medwireNews: Boys with Duchenne muscular dystrophy (DMD) treated with givinostat for 72 weeks have less functional decline on the four-stair climb assessment than those treated with placebo, shows a study published in The Lancet Neurology.
The randomized, double-blind, phase 3 EPIDYS trial was conducted across 41 tertiary sites in 11 countries between 2017 and 2022. The research team enrolled 179 ambulant males (median age 9.8 years) who had genetically confirmed DMD and had completed at least two four-stair climb assessments in a mean 8 seconds or less, had a time to rise of 3 to 10 seconds, and had been taking systemic corticosteroids for at least 6 months.
Eugenio Mercuri (Università Cattolica del Sacro Cuore, Rome, Italy) and colleagues grouped the participants according to baseline vastus lateralis fat fraction (VLFF), as measured by magnetic resonance spectroscopy.
Participants in the intention-to-treat group A had a VLFF of more than 5% but no more than 30%, which the researchers explain is “intended to comprise patients who were not at risk of sudden, complete loss of ambulation but who, if receiving placebo, would show sufficient decline over the study duration in the function, strength, and fat fraction endpoints being tested.”
Participants in group B had a VLFF of either 5% or less or more than 30% and were only included in safety analyses.
The patients were randomly assigned to receive either oral givinostat (n=118) or the equivalent placebo (n=61) twice a day for 72 weeks, with flexible dosing based on weight, starting at a dose of 20–70 mg that was then reduced to 13–47 mg as required for tolerability.
After a safety review in 2018, at which point 46% of boys had been randomly assigned, the dosing regimen was changed to a starting dose of 13–47 mg twice a day, with a reduced dose of 11–37 mg.
The researchers found that after 72 weeks of treatment with the histone deacetylase inhibitor, the mean four-stair climbing time for the 81 participants in the givinostat arm of group A increased by 1.25 seconds, from 3.39 seconds at baseline. This was significantly less than the 3.03-second increase for the 39 patients in the placebo arm, from a baseline time of 3.48 seconds, giving a significant least squares mean difference of 1.78 seconds in favor of givinostat.
When analyzed as velocity, the four-stair climb results at 72 weeks were 0.243 tasks per second for those treated with givinostat and 0.209 tasks per second for those given placebo, with a significant least squares mean difference of 0.034 tasks per second.
Mercuri and colleagues comment that the smaller decline in four-stair climb is “potentially meaningful to patients,” because it “correlates with reduced participation in physical and social activities in daily life and predicts loss of stair-climbing ability and ambulatory capacity.”
They note that post-hoc analysis demonstrated that the results were unaffected by the change in givinostat dosing regimen.
The key secondary endpoints, including change from baseline in the North Star Ambulatory Assessment (NSAA) total score, NSAA cumulative loss-of-function, time-to-rise, the 6-minute walk test, knee extension, elbow flexion, and VLFF, “provided initial evidence to suggest an effect in favour of givinostat over placebo,” the team reports, but “the differences were not significant after multiplicity adjustment.” The investigators point out that multiplicity corrections make achieving significance in rare conditions like DMD difficult because of the small sample sizes involved.
The proportions of patients experiencing adverse events were similar across both the givinostat and placebo arms, at 95% and 93%, respectively, and were mild to moderate in severity.
The most common adverse events with givinostat treatment were diarrhea (36 vs 18% with placebo), vomiting (29 vs 13%), headache (24 vs 23%), and abdominal pain (21 vs 15%).
Treatment-related adverse events occurred more often with givinostat than placebo and included decreased platelet count or thrombocytopenia (31 vs 0%) and increased blood triglyceride concentration or hypertriglyceridemia (22 vs 7%) – both recognized adverse events associated with givinostat use, say Mercuri et al.
In an associated commentary, Janbernd Kirschner (University of Freiburg, Germany) writes that the benefits seen with givinostat treatment “suggest new therapeutic avenues for treating patients with Duchenne muscular dystrophy,” adding that givinostat “could be an additional component […] potentially reducing inflammation and fibrosis,” alongside the effects of corticosteroids and dystrophin-restoring treatments.
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Lancet Neurol 2024; doi:10.1016/S1474-4422(24)00036-X
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