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Lookup NU author(s): Professor Michela GuglieriORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2025 The AuthorsObjectives: Corticosteroid agonists of the glucocorticoid receptor are a mainstay of therapeutics for pro-inflammatory conditions. Vamorolone is a novel partial agonist that is differentiated from the other members of the corticosteroid class by non-metabolism by 11β-hydroxysteroid dehydrogenases, antagonism of the mineralocorticoid receptor, and differential co-factor binding. Our objective was to define the pharmacodynamic response of serum proteins to vamorolone. Methods: Clinical trial participants with Duchenne muscular dystrophy (4 to <7 yr; n = 39; mean [SD] age = 5.3 [1.0]) enrolled in a multiple ascending dose study of vamorolone were studied (24-fold dose range). Dose-response and exposure–response of 1,305 serum proteins were defined by intra-subject longitudinal changes (baseline vs. Day 14). Results: Dose-response analysis identified 159 of 1,305 serum proteins as dose-responsive to vamorolone (12 % of proteins tested; 20 % increased, 80 % decreased). Two inflammatory networks showed drug-responsive suppression. One centered on extracellular serine proteases and lymphotoxins (PI3, KLK7, KLK8, KLK11, lymphotoxins A, B) converging on NFκB. The second centered on cytokines (CCL22/MDC, CCL21, CCL14, CXCL12) and IL23 signaling. In the IL23 network, acutely responsive anti-inflammatory proteins included increases of an inhibitor of IL17 signaling (IL17RC) and decreases of IL23 (IL12B:IL23A). A protein associated with resistance to environmental microbes, PTP1C, showed strong induction and is a novel candidate for aspects of corticosteroid efficacy. Two networks of cell-associated proteins were identified as drug responsive that may represent muscle tissue response (efficacy): connective tissue remodeling upstream of Notch signaling, and plasma membrane proteins impinging on AKT1 signaling. Conclusion: The serum proteome pharmacodynamics of the response to vamorolone was defined.
Author(s): Mummidivarpu S, Dang UJ, Ziemba M, Hathout Y, Clemens PR, Damsker J, Hagerty L, Jusko WJ, Smith EC, Mah JK, Guglieri M, Nevo Y, Kuntz N, McDonald CM, Ryan MM, Castro D, Finkel RS, Conklin LS, McCall JM, Nagaraju K, van den Anker J, Hoffman EP
Publication type: Article
Publication status: Published
Journal: Steroids
Year: 2026
Volume: 225
Print publication date: 01/01/2026
Online publication date: 19/11/2025
Acceptance date: 17/11/2025
Date deposited: 02/12/2025
ISSN (print): 0039-128X
ISSN (electronic): 1878-5867
Publisher: Elsevier Inc.
URL: https://doi.org/10.1016/j.steroids.2025.109721
DOI: 10.1016/j.steroids.2025.109721
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