ELEVIDYS setbacks reflect a dim outlook for Sarepta and DMD therapies

Described by management as “the strongest gene therapy launch in history,” ¹Sarepta’s ELEVIDYS brought high hopes to the Duchenne muscular dystrophy (DMD) community. 

DMD is a rare genetic disorder that begins in early childhood and causes progressive muscle weakness. Death usually occurs in the twenties due to respiratory muscle weakness or cardiomyopathy. There is currently no cure, but treatment can help with symptoms.

Even though DMD is rare, ELEVIDYS’ $3.2 million price tag means Sarepta can generate blockbuster revenue from a few hundred patients.² The DMD market is projected to grow from roughly $2.3 billion to over $5.0 billion by 2033.³ In June 2024, Sarepta was buoyed by expanded FDA approval for ELEVIDYS, with shares surging above $170. 

The company’s fortunes have taken a roller-coaster ride over the past year, following reports that two non-ambulatory patients died of liver failure.⁴ In July, the US FDA ordered Sarepta to halt shipments of the therapy. Distribution later resumed for ambulatory patients in late July, but the hold for non-ambulatory patients remains in place. After the FDA halt, the stock dropped as low as $10.42. As of 10 November 2025, shares closed at $17.27, down roughly 85% year to date.

Third Bridge and its experts are monitoring the DMD treatment market following safety concerns about ELEVIDYS. Here are the key takeaways:

1. Will patients trust ELEVIDYS again?

Communicating to parents that DMD remains a fatal disease without a cure is a difficult conversation for clinicians. Third Bridge experts say that steroids such as prednisone, deflazacort, or vamorolone and exon skipping agents remain the main standard of care for managing DMD until more effective gene therapies become widely available. They admit that it likely makes little difference which steroid a patient takes, and neither patients nor parents report significant benefits.

Some experts have suggested that ELEVIDYS reached the market without extensive prior trials. After all, DMD is a rare and fatal disease with no current cure, affecting roughly 7 per 100,000 males in the general population.⁵ Deciding when to administer a treatment that looks promising, yet still carries some uncertainties and safety concerns, is extremely difficult. 

Conversations with our experts indicate that, even before the fatal reports, some clinicians may have been reluctant to administer ELEVIDYS, particularly for non-ambulatory patients.

“I do not perceive this as a situation where benefits clearly outweigh the risk, at least for the nonambulatory patients. I am aware of people with a lot of experience who were reluctant to dose non-ambulatory patients to begin with, even before these two deaths happened. There was at least in part a significant restraint.”

Sarepta Therapeutics – Elevidys's Clinical Standing & Next-generation Gene Therapy Approaches

The use of ELEVIDYS is currently paused for non-ambulatory patients, which has posed a challenge for Sarepta, as the non-ambulatory patient population represents approximately half of the total DMD population. However, Sarepta appears optimistic about a path forward for their DMD treatments. According to the company’s July update, while they lack clear visibility into the non-ambulatory population, it still represents a significant opportunity. ELEVIDYS’ ambulatory minimum annual opportunity through 2027 is $500 million, with near-term upside as the prevalent population receives treatment.⁶

Third Bridge experts said ELEVIDYS could regain limited access to the non-ambulatory patient market, but demand is expected to fall short of earlier projections, as patient concerns over the therapy’s safety profile weigh on uptake. 

Sarepta is testing a revised immunosuppression regimen in its Cohort 8 study, which adds higher doses of steroids and sirolimus in an effort to reduce liver-related toxicity. Experts questioned the safety of the new approach, saying the mechanism of liver injury remains poorly understood and that the added immunosuppressants may introduce new risks. If successful, the updated regimen could pave the way to resume ELEVIDYS use in non-ambulatory patients. Even so, clinicians may remain cautious and proceed with limited confidence in its safety profile.

Even ambulatory patients may be expressing concern over the two reported deaths, which occurred in the non-ambulatory population, making some hesitant to pursue gene therapy or prompting them to delay their decision. Third Bridge experts say reports of patient fatalities, coupled with worries about the company’s communication practices, could cut ambulatory patient demand by 40–50%. There is a “high likelihood” that ELEVIDYS’ sales to ambulatory patients could stall below $700 million, raising questions about the company’s ability to maintain growth.

The fatal incidents have implications beyond ELEVIDYS, as FDA safety concerns led to the revocation of the platform designation for Sarepta’s AAVrh74 vector. This disrupts plans to expand the gene therapy pipeline, forcing a reassessment since future approvals for programs like limb-girdle muscular dystrophy can no longer rely on the same platform. 

  2. What’s next for Sarepta and DMD treatment?

Financially, Sarepta is managing a challenging debt position. Sarepta currently carries USD 1.1 billion in debt (2030 maturity) and a USD 600 million credit line. It still owes USD 50 million in Arrowhead milestones (of a USD 100 million total) and faces further obligations if small interfering RNA (siRNA) results are positive. 

Our experts say the company’s intense focus on ELEVIDYS has limited its ability to diversify risk, with the therapy accounting for nearly 60% of revenue in Q3 2025.

Sarepta structured its Arrowhead agreement to cover R&D costs for licensed programs, relying on projected ELEVIDYS revenue. With that cash flow now likely to be much smaller, the agreement has become more precarious. Experts also note that the partnership carries additional risks, given a limited collaborative track record and a historically insular approach that could complicate milestone payments and pipeline development.

