When FcγRs I, IIA, and IIIA bind to their ligands, the receptor complex becomes activated and triggers the phosphorylation of the immunoreceptor-activating motifs (ITAMs). This leads to various genes becoming activated, which causes a cytoskeletal rearrangement that mediates phagocytosis in cells of the monocyte/macrophage lineage. Because Syk plays an important role in FcγR-mediated signal transduction and inflammatory propagation, it is considered a good target for the inhibition of various autoimmune conditions, including rheumatoid arthritis and lymphoma. Clinical trials
Fostamatinib has been in clinical trials for rheumatoid arthritis, autoimmune thrombocytopenia, autoimmune hemolytic anemia, IgA nephropathy, and lymphoma. The drug is currently being used in a Phase 1 trail to test the safety of the combination of the study drugs fostamatinib and paclitaxel for patients with ovarian cancer.The investigation of fostamatinib began with studies involving the treatment of mouse models with cytopenia. Mice were used to measure the effectiveness of R788, a small molecule prodrug of the biologically active R406, a Syk inhibitor. In animal models, treatment with R406/R788 was shown to be safe and effective in reducing inflammation and joint damage in immune-mediated rheumatoid arthritis. The models responded favorably to treatment so the study progressed to Phase 2 trials involving humans. Human studies have shown that R788 has good oral bioavailability, biologic activity, is well tolerated, and does not exhibit collagen or ADP-induced platelet aggregation. In NCT00706342, 16 adults with chronic ITP were entered into an open-label, single-arm cohort dose-escalation trials beginning with 75 mg and rising to 175 mg twice a day.
Patients were randomized 2:1 to fostamatinib (100 mg orally twice daily) or placebo twice daily for 24 weeks. Dose could be escalated to 150 mg orally twice daily after one month. The benefit of fostamatinib was assessed based on the percentage of participants who achieved and maintained the pre-determined platelet count between treatment weeks 14 to 24 in fostamatinib and placebo groups respectively. The FIT-1 trial was conducted at 35 sites in Australia, Canada, Denmark, Hungary, Italy, Netherlands, the United Kingdom, and the United States. The FIT-2 trial was conducted at 23 sites in Austria, Bulgaria, Czech Republic, Germany, Norway, Poland, Romania, and Spain.The FDA granted the application for fostamatinib an orphan drug designation and granted the approval of Tavalisse to Rigel Pharmaceuticals.Fostamatinib was approved for medical use in the European Union in January 2020. References
External links
"Fostamatinib". Drug Information Portal. U.S. National Library of Medicine. "Fostamatinib disodium". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT02076399 for "A Efficacy and Safety Study of R935788 in the Treatment of Persistent/Chronic Immune Thrombocytopenic Purpura (ITP) (FIT)" at ClinicalTrials.gov