Patients with Duchenne muscular dystrophy (DMD) are prescribed corticosteroid anti-inflammatory drugs as standard of care, but long-term use comes with significant adverse effects.
For individuals with DMD, corticosteroids have been the only treatment shown to significantly impact physical function, observed Tina Duong, MPT, PhD, director of neuromuscular medicine clinical outcomes research at Stanford University in Palo Alto, California.
"Boys undergoing glucocorticoid treatment often experience improvements in their ability to run, walk, and perform daily activities," Duong told MedPage Today. "Over the long term, these patients also exhibit a slower disease progression compared with those not receiving glucocorticoids."
The side effects of glucocorticoids present significant challenges for families and caregivers, Duong pointed out.
"Weight gain, Cushingoid appearance, behavioral difficulties, and stunted growth are some of the potential adverse effects that require careful consideration," she noted. "This necessitates a close collaboration between families and their clinical teams to weigh the benefits of glucocorticoids against these possible side effects."
In addition to prednisone and prednisolone, both used off-label, two corticosteroid formulations have been approved for DMD in recent years: the glucocorticoid deflazacort (Emflaza) in 2017, and the dissociative steroid vamorolone (Agamree) in 2023.
Deflazacort
Deflazacort is approved for patients ages 2 years and older; a generic version for patients ages 5 and older is now available.
In 2016, a phase III trial of prednisone versus deflazacort showed that both agents improved muscle strength compared with placebo, but deflazacort was associated with less weight gain.
The deflazacort label carries warnings about endocrine, immunologic, cardiovascular, renal, gastrointestinal, behavioral, bone, eye, skin, and vaccination concerns. The most common adverse events with treatment are Cushingoid appearance, increased appetite, weight gain, upper respiratory infection, cough, pollakiuria, hirsutism, central obesity, and nasopharyngitis.
A prospective cohort study in The Lancet that evaluated the long-term effects of glucocorticoids in DMD, including deflazacort, found that treatment was associated with reduced risk in loss of mobility and upper limb function milestones. Subgroup analysis found deflazacort was associated with an increased median age at loss of three clinical milestones by 2.1 to 2.7 years compared with prednisone or prednisolone (P<0.012).
The study added "evidence of the long-term benefits of glucocorticoids and the effect on all causes of mortality -- a very important message because these are fairly cheap and easily accessible drugs -- for the benefit of all patients with Duchenne muscular dystrophy," noted pediatric neurologist Nathalie Goemans, MD, PhD, of University Hospitals Leuven in Belgium, in an editorial accompanying the study.
A 2022 study in JAMA compared three corticosteroid regimens in previously untreated boys with DMD. Daily prednisone and daily deflazacort led to significantly better outcomes compared with intermittent prednisone, with no significant difference between the two daily regimens.
Vamorolone
Last year, the FDA approved vamorolone for DMD patients ages 2 years or older.
"Vamorolone is a new dissociative steroid drug that aims to retain or improve the therapeutic benefit of traditional glucocorticoids while reducing severe adverse side effects associated with long-term administration," wrote Miranda Grounds, PhD, and Erin Lloyd, PhD, both of the University of Western Australia, in a commentary published in the Journal of Neuromuscular Diseases.
The synthetic agent was designed to dissociate pro- and anti-inflammatory steroid functions. It reduced pro-inflammatory signaling in the nuclear factor kappa B (NF-κB) pathway in preclinical studies.
In 2022, a phase II trial showed that, from baseline to week 24, time to stand from supine velocity was significantly greater in boys receiving vamorolone 6 mg/kg compared with placebo. The relative efficacy of prednisone and vamorolone 6 mg/kg was similar for motor outcomes. A trial update in 2024 showed the efficacy of vamorolone 6 mg/kg was maintained over 48 weeks.
Safety data in the phase II trial showed the height percentile declined with prednisone, but not vamorolone. Bone turnover markers also declined with prednisone, but not vamorolone.
The most common adverse events versus placebo were Cushingoid features, vomiting, and vitamin D deficiency. Warnings on the vamorolone label address endocrine, immunosuppression, ophthalmologic, and vaccine concerns as well as effects on cardiovascular, renal, gastrointestinal, and bone function.
A non-randomized open-label extension study found similar efficacy for vamorolone compared with traditional glucocorticoids in two historical control cohorts for up to 30 months, with a relatively beneficial adverse outcome profile for vamorolone.
How new drugs may change the role of steroids in DMD is unclear. DMD treatment now includes four exon-skipping drugs, the histone deacetylase inhibitor givinostat (Duvyzat), and gene therapy with delandistrogene moxeparvovec (Elevidys).
One possible change for the role of steroids was outlined in a review published in the Orphanet Journal of Rare Diseases.
"Although novel dissociative steroids may be a superior substitute to glucocorticoids, other potential therapeutics should be explored," wrote Emma Rybalka, PhD, of Victoria University in Australia, and co-authors.
Fumaric acid esters (FAEs), including dimethyl fumarate (Tecfidera) and diroximel fumarate (Vumerity) -- which are approved to treat multiple sclerosis -- have anti-inflammatory effects with demonstrated efficacy in diseases associated with inflammation and oxidative stress, Rybalka and colleagues observed.
Repurposing or developing new therapies like these that could address the downstream consequences of dystrophin deficiency may be a viable option to improve patient quality of life in DMD, they noted.
"Since they activate alternative receptors/signaling pathways to glucocorticoids, there is also scope for combined FAE and corticosteroid regimens that could synergistically amplify therapeutic potential," they suggested.
Disclosures
Duong reported being an advisory board member for Biogen, CureSMA, Novartis, Roche, and Scholar Rock, and a consultant for Astellas, Avidity, Biohaven, Dyne, Genentech, Novartis, Roche, and Sarepta Therapeutics.
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