Sarepta Completes ESSENCE Confirmatory Trial for AMONDYS 45 and VYONDYS 53, Reports Encouraging Trends and Strong Pipeline Momentum in Q3 2025
Sarepta Therapeutics, Inc a global leader in precision genetic medicines for rare diseases, announced the completion of ESSENCE, its pivotal global Phase 3 trial evaluating AMONDYS 45 (casimersen) and VYONDYS 53 (golodirsen) in patients with Duchenne muscular dystrophy (DMD) amenable to exon 45 or 53 skipping. Alongside this milestone, the company reported its third-quarter 2025 financial results, highlighted by solid product revenues, strong progress in gene therapy programs, and ongoing advancements across its RNA and siRNA pipeline.
ESSENCE Study Overview and Topline Results
ESSENCE was a nine-year, global, Phase 3 randomized, double-blind, placebo-controlled study involving 225 boys with Duchenne muscular dystrophy aged 6 to 13 years. The study was designed to assess the efficacy and safety of AMONDYS 45 and VYONDYS 53, Sarepta’s phosphorodiamidate morpholino oligomer (PMO) exon-skipping therapies, compared with placebo.
The primary endpoint was the 4-step ascend velocity at week 96, a functional measure of motor ability in DMD. While numerical trends favored the treatment group, the observed difference of 0.05 steps/second in least square means (P=0.309) did not achieve statistical significance. However, Sarepta noted that the COVID-19 pandemic, which occurred during the study period, significantly affected trial conduct and participant data.
When Sarepta performed an analysis excluding participants whose blinded study period overlapped with the COVID-19 pandemic (n=57), the data showed a 30% reduction in disease progression over two years on the 4-step ascend velocity (LSM difference of 0.11 steps/second; P=0.09). Sarepta described this as a clinically meaningful effect, underscoring the therapies’ potential to slow disease progression in non-COVID-impacted participants.
Safety Findings Reinforce Long-Term PMO Profile
ESSENCE reaffirmed the favorable safety and tolerability of Sarepta’s PMO therapies. There were no new safety signals, and adverse events were primarily mild or moderate—88% and 10.3% respectively—comparable between the treatment and placebo arms. The most commonly reported events (≥10%) included vomiting, nasopharyngitis, fever, headache, cough, fall, and upper respiratory infections.
Sarepta emphasized that this stable safety profile is consistent with years of real-world experience across its PMO portfolio, which has treated more than 1,800 Duchenne patients worldwide—from infants as young as seven months to adults in their 30s.
Real-World Data Strengthens Clinical Findings
Beyond ESSENCE, Sarepta’s real-world evidence continues to demonstrate meaningful long-term benefits from PMO therapies. Studies have shown that treatment with VYONDYS 53 is associated with a 7.5-year delay in the need for nighttime ventilation, while AMONDYS 45 use correlates with significant slowing of lung function decline and a delay in the need for cough-assist devices.
Across the broader PMO portfolio, Sarepta reports multi-year survival benefits, delays of 3–4 years in loss of ambulation, and a substantial reduction in cardiac deterioration—specifically, a lower risk of left ventricular ejection fraction (LVEF) falling below 55%. Additionally, PMO therapy has been linked to fewer emergency room and hospital visits, illustrating sustained quality-of-life improvements.
Path Toward Traditional FDA Approval
Based on the totality of evidence—from ESSENCE outcomes, real-world data, and favorable safety—the company plans to meet with the U.S. Food and Drug Administration (FDA) to discuss converting AMONDYS 45 and VYONDYS 53 from accelerated approval to traditional approval status.
Sarepta expects that the completion of the ESSENCE trial fulfills its postmarketing requirement and will submit the full results as part of supplemental New Drug Applications (sNDAs) to the FDA. Findings from the study will also be presented at upcoming medical meetings and published in peer-reviewed journals.
“While ESSENCE did not meet statistical significance on its primary endpoint, we believe the results clearly show a treatment effect and clinically meaningful outcomes for Duchenne patients amenable to exon 45 or 53 skipping,” said Dr. Louise Rodino-Klapac, President of Research & Development and Technical Operations at Sarepta. “The data, together with extensive real-world evidence, reinforce our confidence in the benefit of increased dystrophin expression over time.”
Dr. Rodino-Klapac acknowledged the unique challenges of conducting a long-term global trial in a heterogeneous, ultra-rare disease population amid the COVID-19 pandemic. “We are deeply grateful to the families and investigators whose dedication made this possible,” she added. “We remain committed to advancing therapies that can alter the course of Duchenne.”
