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
Authors: Garcia-Manero Guillermo , Madanat Yazan F , Sekeres Mikkael A. , Carraway Hetty E. , Cusnir Mike , McCloskey James , Naqvi Kiran , Schiller Gary J. , Yan Lucy , Gordi Toufigh , Rojkjaer Lisa , Silverman Lewis R. 
Published: December 2024

Introduction: Interleukin receptor-associated kinases (IRAK) 1 and 4 are critical for downstream signaling of IL-1R family and most toll-like receptors (TLR), promoting proinflammatory cytokine production, bone marrow inflammation and cell death. In addition, IRAK 1/4 exhibit complementary and compensatory dependencies via MyD88-independent pathways in MDS and acute myeloid leukemia, inhibiting hematopoietic cell differentiation. Co-targeting both IRAK 1/4 may be necessary to maximally suppress inflammation and leukemic stem/progenitor cell function and restore hematopoiesis in MDS.
R835 is a selective dual inhibitor of IRAK 1/4 that blocks TLR4 and IL-1R-dependent cytokine release in vitro and in vivo. We report the initial dose escalation results from a phase 1b, open-label, single arm dose escalation/expansion study evaluating the safety and preliminary activity of the oral IRAK 1/4 inhibitor R289, a prodrug of R835, in LR-MDS pts (NCT05308264).
Methods: Eligible pts were ≥18 years of age with R/R LR-MDS [very low, low, or intermediate-risk per the Revised International Prognostic Scoring System (IPSS-R)] and either symptomatic anemia (hemoglobin ≤9.0 g/dL) and no RBC transfusions within the prior 16 weeks (wks) [non-TD (NTD)] or TD-anemia [≥2 units (u) RBCs within 8 wks during the 16-wk pre-enrollment period]. Baseline (BL) RBC transfusion burden (TB) within 16 wks prior to study treatment was defined as high (HTB, ≥8 u RBCs) or low (LTB, 3-7 u RBCs). Those with del (5q) must be R/R to lenalidomide. A 3+3 design was used to determine the maximum tolerated dose or recommended dose for expansion. Primary/secondary objectives were safety/PK and preliminary efficacy, respectively. R289 was administered orally in 28-day cycles (250 mg QD, 500 mg QD, 750 mg QD, 250 mg BID). Hematologic improvement-erythroid (HI-E) responses were assessed per IWG 2018 criteria and other responses per IWG 2006 criteria, starting at week 8.
Results: As of the data cutoff date (15 July 2024),19 pts were enrolled [IPSS-R score: very low (n=4, 21%), low (n=9, 47%), intermediate (n=6, 32%)]. Median age was 76 (range 50-83); 68% were males. Most pts had MDS with multilineage dysplasia [n=7, (37%)]. The median number of prior therapies was 4 (range 1-8). Prior therapies included luspatercept [n=15 (79%)], hypomethylating agent (HMA) [n=15 (79%)]. At BL, 15 pts (79%) were HTB, 2 pts (11%) were LTB, and 2 pts (11%) were non-TD. Mean BL absolute neutrophil count (ANC) was 2.52 × 109/L; 3 pts (16%) had an ANC &lt;1 × 109/L. Mean BL platelet count was 153 × 109/L [&lt;100 × 109/L in 4 pts (21%)]. The most frequent (≥20%) treatment emergent adverse events (TEAEs) were diarrhea and fatigue (both n=5; 26%) and nausea (n=4; 21%); all grade (G)1/2. The most frequent G3/4 AEs were pneumonia, anemia, ALT increase and upper GI hemorrhage (all n=2; 10%). Two pts discontinued therapy due to an AE. At doses ≥500 mg QD, R835 plasma concentrations at steady state reached or exceeded concentrations correlating with 50% (n=6) or 90% (n=3) LPS-induced cytokine inhibition as observed in HV.
Fourteen of 19 pts were evaluable for efficacy (received ≥1 dose of study drug with ≥1 efficacy assessment) at the data cutoff; 1 pt withdrew due to an AE, 4 had &lt; 8 wks follow-up (too early to evaluate for response). No responses occurred at 250 mg QD (n=3). Three pts achieved RBC-transfusion independence (RBC-TI) ≥8 wks: 1/6 at 500 mg QD and 2/5 at 750 mg QD. The median duration of RBC-TI was 29 wks (range 12.4-35.9 wks). RBC-TI &gt;24 wks was achieved in 2 HTB pts (28.9 and 35.9 wks) following 3 and 5 prior therapies, including an HMA. One HTB pt at 500 mg QD had a minor HI-E response. One LTB pt achieving TI (750 mg QD) also attained a marrow complete response (BL blasts: 4%).
Conclusions: At data cutoff, R289 was well-tolerated in this heavily pretreated LR-MDS patient population, the majority of whom were HTB. The incidence of G3/4 cytopenias and infections was low. Preliminary efficacy data suggest an on-target biologic drug effect, with RBC-TI/HI-E responses occurring in 36% of patients receiving R289 doses ≥500 mg QD. The responses were durable (&gt;24 weeks) in 2 HTB pts thus far. 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.