Rigel Pharmaceuticals, Inc (SOUTH SAN FRANCISCO, California), a clinical-stage drug company that discovers and develops novel, small-molecule drugs for the treatment of inflammatory/autoimmune diseases and cancer, announced that its lead agent, R788 (fostamatinib disodium), an orally bioavailable spleen tyrosine kinase inhibitor, has successfully treated lupus-prone mice and significantly improved their survival. Administration of the agent in mice prevented the development of renal disease, treated established murine lupus, and resulted in marked attenuation of renal disease. Rigel expects to initiate a phase II clinical trial in lupus in the second half of 2008.

The mice study evaluated the effects of three doses of R788 versus a control group and an untreated lupus-prone group. For 240 days, the R788 groups orally received 10 mg/kg, 20 mg/kg, or 40 mg/kg BID. Baseline, periodic, and terminal measurements of renal enzymes and proteinuria, blood urea nitrogen, and other tests were conducted on all rodent groups.

When R788 was administered prior to or after disease onset, it delayed the onset of proteinuria and azotemia, as well as reduced renal pathology and kidney infiltrates. However, dsDNA autoantibody titers were minimally affected revealing a lack of correlation between autoantibody titers and renal disease.

At study completion, only two of the 29 mice in the 40 mg/kg group had elevated proteinuria compared with 21 of the 30 mice in the control group. All 29 (100%) mice treated with 40 mg/kg of R788 survived the duration of the study, compared to 14 of the 30 (47%) control mice. The mice treated with 10 mg/kg and 20 mg/kg of the agent demonstrated results that were between those of the control group and the 40 mg/kg group. In a separate study, where treatment was initiated after the onset of disease, the majority of the rodents (~95%) given the 40 mg/kg dose had elevated proteinuria levels that decreased following the onset drug treatment.

R788 has a novel mechanism of action, blocking IgG receptor (Fc receptor) signaling in macrophages and B-cells, and addresses multiple inflammatory mechanisms including TNF-α, IL-1 and -6. The agent has shown clinically significant results in treating patients with rheumatoid arthritis and immune thrombocytopenic purpura.