R289 blocks inflammatory cytokine production in response to toll-like receptor (TLR) and interleukin-1 receptor family (IL-1R) signaling. TLRs and IL-1Rs play a critical role in the innate immune response and dysregulation of these pathways can lead to a variety of inflammatory conditions such as psoriasis, rheumatoid arthritis, and inflammatory bowel disease. Chronic stimulation of both receptor systems is also thought to be behind the bone marrow pro-inflammatory environment responsible for persistent cytopenias in lower-risk myelodysplastic syndrome (MDS) patients1.
R289 is a prodrug formulation of R835. In preclinical studies, R835 demonstrated activity in multiple animal models of inflammatory disease2,3 and showed that dual inhibition of IRAK1 and IRAK4 with R835 provided more complete suppression of inflammatory cytokines when compared to an IRAK4-selective inhibitor4.
Development of R289:
In a Phase 1 clinical trial, R835 (active metabolite of R289) established proof-of-mechanism by demonstrating the inhibition of inflammatory cytokine production in response to TLR4 signaling in an intravenous LPS challenge study5. Phase 1 clinical studies of R289 are also complete.
In December 2022, Rigel dosed the first patients in a Phase 1b study of R289 in patients with lower-risk MDS who are refractory or resistant to prior therapies. The primary endpoint for this trial is safety with key secondary endpoints including preliminary efficacy and evaluation of pharmacokinetic properties.