Expanded access program to bring DMD treatment to patients in 1 US state
Experimental exon-skipping therapy targets specific mutations in Duchenne
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The University of Alabama at Birmingham (UAB) has launched an expanded access program to make the experimental exon-skipping therapy delpacibart zotadirsen (del-zota) available to qualifying patients with Duchenne muscular dystrophy (DMD).
Del-zota, which is being developed by Avidity Biosciences, is specifically designed to treat DMD in people with disease-causing mutations that are amenable to exon 44 skipping. Samantha Weaver, an assistant professor at UAB, notes that this represents about 6% of all DMD patients.
“Six percent may not sound like a lot, but it is still meaningful for the patients who qualify,” Weaver said in a university news story. “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 UAB and its associated hospital provide care to approximately 80 people with Duchenne; it is the only clinic in Alabama recognized by the Muscular Dystrophy Association (MDA) via the advocacy organization’s care centers listing. The center is already prepping to enroll eligible patients for the new program, according to UAB.
“This is a really exciting development in Duchenne care,” Weaver said. “Every breakthrough moves us closer to changing the long-term trajectory of this disease.”
DMD is a genetic disorder in which patients produce virtually no dystrophin, a protein essential for preserving muscle health. Lacking dystrophin, people with Duchenne develop progressive muscle damage over time, leading to weakness and mobility limitations.
“In the absence of dystrophin, fragile muscle fibers become susceptible to contractile injury, leading to damage and progressive weakness, Weaver said. A contractile injury occurs when muscle fibers are damaged as a result of normal muscle contraction.
Developments such as routine corticosteroid treatment and multidisciplinary care have dramatically improved outcomes in DMD. While the disease was once usually fatal in childhood, today people with Duchenne live into adulthood. Nonetheless, life expectancy for people with DMD is lower than for the general population, and patients typically have substantial physical disabilities.
Del-zota is showing promise in clinical testing
Exon-skipping is a novel therapeutic strategy that aims to allow people with DMD caused by specific mutations to produce a shortened but functional version of the dystrophin protein. That is expected to help preserve muscle fibers and slow disease progression.
Exons are sections of DNA that code for protein. When a gene is read to produce a protein, the genetic code is copied into a temporary molecule called messenger RNA (mRNA). Interspersing sequences are then removed, and the exons are strung together to form a protein-coding sequence — sort of like putting words together to form a sentence. Many DMD-causing mutations lead the exons to fall out of alignment, resulting in a garbled sequence that can’t produce protein.
The idea behind exon-skipping is to remove one or more exons from the sequence, allowing the remainder to fall back into alignment so that a functional protein can be made. Del-zota specifically targets exon 44, and uses antibodies to deliver the exon-skipping material directly to muscle cells that are affected by DMD. In clinical testing, the therapy is being given via an intravenous, or into-the-vein, infusion.
“Although full dystrophin restoration may not be possible, enough functional protein may create a milder disease phenotype,” Weaver said. “Even partial dystrophin restoration can lead to meaningful improvements in disease severity and progression.”
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.
Recent data from a Phase 1/2 clinical trial dubbed EXPLORE44 (NCT05670730) and its open-label extension(NCT06244082) indicated that del-zota can increase dystrophin levels as designed. Specifically, the data showed average protein production increased to about 25% of what’s seen in people who don’t have DMD.
The increase in dystrophin was accompanied by an 80% drop in levels of a muscle damage marker called creatine kinase, the data also showed.
“We do not currently have therapies that produce this degree of creatine kinase improvement,” Weaver said, adding, however, that “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 new expanded access program will make del-zota available to eligible patients while clinical testing is still ongoing. The program has received institutional approval and is supported through all required regulatory channels, according to UAB.
“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,” Weaver said.
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