It’s been a rocky year for the Duchenne muscular dystrophy (DMD) community, shaken when two patients died after taking Elevidys, Sarepta Therapeutics’ DMD gene therapy. The loss rattled families, advocates, and researchers, serving as a stark reminder of both the promise and peril of experimental genetic medicine. But amid the grief and uncertainty, a bright spot emerged earlier this year: Avidity Biosciences’ RNA therapeutic, del-zota.
In the spring, Avidity reported early mechanistic success—skipping exon 44 in the dystrophin gene to restore production of a near-full-length dystrophin protein at levels associated with asymptomatic disease. At the time, the data showed the therapy could work on a molecular level. Now, with new functional readouts from its EXPLORE44 study, Avidity has revealed that del-zota doesn’t merely slow DMD’s relentless progression—it appears to reverse it.
“We’ve actually seen a reversal of disease,” W. Michael Flanagan, PhD, chief scientific officer at Avidity, told Inside Precision Medicine. “This isn’t just slowing progression. This is actually a reversal of disease. And it’s the first time ever.”
Cracking delivery: “An RNA trojan horse”
RNA therapies have long been constrained by the problem of delivery. “Cells typically resist taking up genetic medicine because they are highly charged and have evolved over billions of years to avoid foreign nucleic acids, which are often viral,” Flanagan explained. Early breakthroughs, like Alnylam’s conjugation of N-acetylgalactosamine (GalNac) to small interfering RNAs, opened the door to liver-targeted therapies. “That was a big leap,” Flanagan said. “You could now deliver to the liver and affect all these diseases that are in the liver. What we’ve concluded is that it is simply the liver. Let’s go beyond the liver.”
DMD, a devastating muscle-wasting disease, required a new solution. Avidity’s team discovered one in biology’s iron transporter, the transferrin receptor. By linking an antibody to this receptor and coupling it with an oligonucleotide, they co-opted a natural transport system to slip RNA payloads into muscle cells. “Basically, the antibody binds to the transferrin receptor and acts like a Trojan horse,” Flanagan said. “Once inside the muscle cell, the antibody detaches, and the RNA payload…can go to work.”
Avidity’s payload of choice for Duchenne is a phosphonodiamidite morpholino oligomer (PMO), a chemistry proven in exon skipping. In the case of exon 44–amenable DMD, the PMO skips the damaged exon, restores the reading frame, and yields functional dystrophin. “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.
EXPLORE44: From biochemistry to biomechanics
The randomized, placebo-controlled, double-blind Phase I/II EXPLORE44 trial enrolled 26 boys and young men with exon 44 mutations. Initial results were promising: skipping of exon 44, robust dystrophin restoration, and dramatic reductions in creatine kinase (CK), a biomarker of muscle damage.
“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.”
Longer-term data from EXPLORE44 and its open-label extension have now gone beyond biochemical markers. 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. We often discuss how everyone recognizes the label ‘Duchenne boys,’ but in the future, we hope they will simply be referred to as ‘boys.’”
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.“
Racing the clock: “Time is muscle”
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. But every month matters. “One model, possibly from a patient advocacy group, is ‘time is muscle,’” he said. “The longer you wait or the longer it takes for us to get to patients, the more muscle they’ve lost, and you may not be able to regain that muscle back depending on where you are in your disease progression. So we feel a tremendous amount of responsibility to do this fast.”
“This will be our first BLA,” Flanagan said. “We’re keenly aware of being the first BLA and really being able to get that right. What I can tell you about manufacturing, because I did lead manufacturing up to about a year ago, is that we’re well on the way to being able to submit that BLA and we’ll have the manufacturing in place. We have high-quality manufacturing groups.”
Importantly, the components of Avidity’s approach are not untested novelties. “This technology, like you indicated, is not—these pieces have already been done before. So it’s the antibody; we have an antibody that’s used across three programs. PMOs have been used widely. This conjugation process has been widely used in oncology with antibody drug conjugates. So all the pieces are well-known entities, well-known processes, and well-known understandings about how they work, and we’re just putting them all together. Of course, we need to have a complete package, and we are confident that our manufacturing will be able to support the BLA filing.”
Beyond muscle: Expanding a platform
With manufacturing and regulatory plans on track, Flanagan turned to the bigger picture—the purpose behind Avidity’s work and the future the company envisions. “For the company, our goal is to profoundly improve people’s lives,” Flanagan said. “We purposely don’t say ‘patients’ lives’; we say ‘people’s lives’ because we understand that rare muscle diseases not only affect the person affected but also the whole family. So we’re trying to make those profound improvements by revolutionizing the delivery of RNA therapeutics.”
Flanagan stressed that del-zota is just the beginning, with two other programs in myotonic dystrophy and Facioscapulohumeral Muscular Dystrophy (FSHD). Avidity is also expanding into precision cardiology, turning to siRNA technology, instead of PMOs, to address the underlying genetic causes of cardiac disease. “We have two additional cases involving different rare muscle diseases, clearly demonstrating how the platform could revolutionize these conditions that currently have unmet needs,” said Flanagan. “There are no therapies for a lot of these diseases. We have a technology and a platform capable of addressing a wide variety of diseases. We are optimistic about the potential applications of antibody all-to-go conjugates in the future.”
That sense of possibility is matched by an awareness of how rare breakthroughs like this can be. “Whether you’re a company, whether you’re investors, whether you’re a scientist at the bench, or whether you’re in communication, like across the board. I mean, these are rare events,” Flanagan said. “It is very difficult to administer active drugs to humans. It doesn’t happen that frequently, and we have three, with two with breakthrough designation.”
As a veteran scientist, Flanagan doesn’t take the moment lightly. “For me as a scientist, we don’t get to work on great drugs that often. Like in your career, you’re lucky to work on one,” he said. “This is one of those drugs.”
For the DMD community—families, advocates, and researchers alike—del-zota represents not just hope but proof: a new class of RNA therapeutics can reach muscle, repair dystrophin, and give boys back their strength. In Flanagan’s words, “They are just boys; you wouldn’t know they have DMD because they look and run like everyone else, and that is our goal. Those things matter.”
