Duchenne Muscular Dystrophy Space on Cusp of Pivotal Era

2025 could be a breakout year for the Duchenne muscular dystrophy space. Although several therapies have entered the market in recent years, there is still considerable unmet need for the 15,000 Americans living with DMD. But with several companies advancing the next generation of treatments—and regulatory paths now established in this sector—experts told BioSpace that new options are on the horizon.

“I think 2025 is going to be quite distinguishing for a number of companies,” said Michael Kelly, chief scientific officer at CureDuchenne, “and I’m expecting ’26 to be much the same because they’re lining up the clinical studies for readouts and approvals.” A nonprofit organization, CureDuchenne invests in several DMD-focused companies including Sarepta Therapeutics, Avidity Biosciences, Dyne Therapeutics and Capricor Therapeutics.

An inherited disorder affecting primarily boys, DMD is characterized by the progressive loss of skeletal, heart and lung muscle. It is caused by a mutation in the gene for the dystrophin protein, leading muscle cells to be fragile and easily damaged. Disease-related mortality is most often related to cardio-respiratory failure, but recent advances have helped many patients live into their early 30s.

From the discovery of the dystrophin gene in 1986, it took 30 years for the first Duchenne muscular dystrophy therapy to reach the market. Eight therapies have now been approved in as many years, marking considerable headway against the life-limiting and eventually fatal neuromuscular disease. The past two years, especially, have seen a rush of innovation in DMD, with the approval of three new medicines—including Sarepta Therapeutics’ Elevidys, greenlit in June 2023 as the first gene therapy for the disease.

Despite this progress, “there’s still more efficacy that we’re hoping for,” Christiana Bardon, managing partner of MPM BioImpact, told BioSpace.

Several companies, including Dyne, Avidity and Wave Life Sciences, are now striving to answer this call. From a new generation of exon skippers to Regenxbio and Solid Bio’s gene therapies, there is plenty of reason to believe that more DMD treatments could soon hit the market.

Four of the eight approved therapies for DMD are exon-skippers, which use antisense oligonucleotides to skip nonfunctional exons, enabling the body to produce a short but functional dystrophin protein. Each exon skipper is amenable to a certain portion of the DMD population based on the patient’s genetic mutation. While mutations may occur throughout the 79 exons of the DMD gene, exons 44–53 are a primary focus for drug developers.

With three approved exon-skipping treatments—Exondys 51, Vyondys 53 and Amondys 45—Sarepta owns the majority of this market. According to the company’s Chief Scientific Officer Louise Rodino-Klapac, these drugs collectively cover about 30% of the DMD population.

They have limited efficacy, however, CureDuchenne’s Kelly told BioSpace. While these therapies are safe, they aren’t very effective at getting into cells, he said. “That limits the amount of the drug that can get in and do the exon skipping that’s needed inside the nucleus of the muscle cell.”

In fact, patients taking the first generation of these drugs produce only 1–2% of the dystrophin protein that people without DMD make, Kelly said. This limitation is why next-gen exon skippers have caught the attention of drug developers.

Wave CEO Paul Bolno told BioSpace that while there is an early understanding of the importance of dystrophin, there is a need for better delivery into the cells to generate more of the protein. Additionally, with first-generation exon skippers, there has been a high degree of inconsistency in expression between patients, he said.

Kelly explained that the next generation of exon skippers add moieties that direct the drug toward the muscle and allow for efficient delivery. The newer versions also go through endosomal escape pathways to put high concentrations of the drugs inside muscle tissues. These changes result in more consistent exon skipping and therefore higher dystrophin expression, he added.

Wave is developing an exon 53 skipper called WVE-N531. In September 2024, the company reported an interim analysis of a Phase II trial at six months showing 9% dystrophin expression consistently across patients. Bolno said Wave expects FDA feedback and guidance this quarter regarding a potential accelerated registration pathway.

Also in September, Massachusetts-based Dyne announced dystrophin expression of close to 9% for its exon 51 skipping candidate, DYNE-251. A registrational expansion cohort is set to begin in mid-2025, and Dyne expects to submit for accelerated approval in the first half of 2026.

