inhibitors,Modulators,Libraries PK PD analysis which showed some improvement in DAS28 at lower exposures, supported by a signifi cant effect in CRP and IL 6. One potential explanation is for a protein carrier effect due to the moderate to poor binding affinity and rapid off rate of GSK315234 compared to the higher affinity OSM recep tor at the site of action in the synovial joint. We hypothesize that GSK315234 binds to circulating OSM. At low doses of GSK315234, it was unable to neu tralise OSM. At a moderate dose, GSK315234 effectively neutralised the activity of OSM. At high doses of GSK315234, all OSM will be complexed to GSK315234. The GSK315234 OSM complex will have a longer half life than OSM.

However, due to the high off rate and low binding affinity of GSK315234 relative to the OSM receptor, GSK315234 acts as a carrier of OSM and OSM is released in the synovial joint. Our results suggest that other factors, such Inhibitors,Modulators,Libraries as accumulation of the OSM com plex and rate of dissociation from GSK315234, need to be properly considered. Nevertheless, both single and repeat dosing with GSK315234 was generally well tolerated. The PK PD analysis selleck chemicals suggested that moderate affinity and rapid off rate of GSK315234 may lead to a U shape dose res ponse.