Dr. Craig McDonald, Professor and Chair of Physical Medicine and Rehabilitation at UC Davis Health and an ESSENCE investigator, echoed that sentiment:
“In both the trial and my clinical experience, boys treated with casimersen and golodirsen have shown preservation of critical functions like walking and stair climbing. These improvements can translate into delayed loss of ambulation and slower respiratory decline, offering a meaningful path to maintaining quality of life.”
Q3 2025 Business and Financial Highlights
Sarepta CEO Doug Ingram praised the completion of ESSENCE as a key milestone that meets the company’s primary postmarketing obligation for its PMO therapies. “This was an extraordinarily challenging study in a complex, ultra-rare disease,” he said. “We look forward to engaging with the FDA to advance these therapies toward traditional approval.”
For the third quarter ended September 30, 2025, Sarepta reported net product revenues of $370 million, driven by strong sales of ELEVIDYS and its PMO therapies EXONDYS 51, VYONDYS 53, and AMONDYS 45. Total revenues reached $399.4 million, compared to $467.2 million in the same quarter last year—a 15% decrease primarily due to lower ELEVIDYS shipments following the temporary suspension of doses to non-ambulatory patients in the U.S.
Despite the revenue decline, Sarepta strengthened its financial position through the refinancing of a majority of its 2027 convertible notes, extending maturities to 2030, and executing a cost restructuring plan aimed at reducing operating expenses. The company reported positive cash flow for the quarter, with cash and investments totaling $865.2 million at the end of September.
Pipeline Progress and Regulatory Updates
Sarepta reported significant progress across its portfolio, including ongoing regulatory discussions for ELEVIDYS and promising early-stage siRNA programs.
- ELEVIDYS (delandistrogene moxeparvovec-rokl): FDA and Sarepta are in the final stages of safety labeling discussions. The anticipated outcome includes a boxed warning and the removal of the non-ambulatory indication from the prescribing label. The company is also working with the FDA on a study evaluating an additional immunosuppression regimen that could allow reintroduction of the non-ambulatory population into the label in the future.
- siRNA Pipeline:
- Facioscapulohumeral Muscular Dystrophy (FSHD): The Phase 1/2 study of SRP-1001 has completed enrollment in the single-ascending dose (SAD) arm, with multiple-ascending dose (MAD) cohort 6 ongoing.
- Myotonic Dystrophy Type 1 (DM1): The Phase 1/2 trial of SRP-1003 has completed SAD enrollment, with cohort 4 of the MAD arm in progress.
- Huntington’s Disease (HD): Sarepta plans to initiate a clinical trial for SRP-1005 by year-end 2025, using a subcutaneous route of administration.
Research Presence at the 2025 World Muscle Society Congress
At the 2025 World Muscle Society (WMS) meeting, Sarepta presented new data on ELEVIDYS and updates from its PMO and LGMD 2E programs. Independent researchers also shared preliminary findings on a prophylactic sirolimus protocol for patients receiving delandistrogene moxeparvovec gene therapy, highlighting safety and tolerability trends. All posters and presentations are available on the company’s investor website.
Financial Performance in Detail
- Revenue:
- Q3 2025 total revenue was $399.4 million, down 15% from Q3 2024 due to lower ELEVIDYS sales and decreased contract manufacturing revenue to Roche.
- Year-to-date (YTD) revenue through September 30, 2025, rose 41% to $1.76 billion, driven by expanded ELEVIDYS approvals and collaboration revenues from Japan and Roche.
- Operating Results:
- Q3 GAAP operating loss was $103.4 million, compared to income of $22.2 million in Q3 2024.
- On a non-GAAP basis, the operating loss was $35.7 million, versus income of $74.9 million a year earlier.
- YTD GAAP operating loss totaled $288.2 million, while non-GAAP operating loss was $122.5 million.
- Net Income (Loss):
- Q3 GAAP net loss was $179.9 million (or $1.80 per share), versus net income of $33.6 million in Q3 2024.
- Non-GAAP net loss was $12.9 million (or $0.13 per share).
- YTD GAAP net loss was $430.6 million, compared to income of $76.2 million in 2024.
- R&D and SG&A Expenses:
- R&D expenses were $218.9 million in Q3 2025, largely reflecting a $100 million milestone payment to Arrowhead under the companies’ DM1 program collaboration.
- Selling, General, and Administrative expenses (SG&A) decreased to $91.9 million, down 29% year over year, reflecting the impact of Sarepta’s cost-reduction and restructuring initiatives.
- Restructuring and Debt Management:
- Sarepta recorded $40.5 million in restructuring charges in Q3, primarily severance and asset depreciation linked to its July 2025 restructuring plan.
- A $138.6 million loss on debt extinguishment was recorded following the refinancing of $700 million in 2027 notes with new 2030 convertible notes.
