Jennifer Lachey, Christopher Rovaldi, Suresh Bobba, Jared Tur, Harveen Natarajan, Ben Snyder, Jasbir Seehra
{"title":"Elritercept是一种改良的Activin受体IIA配体捕获剂,在一期试验中能增加红细胞生成和血栓形成。","authors":"Jennifer Lachey, Christopher Rovaldi, Suresh Bobba, Jared Tur, Harveen Natarajan, Ben Snyder, Jasbir Seehra","doi":"10.1182/bloodadvances.2024014172","DOIUrl":null,"url":null,"abstract":"<p><strong>Abstract: </strong>The transforming growth factor β (TGF-β) superfamily plays a crucial role in regulating biological processes of virtually every tissue and system in the body, including hemostasis and hematopoiesis. Elritercept (KER-050) is an investigational, modified activin receptor type IIA ligand trap designed to bind and inhibit activin A and other select TGF-β superfamily ligands, including activin B, growth differentiation factor 8 (GDF-8), and GDF-11. The objectives of this phase 1 randomized, placebo-controlled study of elritercept were to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic markers of activin inhibition and hematopoiesis in healthy postmenopausal women (N = 48). This study comprised 2 parts: single ascending doses ranging from 0.05 to 4.5 mg/kg; and multiple (up to 2 doses) ascending doses of 0.75 mg/kg administered subcutaneously (SC) every 4 weeks. Elritercept was generally well tolerated at all dose levels, with no dose-limiting toxicities observed. There were no severe or serious adverse events or clinically significant changes in safety laboratory measures. Serum concentrations increased in a dose-proportional manner after single SC doses, with peak concentrations achieved in 4.5 to 6 days and a mean elimination half-life of 12 days. These parameters were comparable after multiple doses. Elritercept elicited rapid, sustained, and dose-dependent increases in reticulocytes, red blood cells, hemoglobin, and platelets without eliciting detrimental changes in white blood cells such as neutrophils and lymphocytes. The time course and duration of changes in these cell populations supported a differentiated pharmacologic profile that is consistent with the stimulation of both early- and late-stage hematologic pathways. The trial was registered at www.anzctr.org.au/ as #ACTRN12619000318189.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"193-201"},"PeriodicalIF":7.4000,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758838/pdf/","citationCount":"0","resultStr":"{\"title\":\"Elritercept, a modified activin receptor IIA ligand trap, increased erythropoiesis and thrombopoiesis in a phase 1 trial.\",\"authors\":\"Jennifer Lachey, Christopher Rovaldi, Suresh Bobba, Jared Tur, Harveen Natarajan, Ben Snyder, Jasbir Seehra\",\"doi\":\"10.1182/bloodadvances.2024014172\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Abstract: </strong>The transforming growth factor β (TGF-β) superfamily plays a crucial role in regulating biological processes of virtually every tissue and system in the body, including hemostasis and hematopoiesis. Elritercept (KER-050) is an investigational, modified activin receptor type IIA ligand trap designed to bind and inhibit activin A and other select TGF-β superfamily ligands, including activin B, growth differentiation factor 8 (GDF-8), and GDF-11. The objectives of this phase 1 randomized, placebo-controlled study of elritercept were to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic markers of activin inhibition and hematopoiesis in healthy postmenopausal women (N = 48). This study comprised 2 parts: single ascending doses ranging from 0.05 to 4.5 mg/kg; and multiple (up to 2 doses) ascending doses of 0.75 mg/kg administered subcutaneously (SC) every 4 weeks. Elritercept was generally well tolerated at all dose levels, with no dose-limiting toxicities observed. There were no severe or serious adverse events or clinically significant changes in safety laboratory measures. Serum concentrations increased in a dose-proportional manner after single SC doses, with peak concentrations achieved in 4.5 to 6 days and a mean elimination half-life of 12 days. These parameters were comparable after multiple doses. Elritercept elicited rapid, sustained, and dose-dependent increases in reticulocytes, red blood cells, hemoglobin, and platelets without eliciting detrimental changes in white blood cells such as neutrophils and lymphocytes. The time course and duration of changes in these cell populations supported a differentiated pharmacologic profile that is consistent with the stimulation of both early- and late-stage hematologic pathways. 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Elritercept, a modified activin receptor IIA ligand trap, increased erythropoiesis and thrombopoiesis in a phase 1 trial.
Abstract: The transforming growth factor β (TGF-β) superfamily plays a crucial role in regulating biological processes of virtually every tissue and system in the body, including hemostasis and hematopoiesis. Elritercept (KER-050) is an investigational, modified activin receptor type IIA ligand trap designed to bind and inhibit activin A and other select TGF-β superfamily ligands, including activin B, growth differentiation factor 8 (GDF-8), and GDF-11. The objectives of this phase 1 randomized, placebo-controlled study of elritercept were to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic markers of activin inhibition and hematopoiesis in healthy postmenopausal women (N = 48). This study comprised 2 parts: single ascending doses ranging from 0.05 to 4.5 mg/kg; and multiple (up to 2 doses) ascending doses of 0.75 mg/kg administered subcutaneously (SC) every 4 weeks. Elritercept was generally well tolerated at all dose levels, with no dose-limiting toxicities observed. There were no severe or serious adverse events or clinically significant changes in safety laboratory measures. Serum concentrations increased in a dose-proportional manner after single SC doses, with peak concentrations achieved in 4.5 to 6 days and a mean elimination half-life of 12 days. These parameters were comparable after multiple doses. Elritercept elicited rapid, sustained, and dose-dependent increases in reticulocytes, red blood cells, hemoglobin, and platelets without eliciting detrimental changes in white blood cells such as neutrophils and lymphocytes. The time course and duration of changes in these cell populations supported a differentiated pharmacologic profile that is consistent with the stimulation of both early- and late-stage hematologic pathways. The trial was registered at www.anzctr.org.au/ as #ACTRN12619000318189.
期刊介绍:
Blood Advances, a semimonthly medical journal published by the American Society of Hematology, marks the first addition to the Blood family in 70 years. This peer-reviewed, online-only, open-access journal was launched under the leadership of founding editor-in-chief Robert Negrin, MD, from Stanford University Medical Center in Stanford, CA, with its inaugural issue released on November 29, 2016.
Blood Advances serves as an international platform for original articles detailing basic laboratory, translational, and clinical investigations in hematology. The journal comprehensively covers all aspects of hematology, including disorders of leukocytes (both benign and malignant), erythrocytes, platelets, hemostatic mechanisms, vascular biology, immunology, and hematologic oncology. Each article undergoes a rigorous peer-review process, with selection based on the originality of the findings, the high quality of the work presented, and the clarity of the presentation.