R289 / Rigel - LARVOL DELTA

Safety and efficacy results from A phase 1b study of R289, a dual irak 1/4 inhibitor, in patients with Relapsed/Refractory (R/R) lower risk myelodysplastic syndrome (LR-MDS). (ASH 2025) - P1/2 | "The median number of prior therapies was 3 (range 1-8); 76% were previouslytreated with luspatercept, 73% with an erythropoiesis stimulating agent, 67% with a hypomethylatingagent, and 6% with imetelstat. R289 was well-tolerated in this elderly, heavily pretreated LR-MDS patient population, themajority of whom were HTB at BL. The incidence of G3/4 cytopenias and infections was low. Allresponding patients had R835 plasma concentrations similar to those at which ≥50% LPS-inducedinhibition of cytokine release was observed in HS, indicating a potential threshold for dose response(≥500 mg QD)."

Clinical • P1 data • Constipation • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Infectious Disease • Inflammation • Myelodysplastic Syndrome • Pneumonia • Respiratory Diseases • HEY1 • IL1R1 • IRAK1 • TLR4

Rigel Presents Updated Data from the Ongoing Phase 1b Study Evaluating R289 in Patients with Lower-Risk MDS at the 67th ASH Annual Meeting and Exposition (Rigel Press Release) - "Key highlights from the updated data as of October 28, 2025, include: 33 patients were enrolled, representing a difficult-to-treat population....Median duration of treatment was 5.5 months (range: 0.9 - 27.7 months). R289 was generally well tolerated across all dose groups in this heavily pre-treated lower-risk MDS patient population....For evaluable transfusion dependent (TD) patients (≥16 weeks follow up) at dose levels of at least 500 mg QD and higher, 6/18 (33%) patients achieved durable red blood cell transfusion independence (RBC-TI) of >8 weeks [500 mg QD (1/3), 750 mg QD (2/5), 500/250 mg QD (1/5), 500 mg BID (2/5)]. Duration of RBC-TI was >16 weeks in 4 patients and >24 weeks in 3 patients."

P1 data • Myelodysplastic Syndrome

Highlights of JTCC Research to be presented at ASH 2025: Myeloproliferative Neoplasms (PRNewswire) - "Preliminary data from the Phase I/II study of nuvisertib, an oral investigational selective PIM1 inhibitor, in combination with momelotinib showed clinical responses in patients with relapsed/refractory myelofibrosis (ABSTRACT 25-3882); Safety and efficacy results from A phase 1b study of R289, a dual irak 1/4 inhibitor, in patients with Relapsed/Refractory (R/R) lower risk myelodysplastic syndrome (LR-MDS) (ABSTRACT 25-13480); Nuvisertib, an oral investigational selective PIM1 kinase inhibitor, showed clinical responses strongly correlating with cytokine modulation in patients with relapsed/refractory myelofibrosis in the ongoing global phase I/II study (ABSTRACT 25-2614)."

Clinical data • Myelodysplastic Syndrome • Myelofibrosis

ASH 2025 tip sheet: Sylvester researchers contribute to more than 35 oral presentations at ASH Annual Meeting (Eurekalert)

Clinical data • Diffuse Large B Cell Lymphoma • Large B Cell Lymphoma • Myelodysplastic Syndrome

R289, a Dual Irak 1/4 Inhibitor, in Patients with Relapsed/Refractory (R/R) Lower-Risk Myelodysplastic Syndrome (LR-MDS): Initial Results from a Phase 1b Study (ASH 2024) - P1/2 | "R835 is a selective dual inhibitor of IRAK 1/4 that blocks TLR4 and IL-1R-dependent cytokine release in vitro and in vivo...Those with del (5q) must be R/R to lenalidomide...Prior therapies included luspatercept [n=15 (79%)], hypomethylating agent (HMA) [n=15 (79%)]...Further evaluation of 250 mg BID and a 500/250 mg daily split dose is ongoing. An expansion cohort is planned to confirm a recommended phase 2 dose."

