According to a new announcement, vamorolone (Agamree; Santhera Pharmaceuticals), an FDA-approved therapy for Duchenne muscular dystrophy (DMD), met its primary end point in the LIONHEART study, a 3-arm trial that assessed the mineralocorticoid receptor antagonist (MRA) effect of the therapy in healthy adult patients who previously had challenges with fludrocortisone. These results reveal the treatment’s dual mechanism as both a newly recognized MRA and previously known glucocorticoid receptor agonist, distinguishing it from traditional corticosteroids.1
Among 30 participants, findings in the study showed a statistically significant increase in the urinary sodium/potassium ratio in vamorolone-treated patients compared with placebo (P <.0001) following a fludrocortisone challenge. Overall, these topline findings highlight the therapy's potential cardioprotective benefits for the Duchenne patient population. In the company announcement, Santhera Pharmaceuticals noted that additional analysis of the data is currently ongoing and will be presented at medical conferences in the future.
“[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,” Karim Wahbi, PhD, MD, cardiologist at the APHP Hospital Cochin, Paris, France, said in a statement.1 “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.”
LIONHEART is an ongoing, open label, randomized, 3-arm, parallel-group, placebo and eplerenone controlled study assessing the MRA effect of vamorolone in healthy adult male patients after a challenge with fludrocortisone. Investigators defined the primary end point of the study as the ratio of sodium to potassium and corresponding logarithm of the ratio in urine at different time-points.
READ MORE: DYNE-251 Increases Dystrophin Level Expression in Phase 1/2 DELIVER Trial of Duchenne
Top Clinical Takeaways
- Vamorolone acted as both a mineralocorticoid receptor antagonist and glucocorticoid receptor agonist, distinguishing it from traditional corticosteroids.
- The LIONHEART study showed a statistically significant increase in the urinary sodium/potassium ratio in patients treated with vamorolone compared with placebo.
- Ongoing studies aim to confirm the long-term benefits of vamorolone in managing cardiac complications in DMD, including its potential to improve outcomes when initiated early.
Recent research has shown that cardiac complications including cardiomyopathy present a leading cause of morbidity and mortality among boys living with DMD. Previous studies demonstrated that treatment with corticosteroids as well as angiotensin-converting enzyme inhibitors delayed the onset of cardiomyopathy, but the addition of MRAs, such as eplerenone, to the standard of care also showed improvement in left ventricular systolic dysfunction, with greater benefits observed when initiated earlier.2-4
“The LIONHEART study is an important milestone to establish the proof of concept for a cardioprotective potential of vamorolone,” Shabir Hasham, MD, chief medical officer of Santhera, said in a statement.1 “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.”
In October 2023, the FDA approved vamorolone oral suspension 40 mg/mL for the treatment of patients with DMD aged 2 years and older.5 Data from phase 2b VISION-DMD study (NCT03439670), recently published in Neurology,6 was the basis for the approval in which the agent met its primary end point of superiority of change in time to stand test (TTSTAND) velocity relative to placebo. The primary end point, superiority in change of TTSTAND velocity, was represented by a difference of 0.06 (95% CI, 0.02-0.10) rises per second from baseline in the treated group (P = .002).
VISION-DMD, a double-blind, placebo-controlled trial included 121 patients with DMD aged 4 to 7 years old. In the study, patients were randomly assigned to 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was assessed using 5 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).
Led by Utkarsh Dang, PhD, MSc, BSc, an assistant professor at Carleton University, 92.6% (112 of 121) of patients completed the study through week 48. For the primary outcome, TTSTANDV, the improvement seen with vamorolone 6 mg/kg/d after 24 weeks of treatment was maintained (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).
Similarly, significant differences between 2 vamorolone dose levels at week 48 were seen 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). Findings on TTRWV and NSAA weren’t significantly different between dose groups; however, 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, the crossover period, to week 48 assessments, 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, which authors noted was possibly because of 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 3 serious AEs reported (perforated appendicitis, asthma, and viral gastroenteritis) that were considered unrelated to the study treatment. Overall, the percentage of participants with at least 1 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).
REFERENCES
1. Santhera Announces Positive Topline Results from LIONHEART Study with AGAMREE® (vamorolone) Demonstrating Unique Mineralocorticoid Receptor Antagonism. News Release. Santhera Pharmaceuticals. Published October 1, 2024. Accessed October 3, 2024. https://www.santhera.com/assets/files/press-releases/2024-10-01_Lionheart_e_final.pdf
2. Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management. Lancet Neurol. 2018;17(4):347-361. doi:10.1016/S1474-4422(18)30025-5
3. Raman SV, Hor KN, Mazur W, et al. Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial [published correction appears in Lancet Neurol. 2015 Feb;14(2):135. doi: 10.1016/S1474-4422(15)70002-5]. Lancet Neurol. 2015;14(2):153-161. doi:10.1016/S1474-4422(14)70318-7
4. Raman SV, Hor KN, Mazur W, et al. Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: results of a two-year open-label extension trial. Orphanet J Rare Dis. 2017;12(1):39. Published 2017 Feb 20. doi:10.1186/s13023-017-0590-8
5. Catalyst Pharmaceuticals Reports FDA Approval of AGAMREE® (vamorolone) for Duchenne Muscular Dystrophy Granted to Santhera Pharmaceuticals. News release. Catalyst Pharmaceuticals. October 26, 2023. Accessed October 4, 2023. https://www.globenewswire.com/en/news-release/2023/10/26/2767947/13009/en/Catalyst-Pharmaceuticals-Reports-FDA-Approval-of-AGAMREE-vamorolone-for-Duchenne-Muscular-Dystrophy-Granted-to-Santhera-Pharmaceuticals.html
6. Santhera announces publication of efficacy, safety, and tolerability data with vamorolone (Agamree) in patients with Duchenne muscular dystrophy in Neurology. News release. February 14, 2024. Accessed October 4, 2024. https://www.biospace.com/article/releases/santhera-announces-publication-of-efficacy-safety-and-tolerability-data-with-vamorolone-agamree-in-patients-with-duchenne-muscular-dystrophy-in-neurology/
