n4-(2-2-dimethyl-3-oxo-4h-pyrid(1-4)oxazin-6-yl)-5-fluoro-n2-(3-4-5-trimethoxyphenyl)-2-4-pyrimidinediamine and Arthritis--Rheumatoid

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 dif

Topics: Aminopyridines; Animals; Antirheumatic Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Humans; Intracellular Signaling Peptides and Proteins; Morpholines; Oxazines; Prodrugs; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Syk Kinase

R788 (fostamatinib) is an oral prodrug that is rapidly converted into a relatively selective spleen tyrosine kinase (SYK) inhibitor R406, evaluated for the treatment of rheumatoid arthritis (RA). This analysis aimed at developing a pharmacodynamic model for efficacy using pooled ACR20 data from two phase II studies in patients with rheumatoid arthritis (TASKi1 and TASKi2), describing the effect of fostamatinib as a function of fostamatinib exposure (dose, R406 plasma concentration) and other explanatory variables. The exposure-response relationship of fostamatinib was implemented into a continuous time Markov model describing the time course of transition probabilities between the three possible states of ACR20 non-responder, responder, and dropout at each visit. The probability of transition to the ACR20 response state was linearly (at the rate constant level) related to average R406 plasma concentrations and the onset of this drug effect was fast. Further, increases of fostamatinib dose resulted in increased dropout and subsequent loss of efficacy. This analysis provided an increased understanding of the exposure-response relationship, and provided support for fostamatinib 100 mg BID an appropriate dose regimen for further clinical evaluation.

Topics: Administration, Oral; Aminopyridines; Antirheumatic Agents; Arthritis, Rheumatoid; Biotransformation; Clinical Trials, Phase II as Topic; Drug Dosage Calculations; Europe; Humans; Latin America; Linear Models; Markov Chains; Mexico; Morpholines; Oxazines; Prodrugs; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Syk Kinase; Treatment Outcome; United States

Fostamatinib is an oral spleen tyrosine kinase (SYK) inhibitor which has been evaluated as a potential treatment for rheumatoid arthritis (RA). Treatment with fostamatinib has been associated with an increase in blood pressure (BP). In this work, we present a pooled analysis of the pharmacokinetic-pharmacodynamic (PKPD) relationship for BP, based on 3 Phase III studies, aiming to increase the knowledge about fostamatinib's effect on BP in the RA population. Fostamatinib is rapidly and extensively converted to R406 after oral administration of fostamatinib, and the PK of R406 could be described by a two-compartment population PK model with first order absorption, with an estimated CL/F of 18.7 L/h. Average steady-state concentrations, predicted based on the individual CL/F estimates, were subsequently used in the PKPD analysis. The population PKPD analysis revealed a concentration dependent increase of BP with increasing R406 concentrations, where a power model and an Emax model best described the increase in SBP and DBP, respectively. The predicted increases were +5.2 mmHg for SBP and +4.2 mmHg for DBP, for a 100 mg bid dose. The impact of covariates on the PKPD relationship was investigated but covariates did only explain a minor part of the overall high variability in BP.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aminopyridines; Antirheumatic Agents; Arthritis, Rheumatoid; Blood Pressure; Double-Blind Method; Female; Humans; Intracellular Signaling Peptides and Proteins; Male; Middle Aged; Models, Biological; Morpholines; Oxazines; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Syk Kinase; Young Adult

To investigate whether a narrow spectrum kinase inhibitor RV1088, which simultaneously targets specific MAPKs, Src and spleen tyrosine kinase (Syk), is more effective at inhibiting inflammatory signalling in rheumatoid arthritis (RA) than single kinase inhibitors (SKIs).. elisas were used to determine the efficacy of RV1088, clinically relevant SKIs and the pharmaceutical Humira on pro-inflammatory cytokine production by activated RA synovial fibroblasts, primary human monocytes and macrophages, as well as spontaneous cytokine synthesis by synovial membrane cells from RA patients. In human macrophages, RNAi knockdown of individual kinases was used to reveal the effect of inhibition of kinase expression on cytokine synthesis.. RV1088 reduced TNF-α, IL-6 and IL-8 production in all individual activated cell types with low, nM, IC50 s. SKIs, and combinations of SKIs, were significantly less effective than RV1088. RNAi of specific kinases in macrophages also caused only modest inhibition of pro-inflammatory cytokine production. RV1088 was also significantly more effective at inhibiting IL-6 and IL-8 production by monocytes and RA synovial fibroblasts compared with Humira. Finally, RV1088 was the only inhibitor that was effective in reducing TNF-α, IL-6 and IL-8 synthesis in RA synovial membrane cells with low nM IC50 s.. This study demonstrates potent anti-inflammatory effect of RV1088, highlighting that distinct signalling pathways drive TNF-α, IL-6 and IL-8 production in the different cell types found in RA joints. As such, targeting numerous signalling pathways simultaneously using RV1088 could offer a more powerful method of reducing inflammation in RA than targeting individual kinases.

Topics: Acetamides; Adalimumab; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Dasatinib; Dose-Response Relationship, Drug; Humans; Inflammation Mediators; Interleukin-6; Interleukin-8; Macrophages; Monocytes; Naphthalenes; Oxazines; Piperidines; Primary Cell Culture; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; RNA, Small Interfering; Signal Transduction; Synovial Membrane; Tumor Necrosis Factor-alpha; Urea

Spleen tyrosine kinase (Syk), a key mediator of immunoreceptor signaling in inflammatory cells, is essential for immune complex-mediated signal transduction initiated by activated receptors for immunoglobulin G. In collagen-induced arthritis, R788/R406, a novel and potent small molecule Syk inhibitor suppressed clinical arthritis, bone erosions, pannus formation, and synovitis. Serum anti-collagen type II antibody levels were unaltered, while the half-life of exogenous antibody was extended when co-administered with R406. Expression of the targeted kinase (Syk) in synovial tissue correlated with the joint level of inflammatory cell infiltrates and was virtually undetectable in treated rats. Syk inhibition suppressed synovial cytokines and cartilage oligomeric matrix protein (COMP) in serum, suggesting a sensitive and reliable biomarker for R406 activity. These results highlight the role of activating Fcgamma receptors in inflammatory synovitis and suggest that interruption of the signaling cascade with a novel Syk inhibitor may be a useful addition to immunosuppressive disease-modifying anti-rheumatic drugs currently used in the treatment of human autoimmune diseases such as rheumatoid arthritis.

Topics: Aminopyridines; Animals; Arthritis, Rheumatoid; Arthus Reaction; Bone Resorption; Collagen Type II; Disease Models, Animal; Female; Immunoglobulin G; Inflammation; Intracellular Signaling Peptides and Proteins; Morpholines; Oxazines; Prodrugs; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, IgG; Signal Transduction; Syk Kinase; Synovial Fluid; Synovitis