On March 21, 2024, the U.S. Food and Drug Administration announced approval of Duvyzat (givinostat), an oral medication for the treatment of Duchenne Muscular Dystrophy (DMD) in patients age six and older.
Duvysat was the first nonsteroidal drug approved to treat all genetic variants of DMD, an inherited progressive condition that causes muscles to weaken over time, particularly those affecting movement, breathing and heart function. Without treatment, DMD can measurably shorten life expectancy. It affects roughly 1 in every 3,600 male infants.
The approval of Duvysat marked a significant advance in efforts to tame the disease, which currently has no cure. It also celebrated a major milestone in the nearly 30-year journey of Pier Lorenzo Puri, MD, professor in the Center for Cardiovascular and Muscular Diseases at Sanford Burnham Prebys Medical Discovery Institute, and collaborators around the world.
“I have been working from the very beginning of my research career to translate early, basic discoveries into a treatment for DMD,” said Puri. “The lack of effective treatments for boys with DMD has left families and patients hopeless since the discovery of this disease. Witnessing the progression of such a disease without any option to counter its progression is cruel and I felt the urgency to help these people.”
“Dr. Puri performed groundbreaking work with an HDAC inhibitor (HDACi) and brought it to be the first non-steroidal therapy approved for DMD,” said Pura Muñoz-Cánoves, PhD, a principal investigator at Altos Labs – San Diego Institute of Science. “His findings have revolutionized the way we think about this complex process of tissue regeneration, and critically, he was able to translate his basic fundamental discoveries to the clinic, with the capacity to drastically change patient lives.”
Specifically, Puri and colleagues discovered in a mouse model of DMD that animals treated with HDACi (a class of drugs that block the action of the enzyme histone deacetylase) show enhanced muscle stem cell function and, subsequently, improved muscle regeneration, accompanied by reduced fibro-fatty infiltration and inflammation and, most importantly, increased muscle force and performance.
DMD is the most frequent form of muscular dystrophy. It is linked to the chromosome X, which harbors the gene coding the protein called dystrophin. As such, the disease develops only in males receiving from their mother the X chromosome carrying mutations in the dystrophin gene that impair production of dystrophin.
Dystrophin is a protein that protects muscles from degeneration after they contract and relax. In its absence, the muscles of boys with DMD are prone to damage and undergo cycles of contraction and degeneration that eventually lead to muscle wasting and reduced function.
For decades, steroids have provided standard-of-care for DMD, but steroids are not disease-specific and chronic use causes many adverse side effects. Puri said his work will not cure DMD, but it provides “the first pharmacological treatment that can delay DMD progression, regardless of the type of mutation, and do so in a financially affordable way.
“The work of Dr. Puri represents the perfect example of how an investigator excelled in fundamental discoveries and then had the great vision, tenacity and resilience to sort out the many obstacles due to biological complexity, eventually paving the way for approval of a treatment for an incurable, devastating disease in humans,” said Muñoz-Cánoves.
Puri noted, however, that FDA approval of givinostat is not the end of the journey.
“The very good news here is that there is room to improve the efficacy (of treatment) for DMD by using already existing compounds or by developing novel molecules endowed with an improved therapeutic potential.”
And so for Puri and colleagues, the journey continues.