elritercept (KER-050)

P2, N=160, Recruiting, Takeda | Trial completion date: Oct 2030 --> Oct 2031

P2, N=135, Recruiting, Takeda | Trial completion date: Jan 2029 --> Feb 2030 | Trial primary completion date: Dec 2026 --> Feb 2028

P2, N=140, Recruiting, Takeda | Trial completion date: Nov 2025 --> Oct 2030 | Trial primary completion date: Jun 2025 --> Oct 2029

The pathobiology of anemia is multifactorial, including progressive bone marrow fibrosis, decreased erythropoiesis due to high hepcidin levels leading to iron sequestration in the reticuloendothelial system, hypersplenism, erythropoiesis inhibition by myelosuppressive JAK inhibitors (ruxolitinib, fedratinib), and others...Conventional agents to manage anemia include erythropoiesis-stimulating agents, danazol, corticosteroids, and immunomodulatory agents, but responses are infrequent and lack durability...Momelotinib and pacritinib (ACVR1/JAK2 inhibitor) are the preferred JAK inhibitors for patients with cytopenias (anemia, thrombocytopenia). Luspatercept and elritercept are activin receptor ligand traps, promoting erythroid maturation and late-stage erythropoiesis...DISC-0974 is a first-in-class anti-hemojuvelin (positive hepcidin regulator) monoclonal antibody that decreased hepcidin expression, increased serum iron, and enhanced erythropoiesis in anemic patients with MF in a phase 1b/2 study. Burgeoning studies of novel anemia-targeted agents and combinations are significantly improving the quality of life and outcomes of patients with MF. The recent approval of momelotinib to treat MF with anemia and the emerging novel anemia-directed strategies in early and advanced clinical development have ushered in a new era in the treatment of MF-related anemia.

These include TGF-β ligand traps (luspatercept, elritercept), activin A receptor type 1 (ACVR1)/activin receptor-like kinase 2 (ALK2) inhibitors (momelotinib, zilurgisertib), and anti-hemojuvelin antibody-based therapies (DISC-0974). Luspatercept and momelotinib are approved for anemia related to lower-risk MDS and MF, respectively, and represent an important addition to the treatment armamentarium, along with imetelstat, a telomerase inhibitor, recently ratified for anemia in lower-risk MDS. A promising strategy to overcome the limitations of existing anemia-directed therapies includes the use of drug combinations with complementary mechanisms (luspatercept + erythropoiesis stimulating agents, luspatercept + momelotinib, DISC-0974 + momelotinib), and harnessing the erythropoietic potential of sodium-glucose co-transporter-2 inhibitors (SGLT-2I). Future research should address the complex pathophysiology of anemia, standardize definitions for anemia with gender-specified cutoffs, implement uniform erythroid response criteria, and consider early therapeutic intervention in clinical trials for anemia-directed therapies.

P2, N=120, Recruiting, Keros Therapeutics, Inc. | Trial completion date: Jun 2025 --> Jan 2029 | Trial primary completion date: Apr 2025 --> Dec 2026

P3, N=225, Recruiting, Keros Therapeutics, Inc. | Not yet recruiting --> Recruiting | Trial primary completion date: Mar 2032 --> Mar 2028

P2, N=176, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College.; Institute of Hematolog

P2, N=176, Not yet recruiting, Hansoh BioMedical R&D Company

P3, N=225, Not yet recruiting, Keros Therapeutics, Inc.

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.