Duchenne muscular dystrophy is one of the therapy areas that has advanced the most in the last ten years. However, advancement frequently consists of one step forward and two steps back, as demonstrated by the news last week regarding the death of a patient using Sarepta’s authorized gene therapy Elevidys. [Read More]
The patient also tested positive for cytomegalovirus (CMV) infection, which can harm the liver and is “a possible contributing factor” to the death, Sarepta said in its announcement. [What is Cytomegalovirus Infection (CMV)?]
It’s difficult to fully connect [the death] to [Elevidys] at this time without additional clinical evidence,” Christiana (Chris) Bardon, managing partner at MPM BioImpact, told BioSpace. Nevertheless, “Any patient death is obviously a great tragedy.” Since these are kids in particular, I believe there is a lot of worry and that we should approach very carefully.
Sarepta’s announcement coincided with the 2025 Clinical & Scientific Conference of the Muscular Dystrophy Association in Dallas, where a number of companies, including Dyne Therapeutics, REGENXBIO, and Genethon, presented new data on their gene therapies and next-generation exon-skipping therapies for Duchenne muscular dystrophy (DMD).
Data from a Phase II trial of Wave Life Sciences’ exon skipping therapy WVE-N531 was released this week, which CEO Paul Bolno described as “unprecedented.” In 11 boys, the medication reversed muscle degeneration, a defining feature of the condition, and greatly improved function, Wave said. [Read More]
Given that Wave, Dyne, and REGENXBIO are all preparing regulatory filings, 2026 might be even more significant.
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Exon Skipping vs. Gene Therapy
Exon skipping, which enable the cellular machinery to skip over a missing exon in order to build a functioning dystrophin protein, and gene therapies make up the majority of treatments now under study for DMD. Since DMD is a heterogeneous disease—that is, the course of the disease varies greatly from patient to patient—experts concur that there is no one-size-fits-all approach to treatment. [What is Exon Skipping?]
According to Bardon, gene treatments for DMD are “potentially complex” and come with a pretreatment immunosuppressive regimen that “may also cause something or worsen something.”
“For those patients who are amenable to exon skipping technology, does a lifetime administration of the skipping technology result in better clinical outcomes for the patients than a gene therapy?” Bardon asked, citing developments in the technology supporting exon skipping, such as those being developed by Dyne and Avidity Biosciences. [Next Generation Exon Skipping Therapies]
According to the non-profit organization CureDuchenne, approved medications sold by Sarepta and NS Pharma that omit exons 51, 53, and 45 may be able to treat up to 29% of all DMD patients. If exon skipping is used for other mutations, up to 80% of patients may benefit.
A mutation in the dystrophin protein gene causes DMD, which makes muscle cells brittle and prone to injury. Compared to gene treatments, which only replace a shortened form of the DMD gene, exon skipping offer a full-length form of dystrophin, which is one argument in favor of them, Bardon said.
But according to Frédéric Revah, CEO of Genethon, a nonprofit gene therapy company based in Paris, the real value is in the exon that is being skipped. “Every component of the [DMD] gene is different, and a longer dystrophin does not necessarily indicate that it is more functional than a shorter one that will recapitulate all necessary components,” he told BioSpace.
“In terms of clinical outcomes, the exon skipping therapies have not been very successful as of yet,” Revah stated. “So, we haven’t arrived yet.”
Good News May Come in the Future
Wave Life Sciences Exon 53 Skipping Therapy
However, a number of businesses are striving to get there, such as Wave, which on Wednesday revealed encouraging results from its exon skipping therapy WVE-N531’s Phase II FORWARD-53 trial.
Wave claims that after 48 weeks, the medication, an oligonucleotide designed for DMD patients who are responsive to exon 53 skipping, restored muscle degeneration and enhanced functional benefit in 11 boys.
During an investor call, Wave CEO Bolno noted that the company has “compelling initial evidence” of myofiber regeneration. “As far as we know, no other clinical data for gene therapy or exon skipping have been able to show myogenic stem cell uptake in the clinic.” According to Bolno, these stem cells are “essential for the regeneration of muscle in DMD” because they generate new myoblasts.
Wave plans to submit a request for accelerated approval of WVE-N531 in 2026 in response to FDA feedback.
Dyne Therapeutics Exon 51 Skipping Therapy
Data from the Phase I/II DELIVER trial, which evaluated DYNE-251 and Exondys 51 head-to-head, was released by Dyne last September. According to the results, the group treated with DYNE-251 had dystrophin expression that was more than ten times higher, and improvements were noted in a number of functional endpoints. According to Dyne, the medication was determined to be safe and to have no significant side effects.