While default risk on 2030 debt maturities remains low, it appears that elevated refinancing stress has prompted management to explore all available options to extend its cash runway. Sarepta announced a restructuring plan that will cut 36% of its workforce, in an effort to reduce annual operating expenses by $400 million by 2026. The company has paused development of most of its gene therapies for limb-girdle muscular dystrophy and will focus on its gene-silencing efforts, primarily its siRNA platform.

The company’s pivot toward siRNA therapies has drawn skepticism from experts over whether Sarepta has sufficient resources to sustain development and whether the approach can deliver the next wave of growth. However, the shift may be necessary to support a potential valuation rebound, as experts we spoke with expressed a highly uncertain and pessimistic outlook for major breakthroughs in DMD over the next five years, expecting only slow and incremental progress at high cost.

Apart from ELEVIDYS, there is growing investor concern about Sarepta’s phosphorodiamidate morpholino oligomer (PMO)  pipeline, which accounted for more than 30% of the company’s revenue in Q3 2025. Shares of Sarepta fell 36% on November 4, as a trial of two of its PMO therapies for DMD, Amondys 45 and Vyondys 53, failed to show clear patient improvement.⁷

This echoes our previous conversations with experts, who noted that exon-skipping therapies face a bleak near-term outlook. Experts described them as “a big disappointment,” offering limited benefit compared with prednisone. While unlikely to become the next winning strategy, they may serve as bridging therapies until more effective gene therapies mature. Our experts say, among players in this space, Dyne Therapeutics’ FORCE platform is viewed more favorably than Avidity’s, largely due to better perceived muscle-targeting capabilities. A clinically meaningful improvement is defined as roughly a three-point gain on the NSAA scale, with 3–10% dystrophin expression seen as a realistic baseline for new therapies.

In another development, on October 26, 2025, Novartis announced the acquisition of Avidity Biosciences. Estimated at roughly $12 billion, the deal is the second-largest pharma acquisition this year. The move underscores big pharma’s excitement for muscle-targeted therapy. Avidity’s RNA therapeutic development platform delivers to Novartis three late-stage antibody oligonucleotide conjugates for the treatment of DMD, facioscapulohumeral muscular dystrophy (FSHD), and myotonic dystrophy type 1 (DM1).

From Avidity’s lead DMD candidate, del-zota, a Third Bridge expert pointed out that ~7% spontaneous exon skipping occurs in exon 44 mutations at baseline, potentially inflating the exon-skipping numbers that Avidity has recorded, while also still believing del-zota will get approved.

Still, over the longer term, Third Bridge experts said gene therapy remains the long-term focus for DMD, even as ELEVIDYS faces regulatory and safety setbacks. The question for Sarepta, however, is whether investors have enough patience and whether ELEVIDYS will emerge as the winner among other gene therapies.

Experts said they continue to favor gene therapy’s mechanism of action as a foundational treatment, with exon-skipping therapies likely to serve as sequential or additive treatments to enhance outcomes. “If presented with ELEVIDYS and an exon-skipping therapy with similar efficacy data, despite all the risks, many would still choose ELEVIDYS,” one expert said, underscoring the community’s enduring hope for a one-time, curative option.

However, next-generation gene therapies appear to show limited differentiation so far. Candidates such as RGX-202, SGT-003, and ELEVIDYS are viewed by our experts as largely similar, with no clear frontrunner. Experts attributed this to the limited understanding of dystrophin’s biological function, noting that a deeper grasp of microdystrophin and its role in disease modification may take at least a decade.

With Sarepta’s future hanging in the balance, for DMD patients and their families, the choice is immediate and wrenching: take a therapy that could improve life expectancy over the next 10 years (but carries potential risks) or, opt for no treatment at all. It is a stark trade-off.

All insights in this article are based on information shared by Third Bridge experts. 

For media enquiries, please contact us at comms@thirdbridge.com.

^{Transcript references:} 

^{1. Sarepta Therapeutics – Elevidys, What Now? – Removal from Markets, Financial Implications & Path Forwardspies Shaking Up DMD Treatment}

^{2. Sarepta Therapeutics – Elevidys's Clinical Standing & Next-generation Gene Therapy Approaches}

^{3. The Next-generation Exon-skipping Therapies Shaking Up DMD Treatment}

^References

^{1.  https://musculardystrophynews.com/news/gene-therapy-elevidys-given-hope-dmd-community-sarepta-exec-says/}

^{2. https://www.biopharmadive.com/news/sarepta-duchenne-elevidys-price-million-gene-therapy/653720/}

^{3. https://www.globaldata.com/media/pharma/duchenne-muscular-dystrophy-market-reach-5-2-billion-7mm-2033-forecasts-globaldata/}

^{4. https://www.reuters.com/business/healthcare-pharmaceuticals/sarepta-shares-slump-after-third-patient-death-this-year-2025-07-18/}

^{5. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0287774#:~:text=Duchenne%20muscular%20dystrophy%20(DMD)%20is,was%2041%20months%20%5B5%5D.}

^{6. https://investorrelations.sarepta.com/static-files/f874b9f5-54f2-48d1-bffd-09c4433c6373}

^{7. https://endpoints.news/duchenne-confirmatory-trial-fails-but-sarepta-to-ask-fda-for-full-approval-anyways/}