The US FDA has approved Italfarmaco’s givinostat (Duvyzat) for Duchenne muscular dystrophy (DMD) patients aged six and older.
DMD is an inherited neurological disorder caused by mutations of the dystrophin gene that lead to progressive muscle deterioration. As patients lose muscle, they face problems walking and breathing, ultimately leading to early death. A mainstay of DMD treatment is corticosteroids, which decrease inflammation and increase total muscle mass. The FDA has also granted accelerated approval to oligonucleotide-based exon-skipping drugs and to a gene therapy that boost dystrophin production, but the clinical benefit of these therapeutics has not yet been demonstrated.
Histone deacetylase (HDAC) inhibition now provides another option. HDAC enzymes are epigenetic regulators that control various cellular functions, including muscle gene expression. Givinostat reduces inflammation and promotes the formation of muscles in a mouse model of DMD, shows preclinical work.
The FDA approved the drug on the basis of a phase III trial in 179 DMD patients, all on a background of corticosteroids, who were randomized 2:1 to givinostat or placebo. The primary endpoint was the change in the 4-stair climb (4SC) time — a measure of muscle function — at 18 months in a prespecified subset of patients. The 4SC time for these givinostat recipients slowed by 1.25 seconds on average over this time, compared with an average slowing of 3.03 seconds for placebo recipients.
“This smaller decline is potentially meaningful to patients, because slower four-stair climb correlates with reduced participation in physical and social activities in daily life and predicts loss of stair-climbing ability and ambulatory capacity,” wrote study investigators in The Lancet Neurology in April.
Side effects of treatment included diarrhoea, abdominal pain, thrombocytopenia, nausea, vomiting and more.
Paediatric neurologist Janbernd Kirschner, at University of Freiburg, welcomed the new drug in a Comment in The Lancet Neurology. “Recognising that no single treatment is likely to arrest the progression of the disease fully, a multifaceted therapeutic strategy might be needed in the future. Alongside corticosteroids and treatments aimed at restoring dystrophin, histone deacetylase inhibition — as provided by givinostat — could be an additional component in the management of Duchenne muscular dystrophy,” he wrote.
Longer-term data in a wider cohort of DMD patients is needed to better assess the new drug’s therapeutic value, he added. “Considering the mixed history of successes and setbacks in the development of treatment for this condition, managing expectations continues to be a major challenge in the daily care of patients and their families, underscoring the need for a balanced and informed approach,” he wrote.
The broader DMD pipeline spans exon skipping, cell therapy, gene editing and more.
