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FDA grants approval to vamorolone for Duchenne muscular dystrophy: a breakthrough in efficacy and safety

On October 26, 2023, the US Food and Drug Administration (FDA) granted approval for Santhera Pharmaceuticals’ vamorolone oral suspension at 40mg/ml, marking a significant milestone in the treatment of Duchenne muscular dystrophy (DMD) for adults and children over the age of 2. This decision followed a Phase IIb trial where the drug demonstrated comparable efficacy and remarkably fewer side effects than the existing standard of care. Vamorolone is poised to become the first medication approved for DMD treatment in both the US and Europe.1,2

Duchenne muscular dystrophy (DMD) is a rare, genetic, neuromuscular disease characterized by chronic inflammation and progressive muscle degeneration due to the absence of dystrophin, an essential muscle protein. This deficiency results from mutations in the DMD gene, which encodes dystrophin. Consequently, individuals with DMD have an increased susceptibility to muscle injury due to contraction-induced damage, leading to ongoing muscle degeneration and gradual loss of function. DMD is a terminal condition, typically resulting in a life expectancy not extending past 40. The cause of mortality in the majority of patients is cardiac and/or respiratory failure.3,4

While there is no known cure for DMD, current multidisciplinary approaches aim to manage the disease and its myriad of symptoms. Glucocorticosteroids are commonly used anti-inflammatory drugs and are the standard of care when there is motor decline. Their primary goal is to improve or maintain compromised muscle function, prevent deformities, and enhance muscle strength.3 However, the challenge with chronic glucocorticoid therapy lies in its multi-mechanistic nature, with an unclear molecular mechanism and harsh side effects that often impact patient compliance. These side effects may include immunosuppression, growth impairment, disruptions in glucose and fat metabolism, bone health issues, delayed puberty, and behavioral changes.3,4

Vamorolone (AGAMREE®) is a dissociative steroidal drug designed for DMD management.2 It offers chronic anti-inflammatory effects that improve muscle pathophysiology and provide protection against cardiac failure.5 Vamorolone targets the same receptor as corticosteroids, known as the glucocorticoid receptor (GR), but it does not lead to glucocorticoid response element (GRE) transactivation, unlike traditional corticosteroids. GREs mediate the transcriptional pathways that lead to the harsh side effects.4 So, this unique dissociative property allows vamorolone to maintain efficacy in the absence of off-target effects, resulting in a notably better safety and tolerability profile. Additionally, vamorolone serves as a mineralocorticoid receptor (MR) antagonist, reducing MR activity, which makes the drug beneficial in countering dystrophic cardiomyopathy and cardiovascular morbidity.1,5

The FDA’s approval of vamorolone was based on data derived from the Phase II VISION-DMD study (NCT03439670). This randomized, double-blind study involved 121 male participants aged between 4 and just shy of 7 years, all of whom were previously untreated for DMD.2 The study aimed to assess the effectiveness and safety profiles of vamorolone compared to a placebo and prednisone (a corticosteroid). Participants were divided into four groups and treated with either a placebo, prednisone, or two different concentrations of vamorolone (2 and 6 mg/kg/day) over a 24-week period. The study successfully met its primary endpoint of time to stand (TTSTAND) velocity from a supine position, with 6mg/kg/day of vamorolone showing significant improvements compared to the placebo (p=0.002).2 Furthermore, the secondary endpoints were also met; 6-minute walk test [vamorolone 6 mg/kg/day vs placebo] and time to run/walk 10 m velocity [vamorolone 6 mg/kg/day vs placebo]. Efficacy was maintained in the extension phase that followed participants to 48 weeks. Vamorolone also exhibited comparable efficacy and a more favorable safety profile compared to prednisone, with no adverse effects on growth and no increase in bone-related issues among the vamorolone-treated participants.1,2,6 Common side effects associated with vamorolone treatment, such as cushingoid features, vomiting, and vitamin D deficiencies, were generally mild to moderate in severity.2

Vamorolone oral suspension (40mg/ml) has been granted Orphan Drug status for DMD in both the US and Europe.7 It has received approval for use in patients aged 2 years and older, and is contraindicated in patients with a known hypersensitivity to vamorolone or any of its inactive ingredients.8 Additionally, vamorolone holds the status of Promising Innovative Medicine (PIM) for DMD from the UK MHRA. Following this FDA approval, Catalyst Pharmaceuticals intends to introduce vamorolone in the United States during the first quarter of 2024. After receiving the recent favorable CHMP (Committee for Medicinal Products for Human Use) opinion regarding vamorolone for DMD, the European Commission (EC) is set to grant approval in the European Union in late 2023, which will make vamorolone the first DMD drug to be approved for use throughout the US and Europe. 1,2

“I am excited for the Duchenne community who have been waiting a long time for an alternative to the current standard of care. Today’s news represents the culmination of many years of research to bring vamorolone to patients”-Eric Hoffman, PhD, President and CEO of ReveraGen BioPharma 1

Written by Molly Bassey

Reviewed by Juliet Lawrence

References:

  1. Santhera Pharmaceuticals. Santhera Receives U.S. FDA Approval of AGAMREE® (vamorolone) for the Treatment of Duchenne Muscular Dystrophy. [Press Release]. 27 October 2023. Accessed 27 October 2023.
  2. Santhera Pharmaceuticals. Our Pipeline: AGAMREE® (vamorolone). 2023. Accessed 27 October 2023
  3. Duan D, Goemans N, Takeda S, et al. Duchenne muscular dystrophy. Nat Rev Dis Primers. Feb 2021; 7(1):13.
  4. Heier CR, Damsker JM, Yu Q, et al. VBP15, a novel anti-inflammatory and membrane-stabilizer, improves muscular dystrophy without side effects. EMBO Mol Med. Sep 2013; 5(10):1569-85.
  5. Heier CR, Yu Q, Fiorillo AA, et al. Vamorolone targets dual nuclear receptor to treat inflammation and dystrophic cardiomyopathy. Life Sci Alliance. Feb 2019; 2(1): e20180018.
  6. Guglieri M, Clemens RP, Perlman JS, et al. Efficacy and Safety of Vamorolone vs Placebo and Prednisone Among Boys with Duchenne Muscular Dystrophy: A Randomized Clinical Trial. JAMA Neurol. Aug 2022; 79(10):1005-1014.
  7. FDA. FDA Roundup: October 27, 2023. [Press Release]. 27 October 2023. Accessed 3 November 2023.
  8. FDA. Prescribing Information for AGAMREE®. 2023. Accessed 3 November 2023.