Corticosteroids are highly effective anti-inflammatory drugs related to the natural hormone, cortisol. The discovery of cortisol derivatives as therapeutic agents for arthritis led to the awarding of the Nobel Prize in 1950 to Drs. Edward Calvin Kendall, Tadeus Reichstein and Philip Showalter Hench “for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects” (https://www.nobelprize.org/prizes/medicine/1950/summary/). While effective, chronic treatment with corticosteroids is accompanied by safety concerns, particularly brittle bones (osteopenia). This led to a 70+ year search for safer alternatives.

Vamorolone has achieved an improved safety profile by removing a single oxygen moiety from the corticosteroid backbone (the 11β position). This differentiates vamorolone from all other members of the corticosteroid class, and vamorolone shows the following unique properties:

  • Loss of a binding site to the glucocorticoid receptor, changing the co-activator/co-repressor binding domain, and leading to relative loss of co-activator and gain of co-repressor binding (Liu et al. 2020). This in turn leads to vamorolone showing less positive regulation of gene transcription (transactivation), and more negative regulation of gene transcription (transrepression) – the latter associated with anti-inflammatory activities (Reeves et al. 2013; Damsker et a. 2013; Heier et al. 2013).
  • Vamorolone is no longer a substrate for the key modulatory enzymes of all other corticosteroids, 11β-hydroxysteroid dehydrogenase 1 and 11β-hydroxysteroid dehydrogenase 2 (HSD11B1, HSD11B2) (Hoffman et al. 2018). Thus, vamorolone is not converted from pro-drug to drug systemically or at local sites of inflammation as other corticosteroids are.
  • Vamorolone is a potent antagonist of the mineralocorticoid receptor (MR), an activity that may be beneficial (Heier et al. 2019). All other corticosteroids are either agonists (increasing blood pressure), or show no activity for the MR.

In Duchenne muscular dystrophy clinical trials, vamorolone has shown similar efficacy (improvements in muscle strength and slowed disease progression) to traditional corticosteroids, while reducing safety concerns (particularly bone morbidities) (Guglieri et al. 2022; Smith et al. 2020; Mah et al. 2022).