Sarepta: Gene therapy Elevidys has given ‘hope’ to DMD community
Company hopes ENVISION supports its full approval in nonambulatory patients
It’s been nearly two years since Elevidys (delandistrogene moxeparvovec-rokl), a gene therapy for Duchenne muscular dystrophy (DMD) developed by Sarepta Therapeutics, was approved by the U.S. Food and Drug Administration (FDA), marking the first time a gene therapy for DMD was authorized in the U.S.
Since its launch, the response to Elevidys has been “overwhelmingly positive,” James Richardson, MD, Sarepta’s chief medical officer, told Muscular Dystrophy News Today in a written Q&A. In fact, Richardson said Elevidys “has been the strongest gene therapy launch in history.”
“This is a community that has waited for years for a treatment that can address the root cause of this devastating disease and significantly slow its progression … Elevidys has given so many families hope because it has been shown to provide clinical benefit and alter the course of disease,” Richardson said.
The FDA originally gave the therapy conditional approval for children ages 4 to 5 who could walk, but last year it granted Elevidys full approval for all ambulatory DMD patients, ages 4 and older. The agency also conditionally authorized Elevidys for people with DMD, ages 4 and older, who cannot walk.
DMD is caused by mutations in the DMD gene, which provides instructions for making dystrophin, a protein essential for maintaining muscle health. Elevidys delivers a gene that encodes a shortened, but functional version of dystrophin to muscle cells.
This is a community that has waited for years for a treatment that can address the root cause of this devastating disease and significantly slow its progression … Elevidys has given so many families hope because it has been shown to provide clinical benefit and alter the course of disease.
While it’s authorized for most patients ages 4 and older, Elevidys shouldn’t be used in those with certain mutations in the DMDÂ gene, specifically deletion mutations in parts of the gene called exon 8 and exon 9. People with these mutations can experience a dangerous immune reaction to the therapy. Roughly 80% of people with DMD are eligible for treatment with the gene therapy, according to Richardson.
Approvals for Elevidys
The FDA’s full approval of Elevidys for ambulatory patients was based largely on data from the Phase 3 EMBARK clinical trial (NCT05096221), which tested the therapy in more than 120 boys with DMD. A recent analysis compared two-year outcomes from 63 participants against data from an external group of untreated boys with DMD.
Results showed the boys given Elevidys had better outcomes in multiple motor function measures. The time it took to stand up increased by less than a second in boys given Elevidys, compared with nearly three seconds in the external group. The time it took to walk or run 10 meters (about 33 feet) was virtually unchanged for boys given Elevidys, whereas the external group was more than a second slower on average. And boys given Elevidys showed improved scores on an overall measure of motor function called the North Star Ambulatory Assessment (NSAA), whereas NSAA scores worsened over time in the external group.
“The boys who received Elevidys were able to perform physical tasks like standing up, walking, and running faster and more efficiently,” said Crystal Proud, MD, an investigator on EMBARK at Children’s Hospital of the King’s Daughters. “The results from the EMBARK study show that, after two years, boys who were treated with Elevidys had much better motor skills compared to boys who didn’t receive Elevidys.”
Proud said the finding shows “Elevidys treatment is positively impacting the trajectory of Duchenne.”
Better outcomes with Elevidys
A similar analysis compared external controls against three-year outcomes in 50 boys treated with Elevidys who’d participated in early studies of the gene therapy or an open-label study called ENDEAVOR (NCT04626674). Results showed motor function measures tended to worsen over time in both groups, but the declines were substantially slower for those given the gene therapy. Five-year data from four boys given Elevidys in the first trial of the gene therapy (NCT03375164) also showed better motor outcomes than is typically seen in DMD.
“Although the cohort of patients is smaller, when we compare all available data to a well-balanced control group, we see that patients treated with Elevidys consistently outperform those who do not receive the treatment,” Proud said.
The boys who received Elevidys were able to perform physical tasks like standing up, walking, and running faster and more efficiently.
Based on these data, Proud said it’s “reasonable to expect that individuals treated with Elevidys will be able to engage in activities that were previously out of reach, or maintain their ability to perform certain activities for a longer period. This includes daily tasks like bathing, dressing, feeding oneself, or even more complex activities like perhaps riding a bike or playing sports.”
“As a physician treating patients with Duchenne, I am eager to observe even more long-term results for those treated with Elevidys,” Proud said. “While we can’t predict exactly what the future holds, the current data is compelling.”
Ongoing research
In addition to the functional outcomes, MRI data from clinical studies of Elevidys suggest that patients given the gene therapy have less muscle tissue degeneration over time.
“This would be a further compelling reason to treat as soon as possible to protect muscle from irreversible damage,” Proud said.
Collectively, Elevidys’ data “demonstrate the significant impact of this gene therapy and its transformative potential to alter the course of the disease and improve patient lives,” Richardson said.
Other clinical trials collecting data on outcomes with Elevidys are ongoing, including ENVISION (NCT05881408), a Phase 3 study testing the therapy in both ambulatory and nonambulatory patients. That trial has finished enrollment in the U.S. and results are expected in 2027, according to Richardson. Sarepta said it hopes ENVISION’s outcomes will form the basis for the therapy’s full FDA approval in nonambulatory patients.
Sarepta is also studying Elevidys in children younger than 4 and the company recently announced plans for a Phase 4 trial called ENDURE that is intended to compare outcomes with Elevidys against standard of care in boys and men with DMD who are eligible for gene therapy.
“The purpose of ENDURE is to collect follow-up data on participants who received Elevidys for up to 10 years post-infusion, and what we hope to learn from this study is what the long-term effectiveness and safety of Elevidys is compared to standard of care in a real-world setting,” Richardson said.
Investigating safety issues after patient’s death
As with any medication, there are risks of side effects with Elevidys, which can include liver damage, nausea and vomiting, fever, and immune reactions. Proud said these side effects “are generally straightforward to address if caught early,” so it’s very important for patients to be carefully monitored after receiving the therapy.
“The most important thing to remember is to immediately consult with your provider if you suspect anything unusual in your child’s health,” Proud said.
Last month, Sarepta reported the death of a young man who developed fatal liver damage after treatment with Elevidys.
“The loss of this young man with Duchenne is a great tragedy and one that we, and the entire Duchenne community, is mourning,” Richardson said. “It’s an unimaginable loss for his family and friends, and we are thinking about them.”
This was the first death on record related to the gene therapy, which so far has been given to more than 800 people with DMD, according to Sarepta. The company is investigating the incident to understand what happened so appropriate safety precautions can be taken.
“When we conclude our investigation, we will evaluate updates to the prescribing information and treatment monitoring guidelines. In this way, we can help assure the best possible treatment outcomes,” Richardson said.
Clinical trials of Elevidys were initially paused following the death, but an independent committee recently recommended that trials of the gene therapy could continue without protocol modifications.
“When it comes to our clinical trials, all safety data is reviewed by an independent data monitoring committee comprised of multi-disciplinarian experts who provide recommendations on stopping studies where there are safety concerns,” Richardson said. “Ultimately, this committee concurred with ours, that the benefit-risk profile remains favorable to continue our clinical trials without any modifications.”
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