During the 66th American Society of Hematology Annual Meeting and Exposition, Claire Harrison, MD, professor of myeloproliferative neoplasms and deputy chief medical officer of Guy’s and St. Thomas’ NHS Foundation Trust in the U.K., presented early results from the ongoing phase II RESTORE trial of the investigational treatment elritercept in participants with myelofibrosis (MF). Early data from this trial, including observed improvements in hemoglobin (Hb) and transfusion burden and either maintained or increased platelets, suggest that this investigational agent has the potential to address ineffective hematopoiesis (IH) and MF- and ruxolitinib-associated cytopenias and provide broad, clinically meaningful benefits to patients with MF.
Elritercept is designed to inhibit activin A and other select transforming growth factor-beta superfamily ligands and, thus, rebalance signaling of activin and bone morphogenetic protein receptors, all known to be disrupted in patients with MF. Based on its mechanism of action, elritercept has the potential to not only improve IH but also positively affect bone health and ameliorate myocardial strain.
The RESTORE trial includes two cohorts of participants with MF and anemia who received elritercept either as monotherapy or in combination with ruxolitinib. The ongoing part I of the trial, in which enrollment has been completed, evaluated dose escalation to determine the appropriate dosing regimen. The Safety Review Committee selected a recommended part II dose of 3.75 mg/kg Q4W with an option to up-titrate to 5 mg/kg Q4W. Part II dose expansion is currently ongoing.
As of the August 30, 2024, data cutoff, the investigators found that elritercept had an acceptable side effect profile, with the most reported adverse events (AEs) being thrombocytopenia and diarrhea. Despite the frequent occurrence of thrombocytopenia, participants, including those with thrombocytopenia at baseline, typically experienced either maintenance or improvement of platelet counts while receiving elritercept. Investigators observed improved Hb levels in both cohorts of evaluable non-transfusion-dependent participants who had at least 12 consecutive weeks of post-baseline Hb data without transfusions. In the monotherapy arm, 44% of evaluable non-transfusion-dependent participants experienced mean increases in Hb of at least 1.0 g/dL over 12 weeks during the first 24 weeks of treatment, and 10% experienced mean increases in Hb equal to or greater than 2 g/dL. In the combination cohort, 56% of participants treated with a minimum of 3 mg/kg experienced a mean increase in Hb of at least 1 g/dL.
Among participants requiring three or more red blood cell units per 12 weeks at baseline and treated with combination therapy at an elritercept dose of 3 mg/kg or higher, 63% experienced at least a 50% reduction in transfusion burden over any 12 weeks during the first 24 weeks, and more than one-third became transfusion independent. Researchers observed reductions in spleen volume at week 24 in evaluable participants in monotherapy and combination cohorts who had baseline splenomegaly and a week-24 assessment. A total of 40% of evaluable participants in both cohorts achieved a 10% reduction in spleen volume at week 24, and 88% of evaluable participants in the combination cohort who received elritercept at 3 mg/kg or higher experienced some reduction in spleen volume at week 24. “The spleen is important because it links to survival benefits in patients,” Dr. Harrison said.
In both cohorts, more than two-thirds of participants with elevated total symptom scores at baseline experienced improvements in MF symptoms at week 24. Additionally, investigators observed that patients in both the monotherapy and combination cohorts experienced broad improvements across the symptom domains. Dr. Harrison emphasized that the disease burden of patients enrolled in the study was high, and their symptoms seemed to improve with treatment. While acknowledging that the phase II trial is primarily a proof-of-principle, she said thus far, “it’s all looking good.” She added that the trial is ongoing, and patients are still being recruited.
Any conflicts of interest declared by the authors can be found in the original abstract.
Reference
Harrison C, Chee LCY, Devos T, et al. Hematological improvement and other clinical benefits of elritercept as monotherapy and in combination with ruxolitinib in participants with myelofibrosis from the ongoing phase 2 Restore Trial. Abstract 997. Presented at the 66th American Society of Hematology Annual Meeting and Exposition; December 9, 2024; San Diego, California.
