Myelofibrosis is a rare myeloproliferative neoplasm characterized by bone marrow fibrosis, resulting in impaired blood cell production. The disease is driven by dysregulated JAK-STAT signaling, often involving JAK2 mutations. This promotes expansion of erythroid and megakaryocyte progenitors, with abnormal megakaryocyte maturation. These dysfunctional cells release pro-inflammatory and pro-fibrotic factors, contributing to marrow scarring and worsening cytopenias.

A total of 29 participants were enrolled in Arm A and 44 in Arm B, with median treatment durations of 19 and 24 weeks, respectively. Prior exposure to a Janus kinase inhibitor (JAKi) was reported in 41.4% of participants in Arm A and 97.7% in Arm B, with median (range) durations of 49 (14–526) weeks and 66 (13–631) weeks, respectively. At baseline, 70% of participants had received ≥3 red blood cell units (RBC U) over 12 weeks, 63% had thrombocytopenia (<150×10⁹/L), 63% presented with splenomegaly (volume ≥450 cm³), and 73% had a total symptom score (TSS) ≥10. 

Elritercept was generally well tolerated as both monotherapy and in combination with ruxolitinib. Treatment-emergent adverse events occurring in ≥15% of participants included thrombocytopenia (21%) and diarrhea (19%). One participant experienced an asymptomatic increase in hemoglobin (Hgb), which required a protocol-defined dose reduction and was considered a dose-limiting toxicity.

Among evaluable non–TD6 participants in both arms, 52% achieved a maximum mean Hgb increase of ≥1.0 g/dL over 12 weeks during the first 24 weeks of treatment, while 21% achieved a mean increase of ≥1.5 g/dL. In Arm B, 56% of non–TD6 participants treated with elritercept at doses ≥3 mg/kg achieved a mean Hgb increase of ≥1.0 g/dL. Platelet counts were generally stable or improved in both arms, including among participants with baseline thrombocytopenia. A ≥50% reduction in 12-week transfusion burden was achieved in 39% of evaluable TD3 participants (Figure 1) in both arms during the first 24 weeks, and 24% attained transfusion independence (TI). In Arm B, among TD3 participants receiving ≥3 mg/kg of elritercept, 63% achieved ≥50% reduction and 38% achieved TI. At Week 24, spleen volume reduction (SVR) of ≥10% was observed in 40% of evaluable participants across both arms, while 15% achieved SVR ≥35%. In Arm B, among those treated with elritercept at ≥3 mg/kg, 88% demonstrated some degree of SVR; 50% achieved SVR ≥10% and 25% achieved SVR ≥35%. At Week 24, 67% of evaluable participants showed a reduction in TSS across symptom domains, and five participants (three in Arm A and two in Arm B) achieved a ≥50% improvement.

Conclusion: 

Elritercept is a bioengineered ligand trap designed to target cytopenias, such as anemia and thrombocytopenia, in patients with myelodysplastic syndromes (MDS) and myelofibrosis (MF). It consists of a modified ligand-binding domain from the TGF-β receptor, specifically activin receptor type IIA, fused to the Fc portion of a human antibody to enhance stability and efficacy.

Elritercept was well tolerated as both monotherapy and in combination with ruxolitinib and demonstrated multidimensional clinical activity in patients with myelofibrosis. Improvements in hemoglobin levels, reductions in transfusion burden, and stabilization or increases in platelet counts support its potential to address myelofibrosis-associated cytopenias. Additionally, observed reductions in spleen volume and symptom burden further suggest disease-modifying potential. These findings support continued investigation of elritercept as a novel therapeutic approach in myelofibrosis.