Eteplirsen

iStock, DrWD40 Several companies will head to the FDA seeking approval of new Duchenne muscular dystrophy treatments next year but the death of a patient taking Sarepta’s Elevidys raises important safety questions. Few therapeutic spaces have seen more progress in the past decade than Duchenne muscular dystrophy. However, progress often involves one step forward and two steps back—a reality evidenced by last week’s news that a patient taking Sarepta’s approved gene therapy Elevidys had died. In its announcement, Sarepta revealed that the patient had also tested positive for cytomegalovirus (CMV) infection, which can damage the liver and is “a possible contributing factor” to the death, according to the biotech. “Without more information, clinically, right now it’s hard to totally attribute [the death] to [Elevidys],” Christiana (Chris) Bardon, managing partner at MPM BioImpact, told BioSpace . Still, “Any patient death is, of course, a tremendous tragedy. These are children, especially, so I think that there’s a lot of concern and we need to proceed with great caution.” Sarepta’s news came as several companies—including Dyne Therapeutics , REGENXBIO and Genethon—presented new data on their next-generation exon-skipping therapies and gene therapies for Duchenne muscular dystrophy (DMD) at the 2025 Clinical & Scientific Conference of the Muscular Dystrophy Association in Dallas. Wave Life Sciences piped in this week with data from a Phase II trial of its exon-skipper WVE-N531 that CEO Paul Bolno called “unprecedented.” The drug significantly improved function and reversed muscle damage—a hallmark of the disease—in 11 boys, according to Wave. 2026 could be even bigger, as Wave, Dyne and REGENXBIO are all planning regulatory submissions. “I’m really optimistic about the next generation of DMD therapies because they’re showing dramatically better efficacy by biomarkers than we’ve seen previously,” Bardon said. Exon Skipping vs. Gene Therapy The majority of treatments in development for DMD are either gene therapies or exon-skippers , which encourage the cellular machinery to skip over a missing exon in order to create a functional dystrophin protein. When it comes to treatment modality, experts agree it’s not one-size-fits-all as DMD is a heterogeneous disease, meaning the course of the disease varies widely by patient. Gene therapies for DMD are “potentially complex,” Bardon said, requiring an immunosuppression regimen prior to treatment, “which could also either cause something or worsen something.” Bardon pointed to advances in the technology supporting exon-skippers—such as those being developed by Dyne and Avidity Biosciences—and posed the question: “For those patients who are amenable to skipper technology, does a lifelong administration of the skipping technology result in better clinical outcomes for the patients than a gene therapy?” Approved drugs marketed by Sarepta and NS Pharma that skip exons 51, 53 and 45 could treat up to 29% of all DMD patients, according to the non-profit CureDuchenne, with up to 80% of patients potentially benefiting if exon skipping is applied to other mutations. DMD is caused by a mutation in the gene for the dystrophin protein, leading muscle cells to be fragile and easily damaged. One argument in favor of exon-skippers, Bardon noted, is that they provide a full-length version of dystrophin—as opposed to gene therapies, which replace only a truncated version of the DMD gene. However, Frédéric Revah, CEO of Paris-based nonprofit gene therapy developer Genethon, said the true value lies in which exon is being skipped. “All parts of the [DMD] gene are not equal, and just having a long dystrophin doesn’t mean that you have it more functional than a shorter one that will recapitulate everything that needs to be there,” he told BioSpace . “As of today, the exon skippers have not been very successful in terms of clinical outcomes,” Revah said. “So we’re not there yet.” On the Horizon But several companies are working on getting there, including Wave, which announced positive data Wednesday from the Phase II FORWARD-53 trial of its exon-skipper WVE-N531. The drug, an oligonucleotide intended for DMD patients who are amenable to exon 53 skipping, improved functional benefit and reversed muscle damage after 48 weeks in 11 boys, according to Wave. Notably, the company saw “compelling initial evidence” of myofiber regeneration, Wave CEO Bolno said on an investor call. “We’re not aware of any other clinical data for exon skippers or gene therapy that have been able to demonstrate myogenic stem cell uptake in the clinic.” These stem cells, which produce new myoblasts, are “essential for the regeneration of muscle in DMD,” Bolno said. Following feedback from the FDA, Wave intends to accelerated approval of WVE-N531 in 2026. For patients amenable to exon 51 skipping, Dyne is developing an alternative to Sarepta’s Exondys 51. Last September, Dyne announced data from the Phase I/II DELIVER trial, which compared DYNE-251 and Exondys 51 head-to-head. Results showed that dystrophin expression was more than 10-fold higher in the DYNE-251-treated group, and improvements were recorded across multiple functional endpoints. The drug was found to be safe, with no serious adverse events, according to Dyne. Last week, at the MDA conference, the biotech shared a long-term readout from