Vamorolone (Agamree; Santhera Pharmaceuticals), an FDA-approved therapy for Duchenne muscular dystrophy (DMD), has demonstrated a dual mechanism of action, functioning as both a mineralocorticoid receptor antagonist (MRA) and a glucocorticoid receptor agonist. This was highlighted in the LIONHEART study, a 3-arm trial assessing the MRA effect of vamorolone in healthy adult patients who previously had challenges with fludrocortisone. The findings suggest potential cardioprotective benefits for the DMD patient population.
The LIONHEART study, an ongoing, open-label, randomized, 3-arm, parallel-group, placebo and eplerenone-controlled study, evaluated the MRA effect of vamorolone in healthy adult male patients after a fludrocortisone challenge. The primary endpoint was defined as the ratio of sodium to potassium and the corresponding logarithm of the ratio in urine at different time points. Among the 30 participants, the study showed a statistically significant increase in the urinary sodium/potassium ratio in vamorolone-treated patients compared with placebo (P < .0001) following the fludrocortisone challenge.
Clinical Implications
"[MRA] are strongly recommended but late when cardiac function is already reduced and tend to be used in the presence of myocardial fibrosis as detected in magnetic resonance imaging," said Karim Wahbi, PhD, MD, cardiologist at the APHP Hospital Cochin, Paris, France. "What is intriguing about this mechanistic study is whether there is a synergistic benefit of the anti-inflammatory and MRA effects of vamorolone on the evolution of cardiac disease in children who started treatment early or if vamorolone could be of benefit to those who are already experiencing cardiac symptoms and wish to remain on a corticosteroid."
Shabir Hasham, MD, chief medical officer of Santhera, stated, "The LIONHEART study is an important milestone to establish the proof of concept for a cardioprotective potential of vamorolone. We continue to collect data from patients who have been on vamorolone for up to seven years allowing us to better characterize long-term outcomes including any beneficial impact on cardiac complications in DMD."
Vamorolone's Approval and Prior Studies
In October 2023, the FDA approved vamorolone oral suspension 40 mg/mL for treating DMD patients aged 2 years and older. The approval was based on data from the phase 2b VISION-DMD study (NCT03439670), which was recently published in Neurology. The study met its primary endpoint, demonstrating superiority in the change in time to stand test (TTSTAND) velocity relative to placebo, with a difference of 0.06 rises per second (95% CI, 0.02-0.10; P = .002).
The VISION-DMD trial was a double-blind, placebo-controlled study involving 121 DMD patients aged 4 to 7 years. Patients were randomized to receive either 2 mg/kg/d or 6 mg/kg/d of vamorolone for 48 weeks, or 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks before crossover. Efficacy was assessed using five motor outcomes: TTSTANDV, 6-minute walk test distance (6MWD), time to run/walk 10 m velocity (TTRWV), time to climb 4 stairs velocity (TTCLIMBV), and North Star Ambulatory Assessment (NSAA).
Efficacy and Safety Data from VISION-DMD
Led by Utkarsh Dang, PhD, MSc, BSc, an assistant professor at Carleton University, 92.6% (112 of 121) of patients completed the VISION-DMD study through week 48. The improvement seen with vamorolone 6 mg/kg/d after 24 weeks of treatment was maintained at week 48 for the primary outcome, TTSTANDV (week 24 least square mean [LSM], 0.052 [SE, 0.0130] rises/s vs week 48 LSM, 0.0446 [SE, 0.0138]). Assessment of dose dependency of motor outcomes showed a difference between vamorolone at a dose of 2 mg/kg/d vs 6 mg/kg/d for TTSTANDV after 48 weeks of treatment (LSM, 0.0500 [SE, 0.0186] rises/s; 95% CI 0.0126–0.0874; P = 0.010).
Significant differences between the two vamorolone dose levels at week 48 were also observed for 6MWD (LSM, 34.7634 [SE, 17.0194] m; 95% CI 0.4506–69.0761 m; P = 0.047) and TTCLIMBV (LSM, 0.0531 [SE, 0.0238] m; 95% CI 0.0052–0.1010 m; P = 0.031). While findings on TTRWV and NSAA were not significantly different between dose groups, performance remained better, on average, in the higher dosed group.
Vamorolone continued to show efficacy in those who switched from placebo midway through the study. From week 24 to week 48, treatment with vamorolone 6 mg/kg/d resulted in greater response on 6MWD (LSM difference, 34.1 m; 95% CI, –4.48 to 72.7 m; P = .082) and TTCLIMBV (LSM difference, 0.066 m; 95% CI, –0.001 to 0.133 m/s; P = .053). Dose-dependent differences in this post-hoc analysis were not statistically significant, possibly due to low power.
Throughout the 48-week trial, the most common adverse events (AEs) for vamorolone-dosed groups included upper respiratory tract infection, vomiting, cough, pyrexia, and diarrhea. There were no deaths during the study, and three serious AEs were reported (perforated appendicitis, asthma, and viral gastroenteritis) that were considered unrelated to the study treatment. The percentage of participants with at least one drug-related AE continued to be lower in the vamorolone 2 mg/kg group vs the 6 mg/kg group in period 2 (17.9% vs 39.3%, respectively).