Clinical • P1 data • Acute Myelogenous Leukemia • Anemia • Fatigue • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Oncology • Pneumonia • Respiratory Diseases • IL1R1 • IRAK1 • MYD88 • TLR4

Presentation 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 (R/R) Lower Risk Myelodysplastic Syndrome (LR-MDS) (Rigel Press Release) - "As of the data cutoff date (July 15, 2025), 33 patients were enrolled in the dose escalation part of the study. Patients had a median age of 75 with a median of 3 prior therapies and 61% were high transfusion burden at baseline...R289 was generally well tolerated across all dose groups...For evaluable transfusion dependent patients (≥16 weeks follow up) at dose levels of at least 500 mg QD and higher, 4/13 patients (31%) achieved durable red blood cell transfusion independence (RBC-TI) for >8 weeks (500 mg QD [1/3], 750 mg QD [2/5], 500/250 mg QD [1/5]). Duration of RBC-TI was >16 weeks in 3 patients, >24 weeks in 2 patients, and >12 months in 1 patient. The median time to onset of RBC-TI was 2.2 months and the median duration of RBC-TI was 24.3 weeks....Updated data as of an October 28, 2025, data cutoff will be presented during the oral presentation."

P1 data • Myelodysplastic Syndrome

Rigel Announces First Patient Enrolled in the Dose Expansion Phase of its Phase 1b Study of R289 in Patients with Lower-Risk MDS (Rigel Press Release) - "Rigel's open-label, Phase 1b study of R289 is evaluating the safety, tolerability, pharmacokinetics and preliminary activity in patients with R/R lower-risk MDS (NCT05308264)."

Enrollment open • Myelodysplastic Syndrome

Clinical Development (Rigel Press Release) - "Rigel continues to advance its Phase 1b clinical study evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of R289, a novel and selective dual interleukin receptor-associated kinases 1 and 4 (IRAK1/4) inhibitor, in patients with relapsed or refractory (R/R) lower-risk myelodysplastic syndrome (MDS). Enrollment in the dose escalation part of the study was completed in July. The company expects to share updated data from the study later this year and plans to initiate the dose expansion part of the study in the second half of this year."

P1 data • Trial status • Myelodysplastic Syndrome

C-906289-002: Study of R289 in Patients With Lower-risk Myelodysplastic Syndromes (LR MDS) (clinicaltrials.gov) - P1/2 | N=86 | Recruiting | Sponsor: Rigel Pharmaceuticals | N=34 ➔ 86 | Trial completion date: May 2025 ➔ Dec 2026 | Trial primary completion date: May 2025 ➔ Aug 2026

Enrollment change • Trial completion date • Trial primary completion date • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

R289: “R289 was generally well tolerated in this heavily pre-treated LR -MDS patient population, the majority of whom were HTB”; Myelodysplastic syndrome (Rigel) - Investor Event with KOL Insights on Polycythemia Vera (PV) and the Hepcidin Mimetic Rusfertide

P1 data • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

C-906289-002: Study of R289 in Participants With Lower-risk Myelodysplastic Syndromes (LR MDS) (clinicaltrials.gov) - P1/2 | N=34 | Recruiting | Sponsor: Rigel Pharmaceuticals | Phase classification: P1b ➔ P1/2

Phase classification • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • CRP • TNFA

Rigel Announces R289 Granted Orphan Drug Designation by the FDA for MDS (PRNewswire) - "Rigel Pharmaceuticals, Inc...today announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug designation to R289 for the treatment of myelodysplastic syndromes (MDS)....Rigel's potent and selective dual inhibitor of IRAK1 and IRAK4, is being studied in an ongoing Phase 1b study evaluating the safety, tolerability, pharmacokinetics and preliminary activity in patients with LR-MDS who are relapsed or refractory to prior therapies."

Orphan drug • Myelodysplastic Syndrome

Rigel Highlights Initial Data from Ongoing Phase 1b Study Evaluating R289 in LR-MDS at the 66th ASH Annual Meeting and Exposition (PRNewswire) - P1b | N=34 | NCT05308264 | Sponsor: Rigel Pharmaceuticals | "Key highlights from the interim data as of October 25, 2024, include: 22 patients were enrolled....For the 18 efficacy evaluable patients (≥1 dose of R289 with ≥1 efficacy assessment), hematologic responses occurred in 40% (4/10) of evaluable transfusion dependent patients receiving R289 doses ≥500 mg QD. Red blood cell (RBC)-transfusion independence (RBC-TI) ≥8 weeks was achieved by three patients (1 at 500 mg QD and 2 at 750 mg QD); two HTB patients achieved RBC-TI >24 weeks. The median duration of RBC-TI was 29 weeks (range 12.7-51.9 weeks)....The patients achieving RBC-TI had peak hemoglobin increases exceeding 2.0 g/dL compared to baseline."

