Vamorolone, an experimental treatment for Duchenne muscular dystrophy (DMD), combines the benefits of two existing therapies — prednisone and eplerenone — on heart and muscle health, but with less detrimental side effects, a study in animal models of the disease reports.
The study, “Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy,” was published in Life Science Alliance.
DMD, the most common type of muscular dystrophy, is caused by mutations in the DMD gene that provides instructions for the production of the dystrophin protein. Dystrophin works together with other proteins to strengthen muscle fibers and protect them from injury as muscles contract and relax.
Both skeletal and cardiac muscles are typically affected as patients age, because dystrophin is primarily found in these muscles. Heart disease, also known as cardiomyopathy, is common in DMD patients.
Prednisone, an agonist of the glucocorticoid receptor (GR), is a potent anti-inflammatory medicine and considered the golden standard for treating DMD. But its long-term use is associated with severe side effects, including bone fragility, stunted growth, weight gain, behavior issues, cataracts, and adrenal suppression.
Eplerenone, an antagonist of the mineralocorticoid receptor (MR), has been shown to slow the progression of heart disease in DMD patients, and has been used for decades to treat heart failure and high blood pressure.
“Some drugs can interact with both the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) since these two drug targets evolved from a common ancestor. However, we find these two drug targets can play distinctly different roles in heart and skeletal muscle,” Christopher Heier, PhD, assistant professor at Children’s National Health System and lead author of the study, said in a press release.
“In our study, the experimental drug vamorolone safely targets both the GR to treat chronic inflammation and the MR to treat the heart,” he added.
To test the efficacy and safety of different MR antagonist compounds, researchers treated healthy and DMD mice (mdx mice) with either a daily dose of a vehicle solution (as a control group), eplerenone (100 mg/kg), spironolactone (20 mg/kg), or vamorolone (20 mg/kg). All animals had a pump implanted under the skin that released either a vehicle solution (control) or aldosterone, a mineralocorticoid hormone that activates the MR.
Results showed that aldosterone treatment and MR activation led to a significant increase in kidney size and high blood pressure in both healthy and DMD mice. But in the DMD animals, eplerenone, spironolactone, and vamorolone all prevented kidney enlargement and elevated blood pressure.
MR activation triggered by aldosterone also increased the size of the heart and caused tissue fibrosis (scarring) in DMD animals, which were mitigated by all MR antagonists. MR activation also impacted heart function in the DMD animals, a side effect prevented by vamorolone, eplerenone, and spironolactone treatment.
Regarding safety, the researchers reported that daily prednisone therapy was associated with side effects, including hyperinsulinemia (excessive levels of insulin in the blood), while vamorolone aided heart function without associated side effects.
“These findings have the potential to help current and future patients. Clinicians already prescribe several of these drugs. Our new data support the use of MR antagonists such as eplerenone in protecting DMD hearts, particularly if patients take prednisone,” Heier said.
He also noted that vamorolone is currently in a Phase 2b clinical trial [VISION-DMD trial, NCT03439670]. That trial is enrolling boys with DMD, ages 4 to 7, at sites across the U.S., Canada, Australia, Israel and select European countries; information is available here. It is expected to finish in May 2020.
“Our data provide new insights into steroid mechanisms of action, elucidate the molecular pathogenesis of dystrophic cardiomyopathy, and identify vamorolone as a first-in-class drug that targets dual receptors to treat both inflammation and heart failure pathways,” the researchers wrote.
Vamorolone is being developed by ReveraGen Biopharma.