US FDA-approval of VAMOROLONE for Duchenne Muscular Dystrophy (DMD)*-a novel alternative steroid with unique properties.

New Drugs and Therapeutics

 

On October 26, 2023, the US Food and Drug Administration (FDA) approved AGAMREE (Vamorolone/VBP 15) 6 mg/kg/day for the treatment of Duchenne Muscular Dystrophy (DMD) for patients 2 years of age and older.1 [Catalyst Pharmaceuticals, Coral Gables, Fl.; developed by Santhera Pharmaceuticals (Pratteln, Switzerland www.santhera.com)].

AGAMREE (Vamorolone) is a first-in-class oral medication, that is a novel alternative steroid that binds to the same receptors as corticosteroids and modifies their downstream activity.2,3

Vamorolone is unique in structure compared to glucocorticoids (GCs), such as prednisone and deflazacort. It contains a D-9, 11 double bond modification of the steroid C-ring, which may help explain its differential mechanism of action.3 Vamorolone is similar to GCs in its anti-inflammatory properties (transrepressor effects of GC), but has remarkably fewer metabolic side effects (transactivator effects of GC) than prednisone/prednisolone or diflazocort when used in moderate doses (< 6.0 mg/kg/day), and is antagonistic to the mineralocorticoid receptor 4. Vamorolone is comparable to prednisone/prednisolone and deflazacort in maintaining skeletal muscle function in DMD, and superior to GCs in preserving linear growth and bone health.4  However, at the highest dose tested, 6.0 mg/kg/day, there was greater associated weight gain and increased concern for adrenal suppression as measured by morning cortisol as compared to lower doses.5 The mean change in BMI  however was not significantly higher than patients in the Duchenne Natural History Study receiving GCs.6

It should be noted that vamorolone, like traditional corticosteroids, causes reversible hypothalamic pituitary-adrenal axis suppression and so there is still the risk of development of secondary adrenal insufficiency if acutely ill or if medication is abruptly stopped.7 Recommendations regarding stress dosing with hydrocortisone still apply. Patients should also still be advised to have a medical alert identifier. There is a need for further well- controlled prospective studies between the various glucocorticoid preparations.

 

Prepared on behalf of the PES Drugs and Therapeutics Committee by Brenda Kohn, MD and Daniel Mak, MD

Edited by Sowmya Krishna, MD and Anna Ryabets-Lienhard, DO

 

 

References:

  1. FDA Roundup: October 27, 2023 | FDA. Accessed December 6, 2023. https://www.fda.gov/news-events/press-announcements/fda-roundup-october-27-2023
  2. Guglieri M, Clemens PR, Perlman SJ, et al. Efficacy and Safety of Vamorolone vs Placebo and Prednisone Among Boys With Duchenne Muscular Dystrophy: A Randomized Clinical Trial. JAMA Neurol. 2022;79(10):1005-1014. doi:10.1001/JAMANEUROL.2022.2480
  3. Liu X, Wang Y, Gutierrez JS, et al. Disruption of a key ligand-H-bond network drives dissociative properties in vamorolone for Duchenne muscular dystrophy treatment. Proc Natl Acad Sci U S A. 2020;117(39):24285-24293. doi:10.1073/PNAS.2006890117
  4. Elhalag RH, Motawea KR, Talat NE, Rouzan SS, Shah J. Efficacy of vamorolone in treatment of Duchene muscle dystrophy. A meta-analysis. Front Neurol. 2023;14:1107474. doi:10.3389/FNEUR.2023.1107474/BIBTEX
  5. Hoffman EP, Schwartz BD, Mengle-Gaw LJ, et al. Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function. Neurology. 2019;93(13):e1312. doi:10.1212/WNL.0000000000008168
  6. Mah JK, Clemens PR, Guglieri M, et al. Efficacy and Safety of Vamorolone in Duchenne Muscular Dystrophy: A 30-Month Nonrandomized Controlled Open-Label Extension Trial. JAMA Netw Open. 2022;5(1):e2144178-e2144178. doi:10.1001/JAMANETWORKOPEN.2021.44178
  7. Vamorolone. Am J Health Syst Pharm. Published online December 28, 2023. doi:10.1093/AJHP/ZXAD303

 

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