Rigel's R289 Shows Promise in Lower-Risk MDS with 33% Transfusion Independence Rate at ASH 2025
核心洞察
Rigel Pharmaceuticals reported updated Phase 1b data for R289, an oral IRAK1 (搜索)/4 dual inhibitor, showing 33% of transfusion-dependent lower-risk MDS (搜索) patients achieved red blood cell transfusion independence at doses ≥500 mg daily.
The study enrolled 33 heavily pre-treated patients with median age 75 and median 3 prior therapies, demonstrating R289's tolerability with manageable side effects including diarrhea, constipation, and fatigue.
Peak hemoglobin increases of 2.9 to 6.1 g/dL occurred in patients achieving transfusion independence, with median duration of 22.9 weeks and some patients maintaining independence for over 24 weeks.
Rigel Pharmaceuticals presented encouraging updated data from its ongoing Phase 1b study of R289, an oral prodrug targeting IRAK1 (搜索)/4 pathways, in patients with relapsed or refractory lower-risk myelodysplastic syndrome (搜索) (MDS (搜索)) at the 67th American Society of Hematology Annual Meeting. The data demonstrate preliminary efficacy in a challenging patient population with significant unmet medical needs.
Study Design and Patient Population
The open-label Phase 1b study (NCT05308264) evaluated R289's safety, tolerability, pharmacokinetics and preliminary efficacy in patients with relapsed or refractory lower-risk MDS (搜索). As of October 28, 2025, 33 patients were enrolled representing a difficult-to-treat population with median age of 75 years.
The patient cohort was heavily pre-treated, with a median of 3 prior therapies ranging from 1-8 treatments. Notably, 76% of patients had received luspatercept, 73% had received erythropoiesis stimulating agents, 67% had received hypomethylating agents, and 6% had received imetelstat. At baseline, 61% of patients had high transfusion burden, and 67% were ring sideroblast negative.
Efficacy Results Show Transfusion Independence
For evaluable transfusion-dependent patients with at least 16 weeks of follow-up receiving R289 doses of 500 mg daily or higher, 6 out of 18 patients (33%) achieved durable red blood cell transfusion independence lasting more than 8 weeks. The response rates varied by dose group: 500 mg once daily (1/3 patients), 750 mg once daily (2/5 patients), 500/250 mg once daily (1/5 patients), and 500 mg twice daily (2/5 patients, 40% response rate).
The median time to onset of transfusion independence was 1.9 months, with a median duration of 22.9 weeks. Four patients maintained transfusion independence for more than 16 weeks, and three patients achieved independence lasting more than 24 weeks. Patients achieving transfusion independence experienced substantial hemoglobin improvements, with peak increases ranging from 2.9 to 6.1 g/dL compared to baseline.
Of the six patients who achieved transfusion independence, five had previously received hypomethylating agent therapy, suggesting R289's potential effectiveness in this heavily pre-treated population.
Safety Profile Demonstrates Tolerability
R289 demonstrated a generally well-tolerated safety profile across all dose groups during a median treatment duration of 5.5 months (range: 0.9-27.7 months). The most common Grade 1/2 treatment-emergent adverse events occurring in at least 18% of patients included diarrhea (30%), constipation and fatigue (27% each), and increased creatinine and cough (21% each).
Grade 3/4 adverse events were manageable, with anemia (搜索) occurring in 18% of patients, neutrophil count decrease and pneumonia each affecting 15% of patients, and elevated liver enzymes (ALT and AST) each occurring in 9% of patients. Only one dose-limiting toxicity was reported in the 750 mg dose group, consisting of Grade 4 AST elevation and Grade 3 ALT elevation.
Pharmacokinetic and Mechanistic Insights
At doses of 500 mg daily and higher, steady-state R835 plasma concentrations reached or exceeded levels associated with 50-90% inhibition of lipopolysaccharide-induced cytokine release previously observed in healthy volunteers. This pharmacokinetic data supports the therapeutic rationale for R289's mechanism of action.
R289 functions as a prodrug of R835, a potent and selective dual inhibitor of interleukin receptor-associated kinases 1 and 4 (IRAK1 (搜索)/4). Preclinical studies have shown R835 blocks inflammatory cytokine production in response to toll-like receptor and interleukin-1 receptor family signaling. These pathways play critical roles in innate immune response, and their dysregulation can lead to inflammatory conditions. Chronic stimulation of these receptor systems is believed to create the pro-inflammatory bone marrow environment responsible for persistent cytopenias in lower-risk MDS (搜索) patients.
Regulatory Status and Future Development
R289 has received both Orphan Drug designation for myelodysplastic syndromes treatment and Fast Track designation for previously-treated transfusion-dependent lower-risk MDS (搜索) from the FDA. These designations reflect the significant unmet medical need in this patient population.
The dose escalation phase of the study was completed in July 2025, and the dose expansion phase began in October 2025 with the first patient dosed. Up to 40 patients will be randomized to receive either 500 mg once or twice daily to determine the recommended Phase 2 dose for future clinical trials.
"New therapies are needed for patients with transfusion dependent lower-risk MDS (搜索). We're pleased to share these updated study results, which underscore the potential of R289 to become a treatment option for these patients," said Lisa Rojkjaer, M.D., Rigel's chief medical officer. "We look forward to concluding the dose expansion phase of the study and anticipate selection of the recommended Phase 2 dose for future clinical studies in the second half of 2026."
The data were presented by Dr. Guillermo Garcia-Manero in an oral session at the ASH Annual Meeting, highlighting the clinical significance of these preliminary results in addressing the therapeutic challenges faced by lower-risk MDS (搜索) patients who have exhausted standard treatment options.