GRM-01 is a novel, orally available, non-steroidal, selective glucocorticoid receptor agonist and modulator (SEGRAM) that displays strong transrepression activity (main driver of anti-inflammatory effects) and reduced transactivation activity (main driver of side effects) compared with conventional glucocorticoids. This pharmacological profile 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) versus the human progesterone and mineralocorticoid receptors and functionally displays partial transactivation whilst retaining full transrepression activities. For the latter, GRM-01 demonstrated potent anti-inflammatory efficacy in ex vivo human whole blood assays (interferon- γ suppression IC50,free=13.6 nM) that was similar to prednisolone (IC50,free=3.1 nM). Additionally, in cynomolgus monkeys, a single oral dose of GRM-01 (10 mg/kg) produced strong plasma cortisol suppression (IC50,free=10 nM), a marker of target engagement and GR-mediated transrepression. GRM-01 also demonstrated efficacy in a range of rodent disease models with strong inflammatory components including the B10.mdx mouse model of DMD and two models of experimentally induced inflammation and arthritis.
In Phase 1 healthy volunteer studies, GRM-01 showed dose- and exposure-dependent suppression of cortisol, reflecting GR-mediated transrepression. In the single ascending dose study, a single dose of GRM-01 was associated with ~76% cortisol suppression and inhibited lipopolysaccharide-stimulated interferon-γ production in a whole blood assay to a degree comparable to that observed with a single dose (20 mg) of prednisolone. In the multiple ascending dose (MAD) study, almost full cortisol suppression (≥95%) was observed at the highest investigated MAD dose. All doses of
GRM-01 were safe and well tolerated.
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 We will present the pharmacological and preclinical data points alongside the unpublished Phase 1 data that support the strong transrepression activity of GRM-01.