Rigel Shares Updated Phase 1b Results for R289 in Lower‑Risk MDS at ASH 2024

• R289 continues to be generally well tolerated, and at doses of ≥ 500 mg once daily preliminary efficacy was observed in elderly, heavily pre‑treated lower‑risk MDS patients.
• Red blood cell transfusion independence (RBC‑TI) was achieved by 33 % (6 of 18) of evaluable transfusion‑dependent patients receiving R289 doses ≥ 500 mg once daily, including 40 % (2 of 5) in the 500 mg twice‑daily cohort.

SOUTH SAN FRANCISCO, Calif., Dec. 7, 2025 – Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL), a commercial‑stage biotech focused on hematologic disorders and oncology, presented updated data from its ongoing Phase 1b study of R289, an oral prodrug of the dual IRAK1/4 inhibitor R835, in patients with relapsed or refractory lower‑risk myelodysplastic syndrome (MDS). The results were shared by Dr. Guillermo Garcia‑Manero at the 67th American Society of Hematology (ASH) Annual Meeting in Orlando, Florida.

“New therapies are needed for patients with transfusion‑dependent lower‑risk MDS. These updated results underscore the potential of R289 to become a viable treatment option,” said Dr. Lisa Rojkjaer, Rigel’s chief medical officer. “We anticipate finalizing the dose‑expansion phase later this year and selecting a recommended Phase 2 dose for further trials in the second half of 2026.”

Rigel’s open‑label Phase 1b trial (NCT05308264) evaluates safety, tolerability, pharmacokinetics, and early efficacy in relapsed/refractory lower‑risk MDS. Enrollment in the dose‑escalation segment concluded in July 2025, and the dose‑expansion phase began in October 2025, targeting up to 40 patients randomized to 500 mg once daily or twice daily to determine the optimal Phase 2 dose.

Key highlights (data as of Oct. 28, 2025):

• 33 patients were enrolled, reflecting a difficult‑to‑treat cohort. Median age was 75, with a median of three prior therapies (range 1‑8). Prior treatment exposure included luspatercept (76 %), erythropoiesis‑stimulating agents (73 %), hypomethylating agents (67 %), and imetelstat (6 %). At baseline, 61 % had a high transfusion burden, and 67 % were ring‑sideroblast negative.
• Median treatment duration was 5.5 months (range 0.9‑27.7 months). R289 was well tolerated across all dose groups. The most common grade 1/2 treatment‑emergent adverse events (≥ 18 % of patients) were diarrhea (30 %), constipation (27 %), fatigue (27 %), increased creatinine (21 %) and cough (21 %). Grade 3/4 events occurring in ≥ 10 % included anemia (18 %), neutropenia (15 %), pneumonia (15 %), and elevated liver enzymes (ALT/AST, each 9 %). One dose‑limiting toxicity (grade 4 AST increase/grade 3 ALT increase) was observed at the 750 mg dose.
• Among evaluable transfusion‑dependent patients (≥ 16 weeks follow‑up) receiving ≥ 500 mg once daily, 33 % (6 of 18) achieved durable RBC‑TI lasting more than eight weeks. Breakdown by cohort: 500 mg QD (1/3), 750 mg QD (2/5), 500/250 mg QD (1/5), 500 mg BID (2/5). Four patients maintained RBC‑TI for > 16 weeks, and three for > 24 weeks. Median time to onset was 1.9 months, with a median duration of 22.9 weeks. Responders saw hemoglobin increases ranging from 2.9 to 6.1 g/dL.
• Five of the six patients who achieved RBC‑TI had previously received a hypomethylating agent, suggesting R289’s activity even after standard epigenetic therapy.
• Steady‑state plasma concentrations of R835 at doses ≥ 500 mg once daily met or exceeded levels associated with 50‑90 % inhibition of lipopolysaccharide‑induced cytokine release in healthy volunteers, confirming target engagement.

Presentation details:

Sunday, Dec. 7, 2025, 9:45 am – 10:00 am ET
Session: “Myelodysplastic Syndromes: Clinical and Epidemiological – Moving the Needle Through Novel Approaches in MDS and CMML”
Title: “An Update of Safety and Efficacy Results from a Phase 1b Study of R289, a Dual IRAK 1/4 Inhibitor, in Patients with Relapsed/Refractory Lower‑Risk MDS”
Presenter: Dr. Guillermo Garcia‑Manero

Regulatory status: R289 has received Orphan Drug designation for MDS and Fast Track designation for previously treated transfusion‑dependent lower‑risk MDS from the U.S. Food and Drug Administration.

About R289
R289 is a prodrug of R835, a selective dual inhibitor of interleukin‑receptor associated kinases IRAK1 and IRAK4. Preclinical studies demonstrate that blocking IRAK1/4 disrupts toll‑like receptor (TLR) and interleukin‑1 receptor (IL‑1R) signaling pathways, curbing the pro‑inflammatory cytokine cascade that drives marrow failure in lower‑risk MDS. By attenuating chronic innate immune activation, R289 aims to restore effective hematopoiesis and reduce transfusion dependence.

About Rigel Pharmaceuticals
Rigel Pharmaceuticals (Nasdaq: RIGL) is a biotechnology company dedicated to discovering and developing novel therapies for hematologic disorders and cancer. Founded in 1996 and headquartered in South San Francisco, California, Rigel’s pipeline includes multiple clinical‑stage candidates targeting disease‑modifying mechanisms.

1. R289 is an investigational compound not yet approved by the FDA.
2. Sallman DA et al., “Unraveling the Pathogenesis of MDS: The NLRP3 Inflammasome and Pyroptosis Drive the MDS Phenotype,” Frontiers in Oncology, 2016. DOI: 10.3389/fonc.2016.00151.

Forward‑Looking Statements
This release contains forward‑looking statements regarding the anticipated outcomes of the ongoing Phase 1b study, potential benefits of R289, and Rigel’s development plans. Such statements involve risks and uncertainties, including clinical trial results, regulatory decisions, market acceptance, and competition. Actual results may differ materially from those expressed or implied in these statements. Rigel does not undertake any obligation to update these forward‑looking statements, except as required by law.