According to a note from analysts at BMO Capital Markets, the biotech presented a long-term readout from DELIVER at the MDA conference last week, demonstrating that DYNE-251 retained its functional benefits after 18 months of follow-up. The findings were “supportive” of the drug’s accelerated approval bid. Early in 2026, Dyne hinted about the possibility of a regulatory submission.
Regenxbio RGX-202 Gene Therapy
After Sarepta, REGENXBIO is vying to become the second gene treatment for DMD to hit the market. In support of this, the Maryland-based biotech demonstrated biomarker data from the Phase I/II phase of the AFFINITY DUCHENNE trial at MDA, which revealed “robust microdystrophin and transduction levels” in RGX-202-treated patients of all ages.
According to REGENXBIO, the gene therapy was well-tolerated as of the data cut-off date of February 21. There were no AEs of special interest or serious adverse events (SAEs). The business plans to apply for a biologics license from the FDA in the middle of 2026. [Read More: New Gene Therapies for Duchenne Muscular Dystrophy]
Genethon GNT0004 Gene Therapy
Genethon concluded by presenting data from the GNT-016-MDYF clinical trial, which demonstrated that boys treated with its adeno-associated virus (AAV) vector-based gene therapy GNT0004 experienced stabilization or improvement in functional outcomes and a 68% decrease in creatine kinase (CK) levels, a biomarker of muscle damage, over a two-year period.
According to Revah, Genethon thinks GNT0004 could be the “best in class,” in part because to the gene therapy’s lower size. He went on to say, “We do get very strong results, though with a limited number of patients and at a dose which is lower than any of the doses which are out there.” Elevidys is 1,33×1014 vg/kg, RGX-202 is 2×1014 vg/kg, and GNT0004 is 3×1013 viral genomes/kg. According to Revah, there are financial and safety advantages to this.
According to Revah, Genethon is seeking a partner to expedite development and anticipates putting GNT0004 through pivotal trials this year.
Questions About DMD Treatments
Although three major approvals have been received for Duchenne patients in the past two years, including Elevidys, which has got expanded approval in 2024, there are still a number of unanswered issues, Bardon says.
Safety is the top priority when it comes to gene therapy, and patients need to be carefully chosen, especially those who shouldn’t get it, she said. If a patient “has some sort of existing infection or other medical issue that would make it too dangerous for them,” they should not be considered for treatment. According to Bardon, the second query is how to keep an eye on patients following gene therapy administration “so that we can intervene if they develop any sequelae [or complications].”
Determining The Ideal Age for Treatment
Given that the patient had just tested positive for CMV, which can infect and harm the liver, the fatality linked to Sarepta’s Elevidys highlights the risk.
According to Bardon, determining the ideal age for treatment is the main goal for DMD gene therapy developers after safety. According to her, elderly patients may not profit sufficiently from gene therapy, while younger patients may not be able to because they are still growing. “So, what is the ideal age to reach?”
Finding a more accurate way to quantify clinical efficacy in order to calculate benefit is a major challenge across modalities, according to Bardon. The most widely used scale for assessing function in DMD patients who can walk is the North Star Ambulatory Assessment (NSAA); nonetheless, Bardon noted that it had “a lot of complexity,” in part because of the patients’ development. “As they grow, the NSAA [score] improves, but then it starts to deteriorate and get worse.” Therefore, if I treat a young patient, is their NSAA improving as a result of my medication or as a result of their development?
A remedy for this has been devised by Genethon, which treats trial participants when their NSAA score reaches the maximum. According to Revah, “[this] enables us to in some way reduce the statistical complexity and arrive at statistical significance in a much more natural way.”
According to Bardon, in addition to the NSAA, researchers are evaluating other novel metrics, such as time-to-rise from the floor and the Stride Velocity 95th Centile (SV95C), which proved sensitive to a drop in patients’ short-term walking abilities in a recently published study. According to Rare Disease Advisor, it also demonstrated minimal variability and was linked to recognized clinical outcome evaluations. [What is SV95C?]
The Important Thing is to Solve the Heart Failure Problem
According to Revah, the primary goal of the therapies currently in use is to keep patients who are mobile “as long as possible.” The goal is to “preserve as much autonomy as possible” for people who are unable to walk. Because “at the end of the day, these kids will die out of heart malfunction,” he again underlined the significance of maintaining heart function.
Regarding the future, Revah hopes to see next-generation treatments that use multiple vectors and perhaps gene editing technologies to transduce bigger segments of the dystrophin gene. In order “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,” he again underlined the significance of treating fibrosis.
“The first time that a significant reversal in muscle fibrosis has been observed” with an exon-skipping medication, according to Bolno, was when Wave revealed that WVE-N531 caused a 28.6% decrease in fibrosis.
While expressing her enthusiasm for the new biomarker data, Bardon issued a warning, saying that “we will have to corelate that better biomarker data with improved clinical outcomes for patients.”