P1 data • Myelodysplastic Syndrome

Rigel Announces R289 Granted Fast Track Designation by the FDA for Lower-Risk MDS (PRNewswire) - "Rigel Pharmaceuticals...announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to R289 for the treatment of patients with previously-treated transfusion dependent lower-risk myelodysplastic syndrome (LR-MDS). R289, Rigel's potent and selective dual inhibitor of IRAK1 and IRAK4, is being studied in an ongoing Phase 1b study evaluating the safety, tolerability, pharmacokinetics and preliminary activity in patients with LR-MDS who are relapsed or refractory to prior therapies."

Fast track • Myelodysplastic Syndrome

Rigel Announces Six Poster Presentations at the 66th American Society of Hematology Annual Meeting and Exposition (PRNewswire) - P1/2 | N=34 | NCT05308264 | Sponsor: Rigel Pharmaceuticals | "Initial data from the dose escalation phase using a July 15, 2024 data cutoff date indicate that R289 was generally well tolerated in a heavily pretreated LR-MDS patient population...Fourteen of 19 patients were evaluable for efficacy (received ≥1 dose of study drug with ≥1 efficacy assessment). Per International Working Group (IWG) 2018, RBC-transfusion independence (RBC-TI)/hematologic improvement (HI-E) occurred in 36% of patients receiving R289 doses ≥500 mg QD, with a median duration of RBC-TI of 29 weeks (range 12.4-35.9 weeks). RBC-TI >24 weeks was achieved in 2 high transfusion burden patients following 3 and 5 prior therapies, including a hypomethylating agent. Updated data as of October 25, 2024 data cutoff will be presented during the poster session."

P1/2 data • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Rigel Reports Second Quarter 2024 Financial Results and Provides Business Update (PRNewswire) - "Rigel continues to advance its Phase 1b clinical trial evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of R289...Enrollment in the fourth dose level (250 mg twice daily) of the trial is underway. Preliminary data are expected by the end of 2024...In early August, The University of Texas MD Anderson Cancer Center, with Rigel's support, opened enrollment for a Phase 1b/2 trial of decitabine and venetoclax in combination with olutasidenib in patients with IDH1-mutated AML (NCT06445959)....For the second quarter ended June 30, 2024, total revenues were $36.8 million, consisting of $26.4 million in TAVALISSE net product sales, $5.2 million in REZLIDHIA net product sales, $1.9 million in GAVRETO net product sales, and $3.4 million in contract revenue from collaborations. TAVALISSE net product sales grew 24% compared to $21.3 million in the same period of 2023."

Commercial • Enrollment status • Sales • Trial status • Acute Myelogenous Leukemia • CNS Tumor • Colorectal Cancer • Endocrine Cancer • Head and Neck Cancer • Hematological Malignancies • Immunology • Leukemia • Lung Cancer • Myelodysplastic Syndrome • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology

Phase 1b trial of IRAK 1/4 inhibition for low-risk myelodysplastic syndrome refractory/resistant to prior therapies. (ASCO 2024) - P1b | "R289 is a prodrug for R835, a potent and selective inhibitor of IRAK1 and IRAK4 kinases. Statistical analyses will be primarily descriptive. The trial is currently ongoing at 9 US sites."

P1 data • Hematological Disorders • Hematological Malignancies • Inflammation • Myelodysplastic Syndrome • Oncology • Pain • IL1R1 • IRAK1 • IRAK4 • NLRP3

Rigel Highlights New Data in Three Poster Presentations at the 2024 ASCO Annual Meeting (Rigel Press Release) - "An overview of the study design of the ongoing Phase 1b trial evaluating R289 in patients with LR-MDS will be presented. The primary endpoint for this trial is safety with key secondary endpoints including preliminary efficacy and evaluation of pharmacokinetic properties. Enrollment in dose levels 1 (250 mg QD), 2 (500 mg QD), and 3 (750 mg QD) has been completed. Two additional dose levels with twice daily dosing have been added (250 mg BID and 500/250 mg) and the trial is actively recruiting."

