Background: Mineralocorticoid receptor antagonists (MRA) (eg. Eplerenone) are used for managing DMD patients with cardiac dysfunction or fibrosis. Vamorolone, approved for treatment of DMD, has MRA activity in-vitro and in animal models. It remains unknown whether vamorolone is an MRA in humans.
Objective: To characterize MRA effect of vamorolone in healthy volunteers and establish biomarkers of MRA activity in DMD patients.
Methods: The LIONHEART study is a single dose, open-label, randomized, 3-arm, mechanistic trial to confirm the anti-aldosterone MRA activity of vamorolone assessed by changes in sodium to potassium (Na/K) ratio in urine after a fludrocortisone challenge in 30 male healthy volunteers. Subjects received vamorolone 20 mg/kg, or no drug, or eplerenone 200 mg as positive control. In addition, blood biomarkers for MRA activity from VBP15-004 pivotal trial in 4 to <7 yr DMD participants were analyzed. Results: In LIONHART, the log10 Na/K ratio by treatment arm showed both eplerenone and vamorolone to effectively reverse the decrease in Na/K ratio induced by fludrocortisone. There was no significant difference on urinary Na/K ratio between vamorolone and eplerenone at 4 to 6 hours post-dose, confirming MR antagonistic effect of vamorolone in humans. Vamorolone showed a significant natriuretic effect with no evidence of potassium retention. Both treatments were well tolerated. In DMD participants in the VBP15-004 registration trial, vamorolone at therapeutic dose (6 mg/kg) (but not prednisone) increased serum renin, calcium and phosphate, as well as the protein carriers of these inorganic ions (ASHG [Fetuin A], and Fetuin B), consistent with MR antagonism. Two serum proteins involved in inorganic ion signaling via FGF23 pathways were also increased by vamorolone (klotho, Anosmin-1), but not by prednisone. Conclusions: Taken together, these data confirm vamorolone as an MR antagonist with a potential reduced risk for clinically relevant hyperkalemia. Future research will evaluate its cardioprotective benefits in DMD.