Rigel’s investigational candidate, R289, is an oral, potent and selective inhibitor of interleukin receptor-associated kinases 1 and 4 (IRAK1/4).

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.

  • Rigel is currently enrolling a Phase 1b trial of R289 (NCT05308264) 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.

  1. Sallman, DA et al. Unraveling the Pathogenesis of MDS: The NLRP3 Inflammasome and Pyroptosis Drive the MDS Phenotype. Front Oncol. June 16, 2016. DOI:
  2. Lamagna, C. Preclinical efficacy of R835, a novel IRAK1/4 dual inhibitor, in rodent models of joint inflammation. ABS OP0133 presented at European League Against Rheumatism, June 3, 2020
  3. Lamagna, C. Targeting IRAK1 and 4 signaling with R835, a novel oral small molecule inhibitor: a potential new treatment for systemic lupus erythematosus. ABS OP0046 presented at European League Against Rheumatism, June 3, 2020
  4. Data on file, Rigel Pharmaceuticals.
  5. Taylor, V et al. R835, a Novel IRAK1/4 Dual Inhibitor in Clinical Development, Blocks Toll-Like Receptor 4 (TLR4) Signaling in Human and Mouse. ABS FRI0016 presented at European League Against Rheumatism, June 3, 2020