A long-running confirmatory trial of two of Sarepta Therapeutics’ Duchenne muscular dystrophy drugs has missed its main goal. The development comes just as the company and the FDA work to formally limit the indication of another Sarepta product, the gene therapy Elevidys.
The nine-year-long Essence trial did not show a statistically significant difference for Sarepta’s Vyondys 53 and Amondys 45 compared to placebo on a key measurement of DMD patient mobility, thereby missing its primary endpoint, Sarepta said Monday alongside the release of its third-quarter earnings report.
Specifically, the two exon-skipping agents targeting different Duchenne subpopulations only showed numerical trends toward better outcomes on the 4-step ascend velocity test, which measures how quickly a person can climb a four-step staircase, at 96 weeks. The observed difference was 0.05 steps/second on average, with a high p-value of 0.309 that missed statistical significance.
While Sarepta execs projected confidence amid the swirling developments on Monday, investors apparently have their concerns. The company’s stock was trading down about 36% pre-market on Tuesday to below $15 apiece, compared with around $120 at the beginning of the year.
Generally, the FDA may move to pull a drug from the market if a confirmatory trial fails to verify clinical benefit after an accelerated approval. But, according to Sarepta CEO Doug Ingram on an investor call Monday, rather than potentially pulling the drugs, the company is considering asking the FDA to convert the accelerated approvals for Vyondys and Amondys—granted in late 2019 and early 2021, respectively—into traditional approvals. The FDA’s approvals for the Sarepta meds were among the most hotly debated because they were based on uncertain biomarker data.
The development triggers a feeling of déjà vu. Back in 2023, the phase 3 Embark study of Elevidys also failed on its primary endpoint, but Sarepta pursued—and received—a broad full approval for the DMD gene therapy anyway.
One difference this time is, while Elevidys got its controversial accelerated approval and traditional nod in quick succession within a year, both Vyondys and Amondys have been on the market for years and have accumulated what Ingram called “a wealth of published real-world evidence” on their efficacy across various measurements, such as reduction in the risk of loss of the ability to walk and attenuation in pulmonary decline.
In any case, Ingram suggested that the FDA likely won’t terminate the drugs’ existing approvals because the agency has required a market withdrawal only if “no relevant analysis find sufficient evidence of a clinical benefit,” according to the CEO.
“We believe that we have met that standard and that we have sufficient evidence to discuss with the agency transitioning from accelerated to traditional approval,” Ingram said.
“When we talk to the FDA, I really do not believe that there’s a risk of losing marketing authorization,” Ingram said. “It would make very little sense, given both the benefits we’ve seen with this therapy and considering this extraordinarily beneficial safety profile that we’ve seen over many years.”
There were no new safety signals, with comparable adverse event rates between treatment and placebo groups, according to the company.
One of Sarepta’s main arguments is that the trial was confounded by the COVID-19 pandemic. Nearly all COVID-impacted patients missed doses, and nearly half missed “substantial consecutive doses” during the period, Ingram noted.
Sarepta defined a subgroup of COVID-free patients as those who began and completed their 96 weeks of treatment outside a period between March 2020 and July 2021. Twice as many patients in that period consecutively missed doses than those outside of it, Sarepta’s R&D head Louise Rodino-Klapac, Ph.D., noted on the call.
A post hoc analysis of participants not impacted by the pandemic yielded a 0.11 steps/second difference on the trial’s primary endpoint, with a p-value of 0.09. That translates into a 30% reduction in disease progression over two years, as measured by the 4-step ascend velocity endpoint, Rodino-Klapac said.
The p-value for the post hoc analysis is still worse than 0.05, which is typically considered the bar for statistical significance. But Ingram said FDA leadership recently noted 0.09 as a potentially acceptable p-value in rare diseases. In addition, the post hoc analysis was less powered because it’s a 57-patient smaller population than the overall trial of 225 subjects, Ingram said, arguing that achieving a 0.09 p-value in the group remains impressive.
