Rigel Pharmaceuticals announced on October 8, 2025, that it has enrolled the first patient in the dose expansion phase of its ongoing Phase 1b study evaluating R289 in patients with relapsed or refractory (R/R) lower-risk myelodysplastic syndrome (MDS). The milestone represents a critical advancement for the South San Francisco-based biotechnology company's investigational dual inhibitor of interleukin receptor-associated kinases 1 and 4 (IRAK1/4).
Study Design and Patient Population
The open-label Phase 1b study (NCT05308264) is evaluating the safety, tolerability, pharmacokinetics and preliminary activity of R289 in patients with R/R lower-risk MDS. The dose expansion phase will randomize up to 40 patients with transfusion-dependent R/R lower-risk MDS to receive 500 mg R289 either once daily or twice daily to determine the recommended Phase 2 dose (RP2D) for future development.
"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," said Lisa Rojkjaer, M.D., Rigel's chief medical officer. "The outcome of this phase of the study will be the selection of the recommended Phase 2 dose of R289 for future clinical studies."
Regulatory Recognition and Development Timeline
R289 has received significant regulatory recognition from the FDA, including Orphan Drug designation for the treatment of myelodysplastic syndromes and Fast Track designation for the treatment of previously-treated transfusion-dependent lower-risk MDS. The company completed enrollment in the dose escalation phase of the study in July 2025 and expects to share updated data from the study later this year.
Once the RP2D has been determined, an exploratory cohort of erythropoiesis-stimulating agent (ESA) R/R, or ineligible, lower-risk MDS patients will be evaluated at the RP2D, expanding the potential patient population for the investigational therapy.
Mechanism of Action and Therapeutic Rationale
R289 is a prodrug of R835, an IRAK1/4 dual inhibitor that has demonstrated the ability to block inflammatory cytokine production in response to toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) family signaling in preclinical studies. TLRs and IL-1Rs play a critical role in the innate immune response, and dysregulation of these pathways can lead to various inflammatory conditions.
Chronic stimulation of both receptor systems is thought to cause the pro-inflammatory environment in the bone marrow responsible for persistent cytopenias in lower-risk MDS patients. This mechanistic understanding provides the scientific rationale for targeting IRAK1/4 in this patient population with significant unmet medical needs.
