Hematologic Improvement and Fatigue Reduction with Elritercept (KER-050) in Participants with Lower-Risk (LR) Myelodysplastic Neoplasms (MDS) with Non-Transfusion Dependent Anemia: New Analyses from an Ongoing Phase 2 Trial
Authors: Tan Shuhying , Arnan Montserrat , Chee Lynette C.Y. , Cluzeau Thomas , Diez-Campelo Maria , Giagounidis Aristoteles , Hiwase Devendra , Ross David M , Sekeres Mikkael A. , Valcarcel David , Patel-Shah Bhavna , Yang Ming , Jiang Ying , Yin Jiani , Bobba Suresh , Hankin Montagu , Materna Chris , Graham Christine , Thamake Sanjay , Rovaldi Christopher , Grayson Dena , Salstrom Jen L. 
Published: December 2024

Background: Roughly 80% of patients in the U.S. with MDS develop anemia, and half eventually require regular transfusions, which are associated with reduced overall survival and further decline in quality of life (QoL). Treating MDS-associated anemia early in the disease course may improve prognosis and QoL. 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) to address ineffective hematopoiesis. Data from an ongoing Phase 2 trial (NCT04419649) in LR-MDS demonstrated potential for elritercept to provide durable transfusion independence, including in participants with high transfusion burden (≥4 RBC U/8 wks). Here, in new analyses, we evaluated the effects of elritercept in non-transfusion-dependent (NT) participants with MDS-associated anemia.

Methods: Data are presented as of a data cutoff (DCO) date of 03Apr24 from an ongoing Phase 2 study in LR-MDS for the subgroup of 15 NT participants (0 RBC U/8 wks prior to treatment) out of 87 participants treated with elritercept at the recommended Part 2 dose (RP2D; 3.75-5mg/kg, Q4W). Analyses included the rate of Hematological Improvement-Erythroid (HI-E; IWG 2006; mean hemoglobin [Hgb] increase ≥1.5g/dL over ≥8 wks), change from baseline (CFB) in hematologic and iron homeostasis parameters, and QoL scores assessed using the Functional Assessment of Cancer Therapy-Anemia (FACT-An; 47 items, includes 13-item FACIT-Fatigue subscale) at baseline and after approximately 4, 8, 12, 16, and 24 wks. Minimally clinically important difference (MCID) for FACIT-Fatigue was defined as improvement of ≥3 points.

Results: Eleven participants in the NT subgroup were RS (Ring Sideroblast) positive and 4 were non-RS. Median (range) baseline levels of Hgb, ferritin and hepcidin were 9.2g/dL (8.1-10.5), 417ng/mL (190-1632), and 9.8ng/mL (0-47.4), respectively. Median (range) duration of elritercept exposure was 66 wks (13-145). Elritercept was generally well tolerated, in NT participants with a safety profile consistent with the broader population, as previously reported.

Thirteen (86.7%; RS+ = 90.9%; non-RS = 75%) NT participants achieved HI-E response over the entire treatment period and 11 (73.3%) participants maintained mean Hgb levels ≥11g/dL over at least 8 wks. Responses were durable as supported by observed sustained increases in Hgb (mean increase of 1.5 and 1.7g/dL at wks 24 and 48, respectively). Increased Hgb was also the most common reason for dose modification in NT participants (delay or reduction based on Hgb ≥12g/dL or change &gt;2g/dL in 1 cycle). Five NT participants reduced their dose from 3.75 to 2.5mg/kg and 2 reduced again to 1.5mg/kg, 1 due to a TEAE of neutropenia. HI-E responses were maintained or regained despite dose delay or reduction; one participant maintained HI-E &gt;72 wks despite 2 dose reductions and multiple consecutive dose delays. No NT participants had become transfusion-dependent (&gt;3 RBC U/16 wks) as of the DCO.

Clinically significant improvements in QoL were observed in multiple domains of FACT-An, with 60% and 54.5% achieving a MCID in FACIT-Fatigue by wk 12 and wk 24, respectively. Rapid decreases in ferritin and hepcidin following the first dose were observed that were maintained at 24 wks

Summary: In this first in-depth evaluation of NT participants in the ongoing Phase 2 study of elritercept in LR-MDS, elritercept was generally well tolerated, and robust Hgb responses were observed in most participants. None of the participants were transfusion-dependent as of the DCO. Dose delay and/or reduction occurred in some responders with no compromise in hematologic responses. Clinically meaningful improvements in fatigue, as well as rapid and sustained decreases in ferritin and hepcidin, were observed. Together, these data suggest potential for elritercept to provide durable and sustained benefits to NT participants with LR-MDS by improving anemia, QoL, and iron homeostasis and/or inflammation.