Trial status • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Rigel Reports First Quarter 2024 Financial Results and Provides Business Update (Rigel Press Release) - "In the first quarter of 2024, a total of 390 REZLIDHIA bottles were sold in the U.S., significantly accelerating sales growth over last year. This growth was driven by increased demand, with 326 bottles shipped to patients and clinics...Rigel continues to advance its Phase 1b clinical trial evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of R289...in patients with relapsed/refractory lower-risk myelodysplastic syndrome (LR-MDS). Enrollment in the third cohort of the trial has been completed and the company is planning to include two additional cohorts with twice daily dosing regimens. Preliminary data are expected by the end of 2024...REZLIDHIA net product sales were $4.9 million compared to $1.5 million in the same period of 2023. Contract revenue from collaborations consisted of $2.3 million from Kissei Pharmaceutical Co., Ltd. related to delivery of drug supplies..."

P1 data • Sales • Trial status • Acute Myelogenous Leukemia • Myelodysplastic Syndrome

Rigel Reports Third Quarter 2023 Financial Results and Provides Business Update (PRNewswire) - "Rigel continues to advance its open-label, Phase 1b clinical trial of R289, an investigational, potent, and selective IRAK1/4 inhibitor, in patients with lower-risk myeloid dysplastic syndrome (LR-MDS) who are refractory/resistant to prior therapies. Target enrollment in the second cohort of the trial has been completed and Rigel is currently enrolling patients in the third cohort. Preliminary data results are expected by mid-year 2024."

P1 data • Trial status • Myelodysplastic Syndrome

Rigel Announces Poster Presentations at the 65th American Society of Hematology Annual Meeting and Exposition (PRNewswire) - "This trial in progress poster provides an overview of the study design of the ongoing Phase 1b trial evaluating R289, a potent and selective inhibitor of IRAK1 and IRAK4 kinases, in patients with low-risk myelodysplastic syndrome (LR-MDS) relapsed or refractory to prior therapies."

Clinical protocol • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Study of R289 in Participants With Lower-risk Myelodysplastic Syndromes (LR MDS) (clinicaltrials.gov) - P1b | N=34 | Recruiting | Sponsor: Rigel Pharmaceuticals | N=22 ➔ 34 | Trial completion date: May 2024 ➔ May 2025 | Trial primary completion date: Apr 2024 ➔ May 2025

Enrollment change • Trial completion date • Trial primary completion date • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Rigel Reports Second Quarter 2023 Financial Results and Provides Business Update (PRNewswire) - "Rigel continues to advance its open-label, Phase 1b clinical trial of R289, an investigational, potent, and selective IRAK1/4 inhibitor, in patients with lower-risk myeloid dysplastic syndrome (LR-MDS) who are refractory/resistant to prior therapies. Target enrollment in the second cohort of the trial has been completed and Rigel expects to begin enrollment in the third cohort in the near future."

Trial status • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

PHASE 1B CLINICAL STUDY OF IRAK 1/4 INHIBITION FOR LOW-RISK MYELODYSPLASTIC SYNDROMES REFRACTORY/RESISTANT TO PRIOR THERAPIES: A TRIAL IN PROGRESS (EHA 2023) - P1b | "R289 is a prodrug that is converted to the active drug R835 in the gastrointestinal (GI) tract. Phase I, Myelodysplastic syndrome, Kinase inhibitor, MDS"

Clinical • P1 data • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Inflammation • Myelodysplastic Syndrome • Oncology • Pain • IL1R1 • IRAK1 • IRAK4 • NLRP3 • TLR4

Phase 1b clinical study of IRAK 1/4 inhibition for low-risk myelodysplastic syndromes refractory/resistant to prior therapies. (ASCO 2023) - P1b | "R289 is a prodrug that is converted to the active drug R835 in the gastrointestinal (GI) tract. The trial is currently recruiting at 8 US sites. Clinical trial information: NCT05308264."

Clinical • P1 data • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Inflammation • Myelodysplastic Syndrome • Oncology • Pain • IL1R1 • IRAK1 • IRAK4 • NLRP3 • TLR4