Improvements in Hematological Parameters and Quality of Life (QOL) with Elritercept (KER-050): Results from an Ongoing Phase 2 Trial in Participants with Lower-Risk (LR) Myelodysplastic Neoplasms (MDS)
Authors: Giagounidis Aristoteles , Arnan Monteserrat , Chee Lynette C.Y. , Cluzeau Thomas , Diez-Campelo Maria , Hiwase Devendra , Ross David M , Sekeres Mikkael A. , Tan Shuhying , Valcarcel David , Buckstein Rena , 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: In LR-MDS, anemia and RBC transfusions contribute to impaired QoL, with fatigue being predominant. Improving anemia, transfusion burden, and symptoms are important treatment goals. 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, GDF 8 & 11) to address ineffective hematopoiesis. Results from an ongoing Phase 2 trial in LR-MDS have shown potential for elritercept to provide durable hematological improvement and benefits beyond treating anemia. Here, we show improvement in QoL in transfusion-dependent participants who achieved durable transfusion independence (TI) with elritercept treatment.

Methods: This Phase 2 trial (NCT04419649) enrolled participants with International Prognostic Scoring System-Revised (IPSS-R) Very Low-, Low-, or Intermediate-risk MDS. Analyses included participants receiving the recommended Part 2 dose (3.75 up to 5 mg/kg, N=87) as of data cut off (DCO) of 03Apr2024. Rates of TI≥8 wks and ≥24 wks were analyzed over the first 24 and 48 wks of treatment in a modified intent-to-treat-24 (mITT24) population, including participants who received ≥2 RBC units in the 8 wks before treatment and received ≥24 wks of treatment or discontinued (N=63). Durability of TI was assessed using Kaplan-Meier (KM) estimation. QoL was assessed using the Functional Assessment of Cancer Therapy-Anemia (FACT-An; 47 item) at baseline and after approximately 4, 8, 12, 16, and 24 wks of treatment. Domains of FACT-An including physical (7-item), functional (7-item), social (7-item), emotional (6-item) well-being, the anemia subscale (AnS, 20-item), and FACIT-Fatigue (13-item) were analyzed separately.

Results: Among mITT24 TI-evaluable participants, 41.3% achieved TI≥8 wks in the first 24 wks of elritercept treatment, including participants with non-RS (ring sideroblasts) and/or high transfusion burden. Responses were durable, with 61.5% of TI≥8 wks participants maintaining TI as of the DCO, and the median duration of response was not reached. Additionally, 25.4% of evaluable mITT24 participants achieved TI≥24 wks over the first 48 wks of treatment, and among TI≥8 wks responders, the proportion who maintained TI≥24 wks was 61.5%.

Improvements in QoL based on FACT-An total score were observed in TI responders vs non-responders and increased with greater duration of TI. At wk 24, mean increases in FACT-An total score were greater for TI≥24 wks (13.1, minimally clinically important difference [MCID] = 7) compared to TI≥8 wks responders (4.8) as was the separation vs non-responders (mean difference vs non-responders for TI≥8 and TI≥24 responders were 5 and 16.1 [&gt;2-fold the MCID], respectively). Of the FACT-An domains, differences in AnS score, especially the FACIT-Fatigue component, were major drivers for improvements observed in TI≥24 wks vs TI≥8 wks responders. Baseline FACIT-Fatigue scores for TI≥8 / TI≥24 responders were 28.4 / 28.2 vs. non-responders 30.4 / 30.0 indicating similar level of fatigue in both populations. At wk 24, mean increases from baseline in fatigue score were greater for TI≥24 (6.6, MCID = 3) compared to TI≥8 wks responders (2.0), as was the separation vs non-responders (mean difference vs non responders for TI≥8 / TI≥24 responders = 3.2/ 9.4 [&gt;3-fold the MCID]). FACIT-Fatigue scores improved over time in TI≥24 wk responders; mean increases of 2.9 were observed at wk 4 and reached 6.6 by wk 24. Similarly, the proportion of TI≥24 wk responders vs non-responders whose change in FACIT-Fatigue met the MCID was 54% vs 20% at wk 4, improving to 75% vs 16% at wk 24. Items driving observed improvements in FACIT-Fatigue score were related to both fatigue experience and fatigue impact.

Summary: These findings support the potential for elritercept to produce durable TI that is associated with clinically meaningful improvements in QoL, thus addressing important goals in treating LR-MDS. Fatigue burden (both experience and impact) was a primary driver of the observed improvements in QoL in TI responders vs non-responders. Importantly, clinically meaningful improvements in fatigue scores were observed early and continued to improve over time in participants with more durable TI responses.