There are currently no exon skippers for exon 44, which applies to 6% of patients with DMD. Avidity aims to address this population with del-zota. Data reported in August 2024 from a Phase I/II-turned-registrational trial showed the therapy increased levels of dystrophin production by an unprecedented 25%. Dosed every six weeks, del-zota reduced creatine kinase levels in the blood—a biomarker for muscle damage—to the near-normal range. Avidity is planning a BLA submission for del-zota by the end of this year.

Since its full approval and label expansion in June 2024, Sarepta’s Elevidys is now available to both ambulatory and non-ambulatory patients 4 years and older with a confirmed mutation in the DMD gene, representing up to 80% of the DMD patient population, Rodino-Klapac said. “And we’re not stopping there.”

One factor restricting the therapy’s reach is its adeno-associated virus (AAV) delivery method, as around 15% of patients have antibodies to the vector and are therefore ineligible for treatment. In an attempt to remedy this, Sarepta has two trials underway to remove those antibodies either by plasmapheresis or imlifidase. If successful, it will be the first time anyone has gone into this antibody-positive population, Rodino-Klapac said. It could also potentially allow for the redosing of Elevidys, which might help to address questions over its long-term durability. Additionally, the company has been generating data in children under 4 years of age with hopes to expand its label to all DMD patients.

“Treating patients young will become the norm, and that will be the main population treated,” Rodino-Klapac predicted.

At Sarepta, the team believes gene therapy is the ultimate therapeutic option for DMD, and the company is prioritizing this part of its portfolio, Rodino-Klapac said. She emphasized the value of a one-time therapy that avoids a chronic treatment that might have other unwanted side effects.

But while Sarepta maintains that Elevidys is having a meaningful impact on patients, the community is seeing mixed results, with less efficacy than practitioners had hoped for. Kelly attributes the lower efficacy to the DMD gene itself.

“The gene is the largest gene in the human genome, and it encodes for a very large protein, which is way too much to package inside of an AAV,” he said. “Nature doesn’t make proteins that large unless it’s got a reason to do so. Dystrophin has got a lot of functionality built into it.”

Elevidys contains a “highly truncated” version of the gene—about one-third the natural size, according to Kelly. This smaller size loses some of the natural activity the protein requires to be efficient, he said. A cure is not possible with a very small version of the protein, Kelly explained, so the goal of current gene therapies is not to cure but to transform DMD into the less severe Becker muscular dystrophy—something he argued Elevidys accomplishes.

“It’s not as good as what we’d hoped for, but it does its job exactly the way that it was programmed—to transform the disease from one to another.”

Regenxbio’s gene therapy candidate RGX-202 can carry a slightly larger version of the DMD gene, Kelly said, because it has a smaller promoter, leaving more space for the gene itself. Early results from a Phase I/II trial were “very encouraging,” he said, with RGX-202 eliciting improvements in strength and time function tests. The first patient in a pivotal phase trial was dosed in November, and a BLA is expected in 2026.

Ultimately, Bolno said a meaningful therapy for DMD must include three characteristics: exposure to muscle cells, high levels of consistent dystrophin expression and efficacy beyond muscle cells.

While the approved exon-skipping drugs are limited to skeletal muscle, next-gen assets in development are showing efficacy in getting into the cardiac and lung tissue as well, Kelly said.

In this vein, Capricor Therapeutics submitted a BLA earlier this month for its unique allogeneic cell therapy for cardiomyopathy related to DMD. CEO Linda Marbán told BioSpace she anticipates FDA acceptance with a PDUFA date to be set around September.

Made from donor heart cells, deramiocel is anti-inflammatory, immunomodulatory, antifibrotic and pro-regenerative—meaning it drives the natural cell process to make new cells, Marbán explained.

Natural history studies show that non-ambulatory DMD patients lose 2–4% in upper limb performance per year. In clinical trials, patients taking deramiocel lost less than 1% upper limb performance, Marbán said, meaning the drug is slowing the disease progression by almost 50%. Most importantly, it is slowing the decline of cardiac function, which is what takes many patients’ lives.

“If these trends continue stabilizing cardiac function, not only will [patients] feel and function better, but they also will potentially have extension of their life,” Marbán said.

If approved, deramiocel will be the first and only approved therapy to treat DMD-related cardiomyopathy.

“DMD has become sort of the test case of how you can take an orphan disease, bring it into the public eye and ultimately really drive the development of therapeutics for it,” Marbán said. “There are now tools in the toolbox to treat Duchenne that were never available, and I think more are coming in 2025.”