Skip to content

When you choose to publish with PLOS, your research makes an impact. Make your work accessible to all, without restrictions, and accelerate scientific discovery with options like preprints and published peer review that make your work more Open.


FDA Approves Duvystat, New Oral Treatment for Duchenne Muscular Dystrophy (DMD)

A new drug has entered the arsenal against Duchenne muscular dystrophy (DMD), a genetic disease that affects boys and is challenging to treat. Boys 6 years and older can take Duvystat, to slow the course of the illness. FDA classifies it as a “nonsteroidal treatment” – not a gene therapy, but it affects gene expression.

DMD Basics

DMD affects one in every 3500 to 6000 male births worldwide; that’s approximately 6 per 100,000 in North America and Europe, according to the Muscular Dystrophy Association (MDA).

Symptoms typically begin between ages 2 and 5. Diagnosis is usually from 3 to 6, as muscle weakness worsens, delaying sitting, standing, and walking. Speaking may become difficult. Fat and scar (connective) tissues infiltrate the protein building blocks of healthy muscle, blocking the contractile molecules of actin and myosin from assembling into fibers that form the characteristic striated bands.The disease slowly becomes fatal as the encroaching muscle degeneration leads to chronic inflammation that affects functioning of the heart and lungs.

DMD arises from deletion of all or part of a gene on the X chromosome that encodes a crucial muscle protein called dystrophin. Affected boys inherit the mutation from their mothers, who are carriers, or have a new mutation that happened in the sperm or egg.

The New Drug

Duvyzat (givinostat), a type of drug called an HDAC inhibitor, has been in clinical trials to treat cancers and other disorders of the blood, Crohn’s disease, and a form of juvenile arthritis. It “could have been easily repurposed for DMD,” said Pier Lorenzo Puri at Sanford Burnham Prebys Medical Discovery Institute in San Diego, who has been working on the drug development since 2004. Research also took place in two facilities in Italy, with sponsorship from Italfarmaco S.p.A..

MDA supported development of a mouse model that enabled the preclinical studies of what would become Duvyzat.

Four HDAC inhibitors have been approved so far, to treat blood cancers. These drugs affect which parts of specific genes are transcribed and translated into protein, and which parts are shielded – aka gene expression.

Results from the study that led to the FDA approval appeared in The Lancet Neurology in April 2024 with commentary.

A Scant Protein with Outsize Importance

Slowing the muscle decline of DMD presents two huge challenges: the ubiquity of muscle and a giant gene.

Muscle makes up about 40 percent of body weight. A gene-based treatment would have to alter many cells to exert a noticeable effect.

But even if gene therapy could reach sufficient muscle cells to improve quality of life, another hurdle looms: the dystrophin gene that’s deleted in DMD is huge, the largest in a human genome at 2.2 million DNA bases.

Dystrophin is, ironically, vanishingly scant in muscle tissue, but is of outsize importance, stabilizing the abundant fibers of actin and myosin. Destroy the ability to make dystrophin and skeletal and cardiac muscle fibers fall apart. Muscles stop working, the gargantuan gene gutted or gone.

The gene presents a complex landscape. Sparse regions, the exons, encode the amino acids of dystrophin protein. The exons are nestled amongst the much longer introns, which are DNA sequences that are not represented in the final protein. The 79 exons are transcribed into a 14,000-base-long mRNA, so more than 99% of the gene is supposedly nonfunctional introns. The dystrophin gene is a little like a long novel with only a few pages propelling the plot.

Steroids and Gene Therapies

For decades, treatments for DMD have been generic: painkillers; corticosteroids (Gamree and Emflaza); physical, respiratory, and occupational therapy; nutrition counseling to ease swallowing; and behavioral therapy to maintain cognitive function. Although corticosteroids slow disease progression, weight gain and fragile bones develop with long-term use.

Researchers have been working on developing gene therapy for DMD for decades. Initial clinical trials introduced the gene into boys’ toes, to limit the damage should adverse effects arise.

In 2023, two gene-based treatments became available.

Elevidys is for boys aged 4 to 5 who can still walk. It delivers a shortened dystrophin gene, just 4,558 DNA bases. Inspiration for this strategy comes from the milder Becker muscular dystrophy, in which short but partially active dystrophin usually doesn’t shorten life.

Viltepso works in a similar way. Mimicking a natural type of mutation, called exon skipping, removes chunks of the gene that control the errant splicing that causes some deletions.

What’s an HDAC Inhibitor?

(Trigger warning: Skip if you fear biochemistry.)

Proteins called histones wrap around DNA at regular intervals, winding the molecule into units that resemble tiny spools. Enzymes add or remove three types of small organic chemical groups to histones.

One type of histone addition, acetyl groups, bind in patterns that control which genes are expressed (transcribed into RNA and translated into protein) and which genes are hidden, a little like reading only some of the words on a page. This choreography unfolds through several complex molecular interactions.

Enzymes called acetylases add acetyl groups to specific sites on histones, which neutralizes the histones’ positive charge, removing them from the underlying DNA, which is negatively charged. This clears the way for gene expression. Enzymes called deacetylases remove acetyl groups, which shuts off gene expression.

Adding and removing acetyls is an epigenetic change, because it leaves untouched the underlying DNA sequence. But the pattern of acetyls dotting DNA is transmitted when the muscle cell divides.

Duvyzat reigns in HDAC activity, slowing the cascade of events leading to muscle deterioration. “This drug changes gene expression in cells by altering the three-dimensional folding of DNA and has shown that it can slow DMD progression,” according to MDA. ITF Therapeutics provides the new drug in the US.

Hyperbole or Hope?

With a disease as devastating as DMD, any new treatment option is cause for celebration. And Duvyzat has the advantage of not being targeted to a specific mutation – that is, boys missing just part of the dystrophin gene respond too.

But the language of press releases tends to veer into hyperbole. Duvyzat is “a safe and proven-effective therapy that can have a meaningful impact for people living with DMD,” said Paolo Bettica, MD, PhD, Chief Medical Officer at Italfarmaco Group. Media reports don’t always spell out exactly what “proven-effective” means.

Researchers assess a new treatment for DMD by comparing the ability to walk or step while taking the drug to the “natural history” of the disease – the expected rate of decline without the intervention.

The phase 3 clinical trial, called EPIDYS, checked all the boxes: multicenter, randomized, double-blinded, and placebo-controlled. In it, 179 boys with DMD who were six or older and could still walk received either oral Duvyzat twice daily or placebo, in addition to steroids.

“After 18 months of treatment, patients treated with Duvyzat showed statistically significant less decline in the time it took to climb four stairs compared to placebo. The mean change from baseline to Month 18 in time to climb four stairs was 1.25 seconds for patients receiving Duvyzat compared to 3.03 seconds for patients receiving placebo,” according to the FDA news release. And treated patients experienced “less worsening” in a rating scale of motor function in boys with DMD compared to those in the placebo group.

Even if improvement on Duvyzat is incremental, it’s good news for the DMD community, because it means that it’s possible to slow the pace of muscle degeneration. And the new drug can possibly be combined with other approaches.

“Since the way Duvyzat (givinostat) works is different from other treatments, the combination of this new drug with other therapies may further improve the lives of our patients living with Duchenne muscular dystrophy,” said Barry Byrne Chief Medical Advisor to MDA and Director of the Powell Gene Therapy Center at the University of Florida.

For many disorders, combining therapies is the way to go – even if progress is a little at a time.

Related Posts
Back to top