GRM-01 is a novel, orally available, non-steroidal, selective glucocorticoid receptor agonist and modulator (SEGRAM) that displays reduced transactivation activity (main driver of side effects) and strong transrepression activity (main driver of anti-inflammatory effects) compared with conventional glucocorticoids. It is hypothesized that this combination may lead to an improved benefit-risk profile for patients with Duchenne muscular dystrophy (DMD).
In vitro data indicate that GRM-01 is a potent and selective ligand of the human glucocorticoid receptor (GR), retaining full GR-mediated transrepression activity. In contrast, GRM-01 displays partial GR transactivation (EC50 60.2 nM, efficacy 31.8%) versus prednisolone (EC50 24.3 nM, efficacy 80.5%), and no detectable transactivation at mineralocorticoid (prednisolone EC50 11.8 nM, efficacy 66.4%) or progesterone (prednisolone – no effect) receptors. GRM-01 produced very weak induction of tyrosine aminotransferase (TAT) enzyme activity (a marker of gluconeogenesis and transactivation) in human hepatocyte cell lines (EC50 >10,000 nM, efficacy 14.0%); in comparison, prednisolone elicited full TAT activity (EC50 283 nM, efficacy 92.4%). In human primary hepatocyte cultures, Tat mRNA expression was significantly increased by prednisolone and the dissociated steroid vamorolone versus vehicle, but not by GRM-01, suggestive of lower transactivation potential. In vivo studies also support the reduced transactivation potential of GRM-01. In a rat inflammatory model, blood glucose concentrations after 5 days of treatment were significantly increased, versus vehicle, by prednisolone but not by GRM-01.
The reduced transactivation potential of GRM-01 was also confirmed in Phase 1 studies: plasma glucose levels were assessed over 3 hours in an oral glucose tolerance test. Following both single and repeat dosing, GRM-01 did not produce any clinically relevant changes in this endpoint.
A Phase 2 study in DMD is planned to start in 2026. We will present the pharmacological and preclinical data points alongside the unpublished Phase 1 data that support the reduced transactivation potential of GRM-01.