Predicting the Long-Term Effects of Therapeutic Neutralization of Oncostatin M on Human Hematopoiesis

Clin Pharmacol Ther. 2024 Mar 19. doi: 10.1002/cpt.3246. Online ahead of print.ABSTRACTTherapeutic neutralization of Oncostatin M (OSM) causes mechanism-driven anemia and thrombocytopenia, which narrows the therapeutic window complicating the selection of doses (and dosing intervals) that optimize efficacy and safety. We utilized clinical data from studies of an anti-OSM monoclonal antibody (GSK2330811) in healthy volunteers (n = 49) and systemic sclerosis patients (n = 35), to quantitatively determine the link between OSM and alterations in red blood cell (RBC) and platelet production. Longitudinal changes in hematopoietic variables (including RBCs, reticulocytes, platelets, erythropoietin, and thrombopoietin) were linked in a physiology-based model, to capture the long-term effects and variability of therapeutic OSM neutralization on human hematopoiesis. Free serum OSM stimulated precursor cell production through sigmoidal relations, with higher maximum suppression (Imax ) and OSM concentration for 50% suppression (IC50 ) for platelets (89.1% [95% confidence interval: 83.4-93.0], 6.03 pg/mL [4.41-8.26]) than RBCs (57.0% [49.7-64.0], 2.93 pg/mL [2.55-3.36]). Reduction in hemoglobin and platelets increased erythro- and thrombopoietin, respectively, prompting reticulocytosis and (partially) alleviating OSM-restricted hematopoiesis. The physiology-based model was substantiated by preclinical data and utilized in exploration of once-weekly or every other week dosing regimens. Pr...
Source: Clinical Pharmacology and Therapeutics - Category: Drugs & Pharmacology Authors: Source Type: research