Toll like receptors (TLRs) and the interleukin 1 receptor family (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 has also been implicated in causing a pro-inflammatory bone marrow environment leading to persistent cytopenias in lower-risk myelodysplastic syndrome (LR-MDS) patients1.
R835 is a selective dual inhibitor of IRAK1/4 that blocks TLR4 and IL-1R-dependent systemic cytokine release. In preclinical studies, R835 demonstrated activity in multiple animal models of inflammatory disease2,3 and showed that dual inhibition of IRAK1 and IRAK4 provided more complete suppression of inflammatory cytokines when compared to an IRAK4-selective inhibitor4.
Development of R289:
In a Phase 1 clinical trial, R835 was well tolerated and inhibited LPS-induced inflammatory cytokine production in healthy volunteers, demonstrating proof-of-mechanism.5 Phase 1 clinical studies of R289 (an oral prodrug that is rapidly converted to R835 in the gut) are also complete.
A Phase 1b open-label, multicenter trial of R289 in patients with relapsed/refractory lower-risk MDS is currently enrolling (NCT05308264). The primary endpoint for this trial is safety with key secondary endpoints including preliminary efficacy and evaluation of pharmacokinetic properties.