Myelofibrosis is marked by irregular JAK and TGF-β signaling, ineffective blood cell production, and an enlarged spleen. Although JAK inhibitors can reduce spleen size and improve symptoms, they often lead to dose-limiting cytopenias. Consequently, there is an ongoing search for novel agents to better manage myelofibrosis. Several companies are investigating new mechanisms of action to supplement the established JAK inhibitors, either when patients no longer respond to first-line therapy or in combination with JAK inhibitors in new patients.

Elritercept is an investigational drug, specifically a modified activin receptor type IIA ligand trap, designed to inhibit certain TGF-β superfamily ligands (such as activins A and B, and GDFs 8 and 11) to address hematopoiesis. The potential of elritercept to treat myelofibrosis and ruxolitinib-induced cytopenias is currently being studied in the Phase II RESTORE trial. The primary goal of this trial is to assess the safety and tolerability of elritercept in patients with myelofibrosis-associated cytopenias. The updated results from this trial were presented at the EHA 2024 congress.

The findings showed that elritercept was generally well tolerated by the safety population. Fatigue, thrombocytopenia, and diarrhea were treatment-emergent side events that were observed in ≥15% of cases. There was one dose-limiting toxicity reported from a patient in the 1.5mg/kg dose level of the monotherapy arm. The patient had an increase in hemoglobin of at least 2 g/dL, which met protocol criteria for dose reduction at the end of cycle 1. There were no adverse events associated with this event, and the maximum observed hemoglobin remained within normal limits. Four participants had unrelated treatment-emergent serious adverse events (TESAEs) leading to death. 

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Additional data from the efficacy evaluable patients include:

• Increases in hemoglobin were observed in non-transfusion dependent patients in both monotherapy and combination arms, suggesting that elritercept has the potential to address anemia due to MF and ruxolitinib-associated anemia. 
• Increases in soluble transferrin receptors, reticulocytes and hemoglobin were generally higher with increasing dose levels between 0.75 mg/kg to 3.0 mg/kg. 
• Among 13 evaluable transfusion dependent (TD) participants, the 12 week transfusion burden was reduced by ≥50%. 
• At week 24, reduction in spleen size was observed in 53.1% of patients. Reduction in spleen size in the combination arm generally occurred without an increase in ruxolitinib dose. 
• Decrease in disease symptoms was observed in the majority of the evaluable participants at Week 24. 

KOL insights

“We are encouraged by the preliminary data from the lowest three dose cohorts from the ongoing Phase II clinical trial in Myelofibrosis. Elritercept treatment in combination with ruxolitinib and as monotherapy led to improvements as assessed by changes in markers of hematopoiesis, reductions in spleen size and improvement in Total Symptom Score. We look forward to confirming this profile of benefit in the now enrolling dose confirmation part of our trial.” – MD, United States.

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Conclusion 

A significant portion of individuals on JAK inhibitor therapy quickly develop resistance to the medication. There remains a significant medical need for managing cytopenia in myelofibrosis patients, which is associated with a negative impact on overall survival and quality of life. Combination strategies are being investigated to further decrease MF-related symptoms while overcoming dose-limiting cytopenias, especially in patients who cannot tolerate or whose disease is refractory to JAKi monotherapy. Keros Therapeutics is conducting an open label, two-part, and multiple ascending dose Phase II RESTORE trial to evaluate KER-050 as a monotherapy and in combination with ruxolitinib in patients with MF-associated cytopenias.

Data from the RESTORE trial indicate that elritercept is generally well tolerated and has the potential to address several aspects of myelofibrosis. Improvements in hemoglobin levels and reduction in transfusion burden, along with the maintenance of platelet counts, demonstrate its potential to correct ineffective hematopoiesis and treat MF-associated cytopenias and ruxolitinib-induced cytopenias. Additionally, the data support elritercept’s potential to reduce spleen size and improve symptoms. Enrollment in  Part 2 of the RESTORE trial is ongoing at the RP2D of 3.75 mg/kg with titration to 5 mg/kg to further study effects of elritercept in participants with myelofibrosis.

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