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The US Food and Drug Administration (FDA) has recently approved Duvyzat (givinostat), the first nonsteroidal therapy for children aged 6 years and older who have all hereditary variants of Duchenne muscular dystrophy (DMD).

The application for the drug 's marketing authorization in Europe is also now underway, where DMD affects approximately 0.5 in 10,000 individuals, equivalent to around 25,000 people. The European Medicines Agency (EMA) told Medscape Medical News that the process began in August 2023, but because the evaluation is ongoing, they could not comment on expected timelines. The UK Medicines and Healthcare products Regulatory Agency (MHRA) is also reviewing the drug. In the meantime, patients and doctors can explore the possibility of joining a clinical trial.

Developed by Italian pharmaceutical company Italfarmaco, givinostat is a histone deacetylase (HDAC) inhibitor that modifies cellular gene expression by altering the three-dimensional folding of DNA. It targets pathogenic processes that cause a lack of the muscle protein dystrophin, in turn reducing inflammation and muscle loss.

Paolo Bettica, the chief medical officer and head of drug development at Italfarmaco, told Medscape Medical News that HDAC inhibitors cannot restore dystrophin, but they can counteract the defects caused by its absence, reducing inflammation, fibrosis, and fat infiltration and increasing muscle regeneration.

EMA and MHRA approval of givinostat could represent a significant milestone in the treatment of DMD, offering the potential to improve the quality of life for those living with the condition.

Trial Demonstrates Efficacy and Suggests Broader Applications

The phase 3 EPIDYS clinical trial found that givinostat, a small molecule taken as an oral solution twice daily, was effective in boys aged 6 years or older. The double-masked, placebo-controlled, multicenter study included 179 ambulant boys with DMD who were randomized in a 2:1 ratio (givinostat:placebo) and treated for 18 months.

The trial findings, published in The Lancet Neurology, reported clinically meaningful and statistically significant improvement in the time it took to climb four stairs between the treatment and placebo control groups, with minimal side effects. Clinicians observed slightly increased rates of thrombocytopenia, diarrhea, and hypertriglyceridemia.

Bettica said the analysis of key secondary endpoints, including the North Star Ambulatory Assessment and time to rise test, favored the givinostat group. Additionally, magnetic resonance spectroscopy revealed that givinostat treatment delayed fat infiltration in the thigh muscles, a characteristic of disease progression in DMD. "The literature shows that fat infiltration is related to function, and it is predictive of the loss of ambulation," he said. "So we believe that this is a critical parameter."

Givinostat is more effective in younger patients because it slows muscle damage rather than reverse it. "Givinostat works as long as there are still some muscle fibers," said Bettica. "Duchenne is a progressive disease, and by age 13 or 15, you have lost ambulation."

The results from the EPIDYS trial provide evidence that givinostat has the potential to delay disease progression when added to corticosteroid treatment. Now, Italfaramaco is exploring whether the anti-inflammatory, antifibrotic drug might also be effective for treating patients with Becker muscular dystrophy. "We are currently looking into other applications outside DMD. But that is still a work in progress," Bettica said.

A Broad-Reaching Therapy

Current pharmacologic treatments of DMD primarily include steroids, which are beneficial but have side effects. Vasantha Gowda, a pediatric neuromuscular consultant at Evelina London Children's Hospital, London, England, said that steroids prolong ambulation and delay cardiorespiratory complications, but they can also lead to behavioral issues and osteoporosis and affect height and weight.

Gowda expressed optimism, noting that givinostat's different mechanism of action would be an added benefit alongside existing steroid treatments.

"DMD is a complex, multisystemic disease. There is a place for different drugs with different mechanisms of action and targeting different parts of the process," she told Medscape Medical News. "It's difficult to tease out what the gains are from individual drugs in these children. So we will be looking at cumulative gains from several therapeutic approaches."

Advocacy groups around the world have welcomed givinostat's FDA approval and are pushing for the EMA and MHRA to follow suit.

"It is exciting," said Pat Furlong, founding president and CEO of the nonprofit Parent Project Muscular Dystrophy in the United States. "We need several therapies, and I think this is a critical piece of the puzzle."

Filippo Buccella, founder of Parent Project in Italy, told Medscape Medical News that the approval of givinostat has been long-awaited and will have a broad reach. "[Givinostat] is especially interesting because it is not specific to one mutation but can be effective for any variant of Duchenne."

Buccella, a pharmacist whose son Luca was diagnosed with DMD in 1993, became interested in myostatin inhibition research and, in 2004, began funding research on givinostat for DMD through Parent Project. By 2008, researchers had demonstrated the drug's efficacy in lab and preclinical studies. In 2009, Italfarmaco decided to invest in the drug and begin clinical trials.

By then, Buccella's son was a teenager and unlikely to benefit from the drug. "I always knew givinostat would not help Luca, but we are really happy to have something that can finally help most patients," Buccella said.

"DMD deserves a break," said Gowda. "Having seen what's happened with SMA [spinal muscular atrophy] and all the new therapies coming in, I hope we'll see the same change in the DMD landscape. It would be great to have givinostat on board."

Vasantha Gowda participated in a board meeting at Italfarmaco to consult on givinostat clinical data. Filippo Buccella served on a board as a patient's representative for Italfarmaco. Pat Furlong reported no relevant financial relationships.