Renew Trial in Progress: A Phase 3, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Elritercept (KER-050) for the Treatment of Transfusion-Dependent Anemia in Adult Participants with Very Low-, Low-, or Intermediate-Risk

Background and Significance: In MDS, defects occur at multiple stages of hematopoiesis. Available Erythropoiesis Stimulating or Erythroid Maturation Agents (ES/EMAs) target early or late stages of erythropoiesis, respectively, and are only effective in subsets of patients. For patients with high transfusion burden (HTB) who have diminished erythropoietic capacity and a worse prognosis, ES/EMAs show limited efficacy and durability of response (DOR). Elritercept is an investigational, modified activin receptor type IIA ligand trap designed to inhibit activin A and other select TGF-β superfamily ligands (activin B, GDFs 8, & 11) that is being evaluated in diseases with ineffective hematopoiesis (IH), including MDS (NCT04419649) and myelofibrosis (NCT05037760). In preclinical studies, elritercept increased erythropoiesis and thrombopoiesis and acted on early- and late-stage erythropoietic and megakaryocyte progenitors, indicating a differentiated mechanism of action, potentially due to inhibition of activin A. By eliciting effects on hematopoiesis across multiple differentiation stages and cell lineages, elritercept has the potential to address the complex nature of IH and to provide robust and sustained hematological improvement in patients with MDS who have limited treatment options, including those with HTB and/or non-ring sideroblast (RS) MDS. Study Design and Methods: RENEW (NCT06499285) is a global, multicenter, randomized, double-blind, placebo-controlled Phase 3 study to evaluate the efficacy and safety of elritercept in adults with transfusion-dependent, very low-, low-, and intermediate-risk MDS per IPSS-R (lower-risk [LR] MDS). Eligible participants are aged ≥18 years and have MDS with or without RS and low transfusion burden (LTB, 4 to 7 RBC units per 16 weeks) or HTB (≥8 RBC units per 16 weeks). Approximately 225 participants will be randomized 2:1 to receive either elritercept, administered SC Q4W starting at 3.75mg/kg with up-titration to 5mg/kg after at least 8 weeks of treatment, or placebo. Participants will be stratified by RS status (RS-positive vs non-RS) and baseline transfusion burden (LTB vs HTB). Participants will be enrolled into a double-blind treatment period consisting of a primary phase (24 weeks), secondary phase (24 weeks), and extension phase (until the end of treatment [EOT]). Following EOT, participants will undergo an 8-week safety follow-up period and a long-term follow-up period as per protocol. Every quarter during the long-term follow-up, data will be collected on survival, first dose of the next MDS treatment line, and progression to AML, if applicable. The primary endpoint is the proportion of participants with achievement of transfusion independence (TI) ≥8 weeks from baseline through week 24. Secondary endpoints are the proportion of participants with achievement of TI ≥24 weeks from baseline through week 48, the proportion of participants with HTB achieving TI for ≥8 weeks from baseline through week 24, and the incidence and severity of adverse events (AEs) and serious AEs. The RENEW trial is expected to support the registration of elritercept for the treatment of anemia in adults with LR-MDS.