A Year of DMD Gene Therapy Trial Failures

The gene therapy landscape for Duchenne muscular dystrophy (DMD) has encountered major hurdles in 2023 and 2024, as 2 high-profile trials—Sarepta’s EMBARK and Pfizer’s CIFFREO—failed to meet their primary endpoints.

Both trials aimed to treat DMD by delivering genetic material to help restore dystrophin, the key protein lacking in patients with the disease. However, the results have raised new questions about the viability of gene therapies for DMD while leading to difficult decisions for the companies involved, including layoffs.

Outcomes From EMBARK

Sarepta’s EMBARK trial, which aimed to assess the efficacy and safety of delandistrogene moxeparvovec (Elevidys), did not show meaningful improvements in motor function compared with placebo after 1 year, despite earlier optimism.¹ These results were first announced in October 2023 and supported the submission of an efficacy supplement to the drug’s Biologics License Application, which later led to the drug’s expanded approval.^2,3

The randomized, placebo-controlled trial included 125 boys with DMD, aged 4 to 8 years.¹ Participants received either delandistrogene moxeparvovec or a placebo, with changes in North Star Ambulatory Assessment (NSAA) scores serving as the primary endpoint. The NSAA measures motor function in children with DMD, such as walking, running, and rising from the floor. However, the difference in NSAA scores between the treatment and placebo groups was just 0.65 points—and was neither statistically nor clinically significant.

Despite the primary endpoint not being met, some secondary measures hinted at potential benefits. Children treated with delandistrogene moxeparvovec demonstrated better performance in tasks such as rising from the floor and completing a 10-meter walk or run, and they showed higher micro-dystrophin expression, a biomarker associated with the therapy's intended effect. There were also no new safety concerns introduced in the study, with adverse events managed effectively through monitoring and treatment. Yet, the modest gains did not meet the high expectations surrounding the trial.

“In this early ambulatory patient population, the NSAA may not have been sensitive enough to detect a difference that was statistically significant at 52 weeks,” the EMBARK researchers noted. They cited the natural variability in motor development among boys aged 4 to 7 as a key challenge, complicating efforts to distinguish treatment effects from normal developmental progress.

Adding to the complexities, the children in the trial also received high doses of corticosteroids to mitigate potential immune reactions from the gene therapy. These steroids can temporarily boost muscle function, likely contributing to performance gains in both the treatment and placebo groups. The researchers acknowledged that the use of steroids, though necessary, may have masked the true effect of the therapy over the short duration of the trial.

As other clinical trials continue to study the use of delandistrogene moxeparvovec in other age groups, experts and patients alike hold onto hope for positive results. However, the insignificant increase in NSAA scores for boys aged 4 to 7 has raised concerns, especially amid other DMD trial failures.

“This has caused not only disappointment in the DMD community, but has also triggered discussion on the efficacy of micro-dystrophin and raised questions on how to best assess the efficacy of gene therapy in DMD,” researchers said in a response piece to the EMBARK results.⁴ “Indeed, the positive results obtained in all the remaining key predefined secondary clinical endpoints indicate a positive effect of this drug on various muscle functions in treated patients, and therefore deserve more in-depth considerations.”

Outcomes From CIFFREO

In parallel, Pfizer’s CIFFREO trial also did not meet its primary endpoint.⁵ CIFFREO aimed to evaluate fordadistrogene movaparvovec, another investigational gene therapy for ambulatory boys with DMD aged 4 to 7 years. Like EMBARK, this trial measured changes in the NSAA scores over a year but found no significant improvement compared with placebo. Secondary endpoints, including walk/run velocity and time to rise from the floor, also failed to show meaningful differences between the treatment and placebo groups.

“We are extremely disappointed that these results did not demonstrate the relative improvement in motor function that we had hoped,” said Dan Levy, MD, PhD, development head for DMD at Pfizer, in a news release from June 2024.

