Introduction: Therapeutic options are limited for previously treated, transfusion-dependent (TD) LR-MDS patients (pts).R835 is a selective dual inhibitor of IRAK 1/4 that blocks TLR4 and IL-1R-dependent cytokine release in vitro and in vivo, which potentially may suppress inflammation and leukemic stem/progenitor cell function and restore normal hematopoiesis in MDS. An ongoing multicenter Phase 1b, open-label, dose escalation (DE)/dose expansion (DEx) study is evaluating the oral IRAK 1/4 inhibitor R289, a prodrug of R835, in LR-MDS (NCT05308264). We present updated safety and preliminary efficacy data after completion of enrollment in the DE phase.

Methods: Eligible pts were ≥18 years old with R/R LR-MDS [Revised International Prognostic Scoring System (IPSS-R) score ≤3.5] and either symptomatic anemia (hemoglobin ≤9.0 g/dL and no red blood cell [RBC] transfusions within the prior 16 weeks [w] [non-TD (NTD)] or TD-anemia (≥2 units [u] RBCs within the prior 16 w). Baseline (BL) RBC transfusion burden (TB) within 16 w prior to study treatment was defined as high (HTB, ≥8u RBCs) or low (LTB, 2-7u RBCs). A modified 3+3 design was used to determine the recommended dose(s) for expansion. Primary/secondary objectives were safety, PK, recommended phase 2 dose (RP2D) selection and preliminary efficacy, respectively. R289 was administered orally in 28-day cycles (250, 500, 750 mg QD; 250 mg BID, 500/250 mg QD split dose, 500 mg BID). Hematologic improvement-erythroid (HI-E) responses were assessed per IWG 2018 criteria and other responses per IWG 2006 criteria.

Results: As of 15 July 2025, 33 pts were enrolled in the DE part. Median age was 75 (58% were ≥ age 75); 70% were males. Baseline IPSS-R category was low (67%) or intermediate (33%); 33.3% were ring sideroblast positive. The median number of prior therapies was 3 (range 1-8); 76% were previously treated with luspatercept, 73% with an erythropoiesis stimulating agent, 67% with a hypomethylating agent, and 6% with imetelstat. At BL, 31 pts were TD: 20 pts (61%) were HTB, 11 pts (33%) were LTB; 2 pts (6%) were NTD. Mean BL absolute neutrophil count was 2.4×109/L; (<1×109/L in 4 pts [12%]). Mean BL platelet count was 172×109/L (<100×109/L in 7 pts [21%]). At the data cutoff, 19 pts (58%) had discontinued treatment. The median time on therapy was 5 months (m) (range 0.53-24.4). One dose-limiting toxicity (DLT) occurred at 750 mg QD (grade [G]3 ALT/G4 AST increase); no DLTs were reported in the first 3/6 pts receiving 500 mg BID clearing the 28-day DLT window.The most frequent (≥20%) treatment emergent adverse events (TEAEs) were diarrhea (n=9, 28.1%), constipation/fatigue (both n=8, 25%) and creatinine increased/ALT increased (both n=7; 21.9%); all G1/2 except for 3 G3/4 ALT increased. G3/4 AEs occurring in ≥10% were anemia (n=5, 15.6%) and neutrophil count decreased/pneumonia (both n=4, 12.5%). AEs led to study drug discontinuation in 2 pts.

Of the 33 pts, 22 completed >16 w follow-up (f/u) and were evaluable for HI-E responses per IWG 2018 (1 NTD/21 TD pts). Eleven pts had <16 w f/u: AE (n=2), lack of benefit (n=2), PI decision (n=1). At 500 mg BID, 5 pts were not yet evaluable and 1 withdrew consent. No pts receiving 250 mg QD (n=3) or 250 mg BID (n=6, 1 NTD) achieved an HI-E response. Steady-state (ss) R835 concentrations at these doses were below the threshold for 25% reduction in LPS-induced cytokine release in healthy subjects (HS), vs doses ≥500 mg QD which had ss R835 levels similar to those associated with 50-90% inhibition of cytokine release. For pts receiving doses ≥500 mg QD, 4/13 pts (31%) achieved RBC-TI for >8 w (500 mg QD [1/3], 750 mg QD [2/5], 500/250 mg QD [1/5]). Among the four responders, duration of RBC-TI was >16 w (3), >24 w (2), >12m (1). Median time to onset of RBC-TI was 2.2 m (range 1.7-3.3). Median duration of RBC-TI was 24.3 w (range 12.4- 87.9). One LTB pt achieving TI (750 mg QD) also attained a marrow complete response.

Conclusions: R289 was well-tolerated in this elderly, heavily pretreated LR-MDS patient population, the majority of whom were HTB at BL. The incidence of G3/4 cytopenias and infections was low. All responding patients had R835 plasma concentrations similar to those at which ≥50% LPS-induced inhibition of cytokine release was observed in HS, indicating a potential threshold for dose response (≥500 mg QD). The randomized comparison of 2 doses in the DEx part of the study will determine the RP2D for future clinical trials.

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2025
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