Background:
In Duchenne muscular dystrophy (DMD), long-term glucocorticoid therapy remains the standard of care but is constrained by dose- and duration-dependent side effects. Whilst the side effects of glucocorticoids are driven predominantly by transactivation of specific genes and, to a lesser extent, by a combination of transactivation and transrepression, the anti-inflammatory effects are primarily mediated by transrepression. It was therefore hypothesized that a therapy that shifts the balance towards less transactivation could potentially lead to improved safety and tolerability whilst retaining anti-inflammatory potency.
Objectives:
GRM-01 is a novel, orally available, non-steroidal, selective glucocorticoid receptor agonist and modulator (SEGRAM). In both in vitro and in vivo pharmacological studies, GRM-01 exhibited strong anti-inflammatory (transrepression) activity similar to that of prednisolone. Owing to its pharmacological properties, GRM-01 demonstrated reduced transactivation activity which, in combination with its robust transrepression activity, suggests a differentiated profile with a potentially improved benefit-risk balance for patients.
Results:
In the B10.mdx mouse model, GRM-01 significantly improved skeletal limb muscle function and significantly reduced diaphragm inflammation, without significantly increasing fasting blood glucose. Prednisolone also significantly reduced diaphragm inflammation but had no effect on limb muscle function, and increased fasting blood glucose levels.
In phase I studies in healthy volunteers, GRM-01 produced dose- and exposure-dependent suppression of cortisol (a marker of target engagement and glucocorticoid receptor-mediated transrepression), with near complete suppression at higher doses, and no clinically relevant changes to normal glucose-insulin homeostasis (a marker of glucocorticoid receptor-mediated transactivation).
Conclusions:
Overall, these data demonstrate the SEGRAM profile of GRM-01 and suggest that the drug may have an improved benefit-risk profile in DMD versus conventional glucocorticoids. A phase II study in DMD is planned for 2026. We will present the pharmacological and preclinical data points alongside the unpublished phase 1 data to outline the potential benefits of GRM-01.