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The novel corticosteroid vamorolone was effective and safe in the short-term treatment of boys with Duchenne muscular dystrophy (DMD), with no stunting of growth or negative effects on bone biomarkers, according to a pivotal randomized placebo- and prednisone-controlled trial.

Among over 100 boys not previously treated with corticosteroids, time to stand from supine velocity from baseline to week 24 was significantly greater in those receiving vamorolone 6 mg/kg compared with placebo (least squares mean velocity 0.05 vs -0.01 m/s, P=0.002), reported Eric P. Hoffman, PhD, of the State University of New York in Binghamton, and colleagues.

As for the first-rank secondary endpoint, change from baseline to week 24 in time to stand was also greater with vamorolone 2 mg/kg versus placebo (least squares mean velocity 0.03 vs -0.01 m/s, P=0.02), they noted in .

These changes were at >0.02 rises per second, they added.

Several other secondary endpoints were also met, Hoffman and team said, with clinically meaningful (>30 m) changes from baseline in the 6-minute walk test of 42 m for vamorolone 6 mg/kg versus placebo (P=0.003), and a gain of 37 m for vamorolone 2 mg/kg versus placebo (P=0.009). Time to run/walk 10 meters at 24 weeks was also increased from baseline by 0.24 m/s (P=0.002) in the 6 mg/kg group.

The relative efficacy of prednisone and vamorolone 6 mg/kg was similar for motor outcomes, the authors said. Vamorolone 2 mg/kg also showed a similar effectiveness as prednisone for time to stand and the 6-minute walk test, but was less effective for time to run/walk 10 meters.

DMD standard treatment with oral corticosteroids such as prednisone and deflazacort (Emflaza) delays loss of mobility, but the well-known safety concerns with long-term use, including stunting of growth and adrenal insufficiency, can interfere with adherence to practice guidelines, the group explained.

"Vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug that binds to the same target receptors as the corticosteroid class (glucocorticoid receptor, mineralocorticoid receptor), but shows a distinct chemical structure and differences in mechanism of action," they noted.

Hoffman and team pointed out that despite having no previous exposure to corticosteroids, boys with DMD in all drug treatment groups "showed an unexpected high incidence of adrenal insufficiency at baseline" by both corticotropin (ACTH) stimulation and morning cortisol measures, "with approximately 10% of morning cortisol and 20% of ACTH-stimulated measures flagged as 'LOW.'"

"All drug treatment groups showed further suppression of the HPA [hypothalamic-pituitary-adrenal] axis from baseline ACTH stimulation tests and morning cortisol compared with placebo," they added, noting that this finding needs further study.

Given that symptoms of adrenal insufficiency and DMD overlap, and the treatment for adrenal insufficiency is supplemental glucocorticoids, the authors speculated that "some of the efficacy of both corticosteroids and vamorolone may be treatment of adrenal insufficiency."

From June 2018 to February 2021, Hoffman and colleagues enrolled 133 boys with DMD (mean age 5.4 years, 80% white) from 33 referral centers across 11 countries. They were randomly assigned to receive placebo, prednisone 0.75 mg/kg per day, vamorolone 2 mg/kg per day, or vamorolone 6 mg/kg per day.

Of this group, 114 completed the 24-week treatment period.

Among safety outcomes, a decline in height from baseline was noted with prednisone but not vamorolone 6 mg/kg (change -1.88 percentile vs +3.86 percentile, respectively; P=0.02). Moreover, markers of bone turnover declined with prednisone but not with vamorolone. Adverse event rates were comparable among the four treatment groups.

Study limitations included the short study duration, use of a single corticosteroid regimen, the narrow age range of the study population, and the relatively small number of participants per group, Hoffman and team noted.

This evidence of efficacy and safety of vamorolone over a broad dose range (2-6 mg/kg per day) may enable physicians to adjust dose, based on clinical observations and patient preferences, they concluded. Analysis of the second 24-week treatment period with longer-term treatment and crossover groups and more complete risk/benefit assessments is underway.

Santhera Pharmaceuticals, vamorolone's drug developer, has submitted a rolling new drug application (NDA) for FDA approval of the agent in DMD, though in late June the company that manufacturing concerns would delay finalization of the NDA until later this year.

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