Rigel targets H2 2026 Phase 2 dose pick for R289 after 33% RBC-TI signal
Rigel plans to select a recommended Phase 2 dose for its IRAK1/4 inhibitor R289 in lower-risk MDS by year-end, building on a small dose-expansion cohort that showed transfusion independence in one third of evaluable patients.
Executive Summary
- Rigel Pharmaceuticals plans to pick a recommended Phase 2 dose for its oral IRAK1/4 inhibitor R289 later this year, closing out the dose-finding phase of a trial that has run for roughly four years in lower-risk MDS patients who have exhausted standard options.
- A small transfusion-dependent subset of the dose-escalation cohort achieved durable transfusion independence at higher doses, a signal that has not yet been tested in the larger, randomized dose-expansion cohort now underway.
- No therapy is currently established for patients who have failed erythropoiesis-stimulating agents, luspatercept, and hypomethylating agents, so a dose that reproduces or extends the transfusion-independence signal would fill a gap the field lacks a validated answer for.
- The trial has widened substantially since it started, its enrollment target more than doubled and its completion timeline pushed back over two years, changes that reflect protocol evolution rather than a stalled program given the trial remains actively recruiting.
The milestone
Rigel Pharmaceuticals, Inc. said it anticipates selecting the recommended Phase 2 dose for R289, an oral prodrug that inhibits interleukin receptor-associated kinases 1 and 4 (IRAK1/4), in the second half of 2026, once the dose-expansion phase of its Phase 1b study concludes. "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," Rigel chief medical officer Lisa Rojkjaer said when the company presented updated data at the American Society of Hematology annual meeting in December 2025. The trial, registered as NCT05308264, enrolls adults with relapsed or refractory lower-risk myelodysplastic syndrome who have failed erythropoiesis-stimulating agents, luspatercept, or hypomethylating agents. Rigel+1Rigel Presents Updated Data from the Ongoing Phase 1b Study Evaluating R289 in Patients with Lower-Risk MDS at the 67th ASH Annual Meeting and ExpositionDec 7, 2025Study of R289 in Patients With Lower-risk Myelodysplastic Syndromes (LR MDS)NCT05308264
Probability of SuccessBased on the AppliedXL Probability of Success model. For more information about the methodology, read the research here.
The evidence so far
As of an October 28, 2025 data cut, 33 patients had enrolled in the dose-escalation portion, with a median age of 75 and a median of three prior therapies. Among evaluable transfusion-dependent patients on doses of at least 500 mg once daily, 6 of 18 (33%) achieved red blood cell transfusion independence lasting more than 8 weeks, including 2 of 5 patients on the 500 mg twice-daily regimen. The median time to onset of transfusion independence was 1.9 months and the median duration was 22.9 weeks, with peak hemoglobin increases of 2.9 to 6.1 g/dL. R289 was generally well tolerated, with the most common grade 3/4 adverse events being anemia (18%), decreased neutrophil count and pneumonia (15% each), and elevated liver enzymes (9% each); one dose-limiting toxicity, a grade 4 AST increase with grade 3 ALT increase, occurred in the 750 mg group. Enrollment in the dose-escalation phase completed in July 2025, and the first patient in the dose-expansion phase, which randomizes up to 40 patients to 500 mg once or twice daily, was dosed in October 2025. The recommended Phase 2 dose decision will draw on results from this larger, still-enrolling expansion cohort, not solely the smaller escalation data reported to date. RigelRigel Presents Updated Data from the Ongoing Phase 1b Study Evaluating R289 in Patients with Lower-Risk MDS at the 67th ASH Annual Meeting and ExpositionDec 7, 2025
The trial's evolution
The study has changed considerably since it opened in September 2022. Enrollment was revised from 40 to 22, then to 34, then to 86 patients, and the primary completion date has moved from January 2024 to April 2024, to May 2025, and now to August 2026. Eligibility criteria have been modified multiple times across the trial's history. The trial remains in Recruiting status, and the most recent enrollment change, to its current target of 86, represents the trial settling at a larger size for a later-stage cohort rather than a shortfall against that target. NCT05308264Study of R289 in Patients With Lower-risk Myelodysplastic Syndromes (LR MDS)NCT05308264
The competitive setting
No industry trial evaluating an IRAK1/4 inhibitor in this indication was identified beyond R289's own program, leaving the mechanism without a direct comparator in lower-risk MDS. The broader indication field includes agents with different mechanisms in various phases, among them Bristol-Myers Squibb's luspatercept (a TGF-beta superfamily ligand trap) in Phase 4 and Takeda's elritercept (an activin receptor ligand trap) in Phase 3, both aimed at anemia in MDS through pathways distinct from IRAK1/4 inhibition. R289 holds Orphan Drug and Fast Track designations from the FDA for previously treated, transfusion-dependent lower-risk MDS, signaling recognized unmet need in a population that has exhausted ESAs, luspatercept, and hypomethylating agents, without indicating anything about eventual approval. Given the absence of an established targeted option after these therapies fail, a recommended Phase 2 dose that reproduces the roughly one-third transfusion-independence rate in a larger, randomized dose-expansion cohort would be the result that distinguishes this program from where it stands today. RigelRigel Presents Updated Data from the Ongoing Phase 1b Study Evaluating R289 in Patients with Lower-Risk MDS at the 67th ASH Annual Meeting and ExpositionDec 7, 2025
This analysis was produced using AI-assisted reporting systems, AppliedXL data, and official public records. These systems undergo editorial review, quality checks, and regular audits by human experts. Errors may still occur, as with any automated system. Always consult the linked primary sources. Read our AI Editorial Policy.