Vamorolone: a novel metabolism resistant steroid that suppresses joint destruction in chronic polyarthritis with reduced systemic side effects

Crastin, A, Shanker, A, Sagmeister, MS, Taylor, A, Lavery, GG ORCID: https://orcid.org/0000-0001-5794-748X, Raza, K and Hardy, RS, 2025. Vamorolone: a novel metabolism resistant steroid that suppresses joint destruction in chronic polyarthritis with reduced systemic side effects. Rheumatology, 64 (7), pp. 4371-4381. ISSN 1462-0332

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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.

Item Type:	Journal article
Publication Title:	Rheumatology
Creators:	Crastin, A., Shanker, A., Sagmeister, M.S., Taylor, A., Lavery, G.G., Raza, K. and Hardy, R.S.
Publisher:	Oxford University Press (OUP)
Date:	July 2025
Volume:	64
Number:	7
ISSN:	1462-0332
Identifiers:	Number Type 10.1093/rheumatology/keaf129 DOI 2554259 Other
Rights:	© The Author(s) 2025. Published by Oxford University Press on behalf of the British Society for Rheumatology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Divisions:	Schools > School of Science and Technology
Record created by:	Laura Borcherds
Date Added:	09 Jan 2026 08:44
Last Modified:	09 Jan 2026 08:44
URI:	https://irep.ntu.ac.uk/id/eprint/54993

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