The University of Alabama at Birmingham (UAB) Department of Pediatrics and Children’s of Alabama is expanding access to a promising investigational therapy for patients with Duchenne muscular dystrophy (DMD), offering new hope for families affected by the progressive neuromuscular disease.
Through an expanded access program, they will begin offering delpacibart zotadirsen, a novel antibody-oligonucleotide conjugate (AOC) developed by Avidity Biosciences. The program gives select patients access to the therapy before full U.S. Food and Drug Administration approval while researchers continue evaluating long-term outcomes.
Samantha Weaver, DNP, CRNPSamantha Weaver, DNP, CRNP, assistant professor in the UAB Department of Pediatrics’ Division of Pediatric Neurology, said the therapy represents an important step forward in the treatment of DMD.
“There is still no cure for Duchenne muscular dystrophy, therefore we are always interested in expanding access to therapies that may improve quality of life and slow disease progression,” said Weaver.
Duchenne muscular dystrophy is an inherited neuromuscular disorder caused by changes in the DMD gene, one of the largest genes in the human body. Duchenne muscular dystrophy primarily affects boys because it is inherited in an X-linked pattern. Sequence changes in the DMD gene prevent the body from producing dystrophin, a critical protein that helps protect muscle cells during movement and contraction. Without dystrophin, muscles become increasingly damaged over time.
“In the absence of dystrophin, fragile muscle fibers become susceptible to contractile injury, leading to damage and progressive weakness” explained Weaver.
Early signs of DMD can include delays in walking, enlarged calf muscles, and weakness in the hips and thighs. Symptoms typically worsen throughout childhood, with many patients losing the ability to walk between ages 8 and 12 years of age. In later stages, the disease can affect the heart and lungs, leading to serious complications such as heart and respiratory failure.
UAB and Children’s currently care for approximately 80 patients with Duchenne muscular dystrophy through the multidisciplinary Muscular Dystrophy Association (MDA) clinic, the only nationally designated MDA care center in the state.
Over the past two decades, advances in genetic research have significantly improved treatment options for DMD. While early therapies focused primarily on reducing inflammation through long-term steroid use, newer approaches aim to address the root cause of the disease via dystrophin restoration.
Steroids remain a standard treatment to help slow the inflammatory damage that occurs alongside muscle breakdown. Combined with multidisciplinary care, these therapies have improved life expectancy for many patients.
“Thanks to routine corticosteroid treatment and coordinated multidisciplinary care, life expectancy for individuals with Duchenne muscular dystrophy has improved dramatically, with many patients now surviving into adulthood,” noted Weaver.
Delpacibart zotadirsen is an antisense-oligonucleotide conjugate, or AOC. An AOC uses a laboratory-made genetic molecule or PMO to bind to dystrophin RNA. The PMO helps the cell bypass the faulty sections of genetic instructions. A new “genetic blueprint” is formed, one that provides instructions for restored dystrophinproduction.
Rather than permanently changing DNA, AOC therapy works by modifying RNA instructions after they are copied from the gene but before they are used to build proteins.
“Although full dystrophin restoration may not be possible, enough functional protein may create a milder disease phenotype,” explained Weaver. “Even partial dystrophin restoration can lead to meaningful improvements in disease severity and progression.”
Earlier generations of exon-skipping therapies have provided modest results. Passive uptake of molecules into muscle cells produced small increases in dystrophin on muscle biopsy and limited improvements in motor function. While those therapies received accelerated FDA approval, researchers continued working to improve the selectivity of these treatments.
Delpacibart uses an antibody-mediated delivery system designed to improve uptake into muscle cells. By selectively binding to muscle cells, researchers can better tailor dosing andreduce the risk of toxicity.
According to Weaver, this next-generation approach may significantly improve dystrophin production compared to previous therapies.
In randomized, placebo-controlled trials, data supported a mean increase of approximately 25 percent of normal dystrophin production from baseline after four months of treatment, with some patients reaching as high as 54 percent restoration. Researchers also observed more than an 80 percent reduction in creatine kinase, a muscle enzyme that is typically elevated in patients with DMD due to ongoing muscle damage.
“We do not currently have therapies that produce this degree of creatine kinase improvement,” said Weaver. “Although these findings are encouraging in small research numbers, how these will translate to actual strength and slowing of disease is still being studied.”
The therapy is delivered once every six weeks because it does not permanently alter DNA and must be re-dosed to maintain its effect.
Only a small percentage of patients with Duchenne muscular dystrophy are eligible for exon 44 skipping therapy. Weaver estimates about 6 to 7 percent of patients have gene variants that make them candidates for this treatment.
While that percentage is relatively small, Weaver emphasized the broader significance of the program.
“Six percent may not sound like a lot, but it is still meaningful for the patients who qualify,” said Weaver. “More importantly, if this approach continues to succeed, the hope is that the same technology can be adapted to target other variants and help many more patients in the future.”
The expanded access program has received institutional approval and is supported through all required regulatory channels. UAB is now preparing to enroll eligible patients.
For families affected by Duchenne muscular dystrophy, each scientific advancement represents another step toward better treatment options and improved outcomes.
“This is a really exciting development in Duchenne care,” said Weaver. “Every breakthrough moves us closer to changing the long-term trajectory of this disease.”