GRM-01 is a novel Phase 2-enabled, orally available, non-steroidal selective glucocorticoid receptor agonist and modulator (SEGRAM) that was evaluated in the mdx model of DMD. Male, 4- to 5-week-old B10.mdx mice (strain C57BL/10ScSn-Dmdmdx/J) were dosed orally for 42 days with vehicle (qd dosing), GRM-01 (0.5mg/kg/day, 1 mg/kg/day, and 2 mg/kg every other day [qod]) or prednisolone (5 mg/kg/day). Wild-type mice (strain C57BL/10ScSn) treated with vehicle (qd dosing) were assessed in parallel. Notable findings are as follows.
On Day 33 (N=11-12 mice/arm), GRM-01 produced significant improvements versus mdx-vehicle in the mean body weight (BW)-normalized forelimb grip strength at doses of 0.5 mg/kg/day and 2 mg/kg qod, with respective Recovery Scores (Deconinck et al. Nat Med. 1997:1216) of 71% and 64%.
On Day 42 (N=6-8 mice/arm), GRM-01 at a dose of 2 mg/kg qod produced a significant increase versus mdx-vehicle in the mean BW-normalised, peak isometric torque force, with a Recovery Score of 130%.
In contrast, prednisolone did not significantly improve, versus mdx-vehicle, either of these muscle function outcomes.
Histological analysis (N=7-8 mice/arm) indicated that GRM-01 at doses of 1 mg/kg/day and 2 mg/kg qod significantly reduced, versus mdx-vehicle, the mean percent area of inflammatory foci in the diaphragm by 57% and 70%, respectively. Prednisolone produced a similar, significant reduction of 65% in this outcome. These findings support the strong transrepression activity of GRM-01.
In contrast to all doses of GRM-01, prednisolone significantly increased, versus mdx-vehicle, fasting blood glucose levels by 25% on Days 21 and 42 (N=17-18mice/arm), supporting the reduced transactivation potential of GRM-01 relative to prednisolone.
Overall, GRM-01 demonstrated SEGRAM-like in-vivo pharmacology – potent transrepression with weak transactivation – and showed functional and histological benefits in the mdx model. These data support its evaluation as a treatment for DMD.