“Had we seen this effect size in a sample size similar for the whole trial population, we would expect it would have reached statistical significance,” Rodino-Klapac said.
As one analyst noted on that call, Sarepta changed the primary endpoint of the current Essence trial just under a year ago. The original design used the 6-minute walk test, which remains a secondary functional endpoint.
Sarepta on Monday did not share specific results on any of the four secondary endpoints of Essence. Rodino-Klapac only said that the company determined 4-step ascend velocity to be the most sensitive endpoint and that the additional analyses—including one focused on patients most at risk for functional decline—showed it was the right endpoint for the study.
Based on the results, Sarepta will request a meeting with the FDA by the end of the year, and the meeting is expected to take place in the first quarter of 2026, Rodino-Klapac said.
Elevidys to get restricted label
Before the Essence confirmatory trial readout, most of the attention around Sarepta had been on its gene therapy, Elevidys. After pausing Elevidys treatment in DMD patients who are no longer able to walk independently, Sarepta said Monday that it is working with the FDA to formally remove the non-ambulatory indication from the gene therapy’s label.
The label update, along with a box warning about liver toxicity, is expected to be finalized “in the near-term,” Sarepta said in its third-quarter earnings report.
The company and the FDA are still discussing Sarepta’s proposal of a study to potentially add the non-ambulatory use back in Elevidys’ approval, the company added.
In the third quarter, Elevidys pulled in sales of $131.5 million, down sharply from $282 million in the second quarter. Expectations were low as analysts’ consensus was hovering at around $93 million, according to the team at Jefferies, which, in an Oct. 8 note, projected $130 million in sales for the troubled gene therapy in the third quarter.
Sarepta paused all shipments of Elevidys for about a week in July at the request of the FDA before resuming deliveries for ambulatory patients at the end of July. Before that, the company and its ex-U.S. partner Roche had stopped dosing non-ambulatory patients beginning in mid-June following a second patient death from acute liver failure. The DMD population is estimated to be about 50-50 split between ambulatory and non-ambulatory patients, with non-ambulatory patients typically being older because of the progression of the disease.
The hope on the Street, according to Jefferies analysts, is that Elevidys can at least be a $500 million-plus product annually in ambulatory patients. And the third-quarter number appears to support that scenario.
“We certainly feel very comfortable about that kind of baseline concept of $500 million for Elevidys,” Ingram said on the call.
During the full-on commercialization halt, 14 patients canceled their pending infusions, Sarepta’s chief commercial officer, Patrick Moss, said on the call. After the ambulatory portion of the pause was lifted, 11 of those patients rescheduled and dosed in August, and “the remainder are still working through the system,” he said.
According to Moss, Sarepta did not see any “unfavorable shifts in coverage” for Elevidys from payers despite the pause.
Nevertheless, because of delays caused by disruptions from the pause, combined with typical seasonal dynamics such as the holidays, Sarepta expects fourth-quarter uptake of Elevidys to be flat to slightly down from the third quarter, Moss said.
So far, the liver-related deaths have only occurred in non-ambulatory patients, but some investors remain concerned about the potential risk of death emerging in ambulatory patients.
To mitigate the liver toxicity, Sarepta is proposing adding the immunosuppressant sirolimus. In a small, single-center study, researchers at the Vanderbilt University Medical Center in Nashville, Tennessee, reported that low-dose sirolimus prophylaxis appears to be safe and well tolerated in DMD patients receiving Elevidys. None of the six patients who got the regimen developed acute liver injury, according to preliminary results presented at the 2025 World Muscle Society congress in October.
As the third-party research is encouraging, Sarepta is finalizing the design of cohort 8 of its Endeavor trial as the registrational study with the FDA to demonstrate the effect of additional prophylactic immunosuppression in non-ambulatory patients. However, analysts at Evercore ISI in a Tuesday note questioned whether the FDA will ask for additional efficacy data beyond safety for the new prophylactic regimen to reapprove Elevidys in the non-ambulatory population.