Vamorolone : a novel metabolism resistant steroid that suppresses joint destruction in chronic polyarthritis with reduced systemic side effects
Crastin, Ana Shanker, Arjan Sagmeister, Michael S Taylor, Angela Lavery, Gareth G Hardy, Rowan S
Crastin, Ana
Shanker, Arjan
Sagmeister, Michael S
Taylor, Angela
Lavery, Gareth G
Hardy, Rowan S
Citations
Altmetric:
Affiliation
University of Birmingham; Nottingham Trent University; Sandwell and West Birmingham NHS Trust
Other Contributors
Publication date
2025-04-02
Subject
Collections
Research Projects
Organizational Units
Journal Issue
Abstract
Objectives: Vamorolone, a dissociated steroidal compound with reduced side effects, offers a promising alternative to traditional glucocorticoids for inflammatory diseases. Unlike conventional glucocorticoids, vamorolone lacks the hydroxyl or ketone groups required for metabolism by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a key enzyme that modulates glucocorticoid activity. This study investigates vamorolone's resistance to 11β-HSD1 metabolism and assesses its therapeutic efficacy in the murine tumour necros factor-alpha-overexpressing (TNFtg) model of polyarthritis. Methods: 11β-HSD1 metabolism and action were examined in Hs68 and primary leucocyte culture. Vamorolone 20 mg/kg/day, prednisolone (standard of care) or vehicle were administered by gavage to TNFtg or TNFtg 11β-HSD1 knock-out (TNFtg11BKOKO) animals. Body weight and disease severity were scored daily, and markers of inflammation, joint destruction and side effects assessed at day 56 of age. Results: Vamorolone was entirely resistant to 11β-HSD1 metabolism in vitro. Vamorolone demonstrated comparable anti-inflammatory actions in TNFtg mice, with a comparable reduction in joint inflammation, serum interleukin-6 (IL-6) and synovitis relative to prednisolone. However, vamorolone-treated mice did not experience typical glucocorticoid side effects, including adrenal atrophy, body weight reduction, muscle wasting or inhibition of anabolic bone metabolism. These benefits persisted in 11β-HSD1 knockout mice, indicating that the efficacy of vamorolone is largely independent of 11β-HSD1 metabolism. Conclusion: The findings suggest that at the effective anti-inflammatory dose examined in this study, vamorolone possesses a reduced profile of deleterious systemic effects relative to prednisolone. Whilst highlighting its potential for broader clinical application in inflammatory conditions, it remains unclear whether these side effects would remain mild at markedly higher doses.
Citation
Crastin A, Shanker A, Sagmeister MS, Taylor A, Lavery GG, Raza K, Hardy RS. Vamorolone: a novel metabolism resistant steroid that suppresses joint destruction in chronic polyarthritis with reduced systemic side effects. Rheumatology (Oxford). 2025 Apr 2:keaf129. doi: 10.1093/rheumatology/keaf129. Epub ahead of print
Type
Article