Due to the deaths of two patients following the use of Elevidys, a DMD gene therapy from Sarepta Therapeutics, the DMD community has had a difficult year. Families, activists, and researchers were all shaken by the loss, which served as a sobering reminder of the dangers and potential benefits of experimental genetic therapy. But earlier this year, a glimmer of hope appeared amid the sadness and uncertainty: Del-Zota, an RNA therapy from Avidity Biosciences. Avidity reported early mechanistic success in the spring, restoring production of a near-full-length dystrophin protein at levels linked to asymptomatic disease by bypassing exon 44 in the dystrophin gene. The evidence at the time suggested that the treatment might have molecular effects. According to Avidity’s latest functional readouts from its EXPLORE44 research, del-zota doesn’t just delay the unrelenting advance of DMD; it seems to reverse it.
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What is DEL-ZOTA?
Del-zota is designed to deliver phosphorodiamidate morpholino oligomers (PMOs) to skeletal muscle and heart tissue to specifically skip exon 44 of the dystrophin gene to enable dystrophin production in people living with Duchenne muscular dystrophy with mutations amenable to exon 44 skipping (DMD44).
Learn More: Mutations and Deletions Amenable to Exon 44 Skipping Therapies for Duchenne Muscular Dystrophy
Reverses the Progression of Disease
‘We’ve actually seen a reversal of disease,’ W. Michael Flanagan, PhD, chief scientific officer at Avidity. ‘This isn’t just slowing progression. This is actually a reversal of disease. And it’s the first time ever.‘
Phosphonodiamidite morpholino oligomer (PMO), a chemical that has been shown to be effective in exon skipping, is Avidity’s preferred RNA payload for Duchenne. The PMO bypasses the damaged exon in exon 44-amenable DMD, restores the reading frame, and produces functional dystrophin.
Full-Length Dystrophin Is Not a Dream
“It’s really a way to get rid of the damaged exon and provide what is a high-quality, near-full-length dystrophin, and that’s what our technology has been able to do,” Flanagan said.
26 boys and young men with mutations in exon 44 were recruited for the Phase I/II EXPLORE44 research, which was randomized, placebo-controlled, and double-blind. The first findings were encouraging: exon 44 skipping led to significant decreases in creatine kinase (CK), a biomarker of muscle injury, and strong dystrophin repair.
“In cases where there is one damaged allele, they likely produce around 50% and remain asymptomatic,” Flanagan noted. “We’re reaching levels that are near normal levels or at least asymptomatic levels of dystrophin. These results show that CK goes dramatically down to near-normal levels. I don’t think any other program in Duchenne has ever shown the near normalization of CK levels. And we see that about 50% of people treated with del-zota are in the normal range. The rest of them are hovering just above the normal range.” – What is creatine kinase? –
Boys Growing and Building Muscle
The changes are visible in the boys themselves: climbing stairs with new ease, standing from the floor faster, or—among non-ambulatory patients—reaching farther across the dinner table.“What we’ve seen is unprecedented,” Flanagan said. “It’s what happens when you make high-quality dystrophin and protect muscles from damage. And boys are growing and building muscle, and you’ll see this reversal of disease across multiple different functional endpoints. That’s big news! That’s what people care about.
A Patient or Family-Friendly Dosing Regimen
Del-zota is dosed every six weeks, which Flanagan calls “a patient or family-friendly dosing regimen,” compared to some PMOs on the market, which require weekly dosing. “It is extremely difficult for families to travel and engage in such activities, or it has to be home infusions,” said Flanagan. “This is really family-friendly. You can go on a vacation. You can go on a cruise and participate in these activities every time, with dosing occurring every six weeks. We believe that this is not only an unprecedented reversal of disease, but it also has favorable safety features and is very convenient for patients.“ – Read More: Del-zota EXPLORE44-OLE Functional Data –
Biologics License Application (BLA)
Avidity expects to submit its first biologics license application (BLA) by year’s end under accelerated approval. “We’re working hard on it right now and have writing sections and reviewing sections,” Flanagan said. “This will be an accelerated approval. So we have all the dystrophin we need. In fact, we added patients at the end of last year to build up our safety database, but we didn’t need any additional patients for biopsies. So that was very patient-friendly because we had enough difference in dystrophin that the agency was convinced that our dystrophin levels were unprecedented.”With breakthrough designation secured, Flanagan hopes for a fast FDA review and a potential launch in 2026 or 2027.
Read More: Upcoming Exon 44 Skipping Therapies for the Treatment of Duchenne Muscular Dystrophy
Save the life of my son. He exon 44 amenable child.