Rigel Pharmaceuticals Begins Phase 1b Dose Expansion Of R289 In Relapsed Or Refractory Lower-Risk MDS

Rigel Pharmaceuticals, Inc., a commercial-stage biotechnology company specializing in hematologic disorders and oncology, has announced that the first patient has been enrolled in the dose expansion phase of its ongoing Phase 1b clinical study evaluating R289 in patients with relapsed or refractory (R/R) lower-risk myelodysplastic syndrome (MDS). R289 is Rigel’s potent and selective dual inhibitor of interleukin receptor-associated kinases 1 and 4 (IRAK1/4), a promising mechanism aimed at modulating pro-inflammatory pathways implicated in MDS.

"Today marks an important step in the evaluation of R289 for the treatment of patients with transfusion-dependent lower-risk MDS, a disease with a persistent unmet need despite the availability of approved agents. In the dose expansion phase of this study, patients with transfusion dependent R/R lower-risk MDS will be randomized to receive a 500 mg R289 dose either once or twice daily. The outcome of this phase of the study will be the selection of the recommended Phase 2 dose of R289 for future clinical studies. We remain grateful to our investigators for their continued support of our program," said Lisa Rojkjaer, M.D., Rigel's chief medical officer. 

The open-label Phase 1b trial (NCT05308264) is assessing the safety, tolerability, pharmacokinetics, and preliminary efficacy of R289 in patients with R/R lower-risk MDS. Following completion of the dose escalation phase in July 2025, Rigel has now initiated the dose expansion stage, enrolling up to 40 patients randomized to receive 500 mg once or twice daily to establish the recommended Phase 2 dose (RP2D). Once the RP2D is determined, Rigel plans to include an exploratory cohort of erythropoiesis-stimulating agent (ESA)-resistant or ineligible lower-risk MDS patients to further assess R289’s therapeutic potential. Updated clinical data from this study are expected later in 2025.

R289, a prodrug of R835, has previously received Orphan Drug designation for myelodysplastic syndromes and Fast Track designation from the U.S. FDA for previously treated, transfusion-dependent lower-risk MDS. Preclinical data show that R835 inhibits IRAK1/4 activity, thereby suppressing inflammatory cytokine production triggered by toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling. Because chronic stimulation of these pathways contributes to the pro-inflammatory bone marrow environment driving persistent cytopenias in lower-risk MDS, R289 could offer a novel disease-modifying approach for patients with limited treatment options.