Mineralocorticoid receptor antagonism of vamorolone: Evidence from LIONHEART and VISION-DMD clinical trials

The effect of vamorolone, the first dissociative corticosteroid for Duchenne muscular dystrophy (DMD), at the mineralocorticoid receptor (MR) was investigated in the Phase 1 mechanistic LIONHEART study and using serum samples from boys with DMD in the pivotal VISION-DMD trial. In LIONHEART, 30 healthy adult males were randomized 1:1:1 to vamorolone 20 mg/kg, eplerenone 200 mg, or no treatment arms. A fludrocortisone challenge was administered between -9 h and 24 h after treatment. The LIONHEART primary outcome was urinary Na⁺/K⁺ ratio; additional outcomes were pharmacokinetics, urine Na⁺ and K⁺ concentrations, and safety. In VISION-DMD, boys with DMD aged 4-7 years were treated with vamorolone 2 or 6 mg/kg/d for 48 weeks or with prednisone 0.75 mg/kg/d or placebo for 24 weeks followed by vamorolone 2 or 6 mg/kg/d for 20 weeks following a 4-week washout. Serum sample analysis from VISION-DMD used the SomaScan® 7 K assay. In LIONHEART, vamorolone reversed the decrease in urinary Na⁺/K⁺ ratio induced by fludrocortisone, confirming vamorolone MR antagonism. The maximum MRA effect of vamorolone was observed at 4-6 h post dose and was detectable until approximately 10 h post dose. Vamorolone reversed fludrocortisone induced Na⁺ retention with no evidence of decreased potassium excretion. Vamorolone 20 mg/kg was well tolerated, and results were consistent with known PK parameters. The VISION-DMD results showed vamorolone-specific increases in renin serum levels, as well as klotho, and calcium carrier proteins fetuin A and B, consistent with an MR antagonist effect. The available data confirm the MR antagonistic effect of vamorolone in humans. LIONHEART: NCT06649409; VISION-DMD: NCT03439670.