Pfizer faced further complications after one boy in the phase 2 DAYLIGHT study—which was included in CIFFREO’s cross-trial design—died of cardiac arrest, leading to a dosing pause in the CIFFREO trial.⁶ While the safety profile of fordadistrogene movaparvovec was deemed manageable, the earlier incident highlights the risks inherent in gene therapy trials, especially for complex conditions like DMD.

Following the CIFFREO trial failure, Pfizer announced layoffs at its manufacturing site in Sanford, North Carolina, where the company had invested heavily in gene therapy production.⁷ In October 2024, 75 employees were let go, marking the second wave of layoffs this year after 150 positions were cut in July. Pfizer had initially purchased the new manufacturing site in Sanford to support commercial production of its gene therapies, but those plans have now been abandoned for months and the facility is being put up for sale. Operations will continue at the main facility in the same town.

These layoffs come amid broader financial challenges for Pfizer, which is undergoing cost-cutting measures following underwhelming returns from its investments in research and development. Activist investor Starboard Value recently urged Pfizer’s board to "hold management accountable" for the company’s financial performance, adding pressure on leadership to reassess its strategic priorities.

What This Means for DMD Research

The disappointing outcomes of the 2 anticipated trials highlight the significant challenges in developing gene therapies for DMD, a rare disease with a complex progression. Both trials aimed to restore dystrophin levels, the protein critical to muscle function, but their inability to meet primary endpoints has raised questions about micro-dystrophin gene therapies and how best to measure efficacy in DMD clinical trials.

For patients and families affected by DMD, these setbacks are particularly disheartening. Many had pinned their hopes on the potential of gene therapy to extend mobility and improve quality of life, especially considering Sarepta’s drug was approved by the FDA under the impression it was “reasonably likely” to predict a benefit.⁷

As the companies regroup, researchers are focusing on lessons learned from these trials, including refining patient selection criteria and identifying better outcome measures to capture subtle treatment benefits.⁴

References

1. Mendell JR, Muntoni F, McDonald CM, et al. AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial. Nat Med. Published online October 9, 2024. doi:10.1038/s41591-024-03304-z
2. Sarepta Therapeutics announces topline results from EMBARK, a global pivotal study of ELEVIDYS gene therapy for Duchenne muscular dystrophy. News release. Sarepta Therapeutics. October 30, 2023. Accessed October 30, 2024. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-topline-results-embark-global-0
3. FDA expands approval of gene therapy for patients with Duchenne muscular dystrophy. News release. FDA. June 20, 2024. Accessed October 28, 2024. https://www.fda.gov/news-events/press-announcements/fda-expands-approval-gene-therapy-patients-duchenne-muscular-dystrophy
4. Baranello G, Muntoni F. AAV gene therapy for Duchenne muscular dystrophy: lessons learned from a phase 3 trial. Gene Ther. Published online October 23, 2024. doi:10.1038/s41434-024-00494-6
5. Pfizer provides update on phase 3 study of investigational gene therapy for ambulatory boys with Duchenne muscular dystrophy. News release. Pfizer. June 12, 2024. Accessed October 28, 2024. https://investors.pfizer.com/Investors/News/news-details/2024/Pfizer-Provides-Update-on-Phase-3-Study-of-Investigational-Gene-Therapy-for-Ambulatory-Boys-with-Duchenne-Muscular-Dystrophy/default.aspx
6. Masson G. UPDATE: Pfizer's phase 3 gene therapy trial fails to improve function for boys with Duchenne muscular dystrophy. News release. Fierce Biotech. June 12, 2024. Accessed October 28, 2024. https://www.fiercebiotech.com/biotech/pfizers-phase-3-gene-therapy-trial-fails-improve-function-boys-duchenne-muscular-dystrophy
7. Dunleavy K. Pfizer lays off 75 more workers in North Carolina in wake of late-stage DMD trial fail. News release. Fierce Biotech. October 22, 2024. Accessed October 28, 2024. https://www.fiercepharma.com/pharma/pfizer-lays-75-more-workers-north-carolina-wake-late-stage-dmd-trial-fail