Sarepta joins Pfizer in failed DMD gene therapy trial

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

Both studies aimed to treat DMD by delivering genetic material to help restore dystrophin, the key protein missing 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.

Results from EMBARK

from Zarephath EMBARK trialwhich aimed to assess the efficacy and safety of delandistrogen moxeparvovec (Elevys), showed no meaningful improvements in motor function compared to placebo after 1 year, despite earlier optimism.¹

The randomized, placebo-controlled trial included 125 boys with DMD aged 4 to 8 years. Participants received 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 getting up from the floor. However, the difference in NSAA scores between the treatment and placebo groups was only 0.65 points – and was neither statistically nor clinically significant.

Despite not meeting the primary endpoint, some secondary measures indicated potential benefits. Children treated with delandistrogen moxeparvovec showed better performance on tasks such as getting up from the floor and completing a 10-meter walk or run, and they showed higher expression of microdystrophin, a biomarker related to target effect of the therapy. No new safety concerns were also introduced in the study, with side effects managed effectively through monitoring and treatment. Still, the modest gains did not meet the high expectations surrounding the trial.

“In this early outpatient 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 natural variability in motor development in boys aged 4 to 7 years as a major challenge, complicating efforts to distinguish treatment effects from normal developmental progression.

Adding to the complexity, the children in the study were also given high doses of corticosteroids to blunt possible immune responses resulting 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, while necessary, may have masked the true effect of the therapy during the short duration of the trial.

As other clinical trials continue to explore the use of delandistrogen moxeparvovec in other age groups, experts and patients continue to hope for positive results. However, the insignificant increase in NSAA scores for boys ages 4 to 7 has raised concerns, especially amid other failed DMD trials.

“This has not only led to disappointment in the DMD community, but has also sparked debate about the efficacy of micro-dystrophin and raised questions about how best to assess the efficacy of gene therapy in DMD,” researchers said. in a study. response piece to the EMBARK results.² “Indeed, the positive results obtained in all other 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.”

Results of CIFFREO

At the same time Pfizer’s CIFFREO trial also did not meet the primary endpoint.³ CIFFREO aimed to evaluate fordadistrogene movaparvovec, another experimental gene therapy for outpatient boys with DMD aged 4 to 7 years. Similar to EMBARK, this study measured changes in NSAA scores over one year, but found no significant improvement compared to placebo. Secondary endpoints, including walking/running speed and time to rise from the floor, also showed no 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 for,” Dan Levy, MD, PhD, development lead for DMD at Pfizer, said in a press release.

Pfizer faced further complications after a boy in the Phase 2 DAYLIGHT trial – which was included in the CIFFREO cross-trial design –died of cardiac arrestleading to a dosing pause in the CIFFREO study.⁴ Although the safety profile of fordadistrogene movaparvovec was considered manageable, the earlier incident highlights the risks inherent in gene therapy trials, especially for complex conditions such as DMD.

After the failure of the CIFFREO trial, Pfizer decided announced layoffs at its manufacturing site in Sanford, North Carolina, where the company had invested heavily in gene therapy manufacturing.⁵ In October 2024, 75 employees were laid off, marking the second wave of layoffs this year after 150 job cuts 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 plant is being put up for sale. Operations will continue at the main facility in the same city.

The layoffs come amid broader financial challenges for Pfizer, which is undergoing cost-cutting measures after disappointing returns from its research and development investments. Activist investor Starboard Value recently urged Pfizer’s board to “hold management accountable” for the company’s financial performance, increasing pressure on leadership to reassess strategic priorities.

What this means for DMD research

The disappointing results from the two expected trials highlight the significant challenges in developing gene therapies for DMD, a rare disease with a complex progression. Both trials aimed to restore levels of dystrophin, 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 clinical trials of DMD.

For patients and families affected by DMD, these setbacks are particularly disheartening. Many had pinned their hopes on gene therapy’s potential to increase mobility and improve quality of life, especially considering that Sarepta’s drug had been approved by the FDA on the assumption that it “fairly likely” predict an advantage.⁶

As the companies regroup, researchers are focusing on the lessons learned from these studies, including refining patient selection criteria and identifying better outcome measures to capture subtle treatment benefits.²

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. 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
3. Pfizer provides update on phase 3 study of experimental gene therapy for outpatient boys with Duchenne muscular dystrophy. News item. 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
4. Masson G. UPDATE: Pfizer’s phase 3 gene therapy trial fails to improve function in boys with Duchenne muscular dystrophy. News item. Fierce biotechnology. 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
5. Dunleavy K. Pfizer lays off another 75 employees in North Carolina after late-stage DMD trial failure. News item. Fierce biotechnology. 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
6. FDA expands approval of gene therapy for patients with Duchenne muscular dystrophy. News item. FDA. June 20, 2024. Accessed October 28, 2024.