elritercept (KER-050)

This review summarizes novel and promising treatments for anemia in myelofibrosis including transforming growth factor-β inhibitors luspatercept and KER-050, JAK inhibitors momelotinib, pacritinib, and jaktinib, BET inhibitors pelabresib and ABBV-744, antifibrotic PRM-151, BCL2/BCL-XL inhibitor navitoclax, and telomerase inhibitor imetelstat. Standard approaches to treat myelofibrosis-related anemia have limited efficacy and are associated with toxicity. New drugs have shown positive results in myelofibrosis-associated anemia when used alone or in combination.

Reestablishing BM hematopoiesis could obviate the need for compensatory extramedullary hematopoiesis in the spleen, the major driver of splenomegaly in MF patients. In conclusion, KER-050 represents a potentially promising approach for patients with MF and other hematological diseases where ineffective hematopoiesis occurs.

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).

Based on interim findings from this Phase 2 study as of the data cut-off date, KER-050 was generally well- tolerated with longer-term treatment and has the potential to drive hematological improvement and reduce transfusion burden in a broad, lower-risk MDS population. By modulating TGF-β superfamily ligands, KER-050may over time restore a healthy OHN and reduce iron overload to support normal hematopoiesis, even in heavily transfused patients. Enrollment is ongoing and updated safety and efficacy results will be reported at the meeting.

Preliminary results from Part 1 will be presented. At the time of this writing, 5 patients have received KER-050 on study, 3 in Arm 1A and 2 in Arm 1B. Three participants have completed the dose-limiting toxicity (DLT) assessment period and no DLTs have been experienced.

2022 EHA #P776), and changes in bone biomarkers are currently being evaluated in the study. KER-050, thus, represents a potentially promising approach for patients with MDS and other hematological diseases, including myelofibrosis, where ineffective hematopoiesis and defects in bone homeostasis occur.

A total of 31 patients were enrolled in Part 1 Dose Escalation; 26 were transfusion dependent, 18 with HTB (≥ 4 RBC units in 8 weeks prior to day 1). Seven HTB patients (38.9%) received iron chelator therapy. Baseline differences were noted in measures of iron status, erythropoiesis and bone turnover for non-transfused (NT), low transfusion burden (LTB), and HTB patients (Table 1).

Increases in platelets have been observed in HTB patients achieving HI-E or TI which supports the potential of KER-050 as a treatment for multilineage cytopenias in difficult-to-treat HTB patients. Dose escalation is ongoing in this Phase 2 study of anemic patients with MDS; updated data from Part 1 with safety, PD and efficacy data from cohorts 4 and 5 will be presented for the first time at the meeting.

At data cut-off (July 10, 2021) with median follow-up of 140 days (range 1 to 169 days), 17 participants had received ≥1 dose of KER-050 across 3 dose levels: 0.75 mg/kg, 1.5 mg/kg and 2.5 mg/kg. Baseline characteristics are described in Table 1. No related serious AEs, dose-limiting toxicities, or dose modifications were reported.

These findings support that RKER-050-targeted ligands regulate multiple stages of the thrombopoiesis pathway in mice. Additionally, our data demonstrate that KER-050 has the potential to accelerate the rate of PLT recovery due to acute depletion, and could represent a potential novel treatment option for thrombocytopenia in patients with MDS, MF and IT.