Durable Clinical Benefit with Ker-050 Treatment: Findings from an Ongoing Phase 2 Study in Participants with Lower-Risk MDS

Background: In myelodysplastic syndromes (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). KER-050 is an investigational, modified activin receptor type IIA ligand trap designed to inhibit select TGF-β superfamily ligands (activins A, B, GDFs 8, 11) that is being evaluated in diseases with ineffective hematopoiesis (IH), including MDS and myelofibrosis. Preclinical studies demonstrated that KER-050 increased erythropoiesis and thrombopoiesis and acted on early- and late-stage erythropoietic and megakaryocyte progenitors. By eliciting effects on hematopoiesis across multiple differentiation stages and cell lineages, KER-050 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 or non-ring sideroblast (RS) MDS.

Methods: Analyses evaluating KER-050 at the recommended Part 2 dose (RP2D; 3.75 - 5 mg/kg q4wk) in participants with lower-risk (LR), RS+ or non-RS MDS from an ongoing Phase 2 study (NCT04419649) are presented as of a data cutoff date of April 3, 2023. The primary endpoint evaluates the safety and tolerability of KER-050. Secondary endpoints of modified IWG 2006 Hematological Improvement-Erythroid (HI-E) and transfusion independence (TI) ≥8 weeks are presented for participants who received ≥24 weeks of treatment or discontinued. DOR and changes in hematological parameters for participants with ongoing TI are presented for the first time.

Results: At baseline, most participants receiving KER-050 at the RP2D (74.6%) required regular transfusions (≥2 RBC units/8 weeks); 52.5% of RP2D participants had HTB (≥4 RBC units/8 weeks) and 20.3% had ≥8 RBC units/8 weeks (Table 1). The median treatment duration was 166 days (range 6 to 649). Most participants (89.8%) had at least 1 treatment-emergent adverse event (TEAE), and 32.2% had TEAEs considered treatment-related (Table 1). The most frequently observed TEAEs in ≥15% of participants were fatigue (22.0%), nausea and diarrhea (18.6% each), epistaxis (16.9%), and COVID-19 and dyspnea (15.3% each). A minority of participants (10.2%) had TEAEs that led to treatment discontinuation. Consistent with prior data, rates of TI for ≥8 weeks were similar regardless of baseline transfusion burden or RS status (Table 1). Among TI responders, 72.7% maintained TI for ≥24 weeks (data not shown), and the median DOR was not yet evaluable as more than half (6/11) had ongoing TI as of the cutoff date (Figure 1). Five of the 6 (83.3%) participants with ongoing TI had HTB at baseline, including one participant with a baseline transfusion burden of 11 RBC units/8 weeks, and all 3 responders with ongoing TI for >60 weeks. One participant with HTB and non-RS MDS had ongoing TI for >72 weeks with a steady increase in hemoglobin from 8.4 to 11.8 g/dL. Erythroid responses were not at the expense of other cell lineages, as levels of platelets and neutrophils generally did not decrease (Figure 1). In fact, 44.1% of participants overall experienced a sustained (≥8 weeks) mean increase in platelet count of ≥30 x 10 ⁹ within the first 24 weeks. Sustained decreases in ferritin were observed in parallel with increases in soluble transferrin receptor (Table 1), and for 3 participants, iron chelator therapy (ICT) was able to be discontinued. Investigation into changes in serum ferritin and ICT with KER-050 treatment will continue as cohorts of participants with MDS and iron overload are enrolled.

Summary: Updated findings from this ongoing Phase 2 study in LR MDS continue to show that KER-050 is generally well-tolerated and has potential to elicit sustained hematological improvements in a broad population of participants with LR MDS, including those with HTB. New data reveal an encouraging DOR, with observed preservation or improvement of multilineage hematopoiesis and sustained decreases in ferritin manifesting clinically with discontinuation of ICT. The study is ongoing and an update with the latest data will be provided at the time of presentation.