Elritercept shows durable responses in lower-risk myelodysplastic neoplasms (LR-MDS) with transfusion dependence: Updated Results from an ongoing Phase 2 trial

Abstract Background: Transfusion dependency is associated with substantial burden to patients with transfusion dependent anemia in the setting of lower-risk myelodysplastic syndromes/neoplasms (LR-MDS). Elritercept, an investigational, modified activin receptor type IIA/IgG1 fusion protein designed to bind and block select TGF-β superfamily ligands (activins A & B, GDF 8 & 11) is under evaluation for anemia in LR-MDS and myelofibrosis. We report updated results from the ongoing Phase 2 trial in LR-MDS (NCT04419649) including hematological improvement, time to and durability of response, and outcomes in patients (pts) with prior erythroid-stimulating agent (ESA) exposure. Additionally, mutational analysis of key MDS-associated genes was performed to explore potential benefit of elritercept in pts with these mutations. Methods: Transfusion dependent pts with International Prognostic Scoring System-Revised (IPSS-R) Very Low-, Low-, or Intermediate-risk MDS were assessed for transfusion independence (TI) and hematologic improvement-erythroid (HI-E) per Modified International Working Group 2006 criteria (mean increase in hemoglobin ≥1.5 g/dL (non-transfusion dependent (NT) + low transfusion burden (LTB)) or reduction in transfusion of ≥4 RBC U/8 weeks (high transfusion burden (HTB)) on treatment compared to 8-week pre-treatment period). TI rates (≥8 weeks and ≥24 weeks) were analyzed over the first 24 and 48 weeks of treatment respectively in a modified intention-to-treat-24 (mITT24) analysis, defined as participants who received ≥2 RBC units in the 8 weeks before treatment and completed ≥24 weeks of treatment or discontinued early; the HI-E analysis patients were defined similarly, except not requiring ≥2 RBC units. TI durability and time to first TI were assessed using Kaplan-Meier (KM) estimation. Genomic DNA from baseline samples were analyzed using targeted next-generation sequencing (NGS). Results: As of April 3, 2025, 78 pts treated with elritercept starting at the recommended Part 2 dose (RP2D; 3.75 mg/kg) were evaluable for the mITT24 analysis of TI and the median exposure was 11.9 months. In the first 24 weeks of treatment, 38.5% of pts achieved TI ≥8 weeks. In the first 48 weeks, 26.9% achieved TI ≥24 weeks (15.5% in patients with HTB) with 75.9% maintaining TI at 48 weeks. Sustained TI ≥24 weeks was observed in 67.3% of pts with TI ≥8 weeks. TI ≥48 weeks was achieved in 20.5% (prior ESA: 13.6%, ESA naïve: 23.2%) of patients over the course of the entire study. A median duration of response of 110.9 weeks among patients who had TI ≥8 weeks in the first 24 weeks was observed. Median time to TI ≥8 weeks was 0.4 weeks (prior ESA: 0.4, ESA naïve: 0.3). HI-E response was measured in 96 pts at the RP2D and achieved in 61.5% [n = 59] with median time to response of 3.1 weeks [25th percentile: 0.3, 75th percentile: 12.4] (prior ESA: 1.4, ESA naïve: 4.1). SF3B1 (64%) was the most frequently mutated gene and found in 91% of RS+ patients (median VAF of 41.4%). Among the mITT24 population that was also sequenced, TI≥8 week responses were observed in 52% of patients with and 25% without SF3B1 mutations. Summary: Elritercept shows durable responses in LR-MDS patients, with efficacy observed in patients with and without SF3B1 mutations as well as prior exposure to ESAs, highlighting its potential to treat transfusion dependent anemia in these patients who otherwise have limited treatment options. These updated findings further support development of elritercept to address the high unmet medical needs in this patient population. A Phase 3 randomized controlled study (RENEW, NCT06499285) is ongoing to confirm these results.