Document Type
Article
Publication Date
11-19-2025
Keywords
Glucocorticoid receptor, NR3C1 gene, Vamorolone, Pharmacodynamics, Serum proteomics
Abstract
Objectives: 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, lympho-toxins 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.
Publisher Attribution
0039-128X/© 2025 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Recommended Citation
Mummidivarpu, Swati; Dang, Utkarsh J.; Ziemba, Michael; Hathout, Yetrib; Clemens, Paula R.; Damsker, Jesse; Hagerty, Laura; Jusko, William J.; Smith, Edward C.; Mah, Jean K.; Guglieri, Michela; Nevo, Yoram; Kuntz, Nancy; McDonald, Craig M.; Ryan, Monique M.; Castro, Diana; Finkel, Richard S.; Conklin, Laurie S.; McCall, John M.; Nagaraju, Kanneboyina; van den Anker, John; and Hoffman, Eric P., "Exposure-response of serum biomarkers to vamorolone, a dissociative corticosteroidal anti-inflammatory drug, in 4- to <7-year children" (2025). Pharmacy Faculty Scholarship. 94.
https://orb.binghamton.edu/pharmacy_fac/94
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
Comments
https://doi.org/10.1016/j.steroids.2025.109721