DELIVER, showing that DYNE-251 maintained its functional benefits through 18 months of follow-up—findings that were “supportive” of the drug’s accelerated approval bid, according to a note from BMO Capital Markets analysts. Dyne indicated the potential for a regulatory submission in early 2026. Meanwhile, REGENXBIO is gunning to bring the second gene therapy for DMD to the market, behind Sarepta. To this end, the Maryland-based biotech presented biomarker data at MDA from the Phase I/II portion of the AFFINITY DUCHENNE trial showing “robust microdystrophin and transduction levels” across patients of all ages treated with RGX-202. As of the Feb. 21 data cut-off, the gene therapy was well-tolerated, with no serious adverse events (SAEs) and no AEs of special interest, according to REGENXBIO. The company is on track for a biologics license application with the FDA in mid-2026. Finally, Genethon presented data from the GNT-016-MDYF clinical trial showing a 68% reduction in creatine kinase (CK) levels—a biomarker of muscle damage—over two years, and stabilization or improvement in functional outcomes in boys treated with its adeno-associated virus (AAV) vector-based gene therapy GNT0004. Genethon believes GNT0004 has the potential to be “best in class,” Revah said, partly because of the gene therapy’s smaller size. “We do get, although with a limited number of patients, very strong results and at a dose which is lower than any of the doses which are out there,” he added. GNT0004 is 3x10 13 viral Genomes/kg, while Elevidys is 1,33x10 14 vg/kg and RGX-202 is 2x10 14 vg/kg. This has both safety and cost benefits, Revah explained. Genethon expects to take GNT0004 into pivotal trials this year and is looking for a partner to accelerate development, Revah said. Questions Remain While Duchenne patients have seen three notable approvals in the past two years, including that of Elevidys in 2023, several questions remain, according to Bardon. For gene therapy, safety is the first priority and patients must be carefully selected,—particularly, those who should not receive them, she said. Patients should not be candidates for treatment if “they either have some sort of existing infection or other medical issue that would make it too dangerous for them.” The second question, Bardon said, is how to monitor patients after administration of the gene therapy “to make sure that if they develop any sequelae [or complications], that we can intervene.” The death attributed to Sarepta’s Elevidys underscores the risk, as the patient had recently tested positive for CMV, which can infect and damage the liver. After safety, Bardon said the key objective for DMD gene therapy developers is identifying the optimal age for treatment. Young patients might not be able to benefit from gene therapy because they are still growing, while older patients might not see enough benefit, she explained. “So, what is the sweet spot in terms of age?” A key challenge across modalities, Bardon said, is finding a better measurement of clinical efficacy to determine benefit. The North Star Ambulatory Assessment (NSAA) is the most prevalent scale to measure function in ambulatory DMD patients—but it comes with “a lot of noise,” Bardon said, partly due to patients’ growth. “The NSAA [score] gets better as they’re growing, but then they start to decline and it starts to get worse. So . . . if I treat a patient who’s young, is their NSAA getting better because of my drug or because they’re growing?” Genethon has developed a workaround for this, treating its trial participants when they reach the maximum score on the NSAA. “[This] allows us to somehow diminish the statistical noise and get to statistical significance in a much more natural way,” Revah said. Aside from the NSAA, researchers are testing other new measurements, according to Bardon, including time-to-rise from the floor and the Stride Velocity 95th Centile (SV95C), which in a recently published study was sensitive to a decline in patients’ ability to walk over short intervals. It also showed low variability and was associated with established clinical outcome assessments, according to Rare Disease Advisor . When it comes to currently available therapies, Revah said the main objective is to keep ambulatory patients ambulatory “as long as possible.” For those who are non-ambulatory, it is to “preserve as much autonomy as possible.” He also emphasized the importance of preserving heart function, “because at the end of the day, these kids will die out of heart malfunction.” As for the future, Revah would like to see next-gen therapies that can transduce larger chunks of the dystrophin gene using double vectors and possibly gene editing tools. He also emphasized the importance of addressing fibrosis, “to enhance muscle function . . . but also to enhance the power of gene therapy, because the existence of fibrotic cells will somehow prevent the gene transfer vector to get to the muscle cells.” Notably, Wave reported that WVE-N531 elicited a 28.6% reduction in fibrosis, representing “the first time that a significant reversal in muscle fibrosis has been observed,” with an exon-skipping therapy, according to Bolno. Overall, Bardon reiterated her excitement over recent biomarker data but cautioned that “we will have to corelate that better biomarker data with improved clinical outcomes for patients.”