gene therapy environment Duchenne muscular dystrophy (DMD) faced major hurdles in 2024 as two 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 repair dystrophin, the key protein missing in patients with the disease. But the results raised new questions about the feasibility of gene therapies for DMD and led to difficult decisions, including layoffs, for the companies involved.

Released from EMBARK

Sarepta EMBARK trialThe study, which aimed to evaluate the efficacy and safety of delandystrogen moxeparvovec (Elevidys), did not show significant improvements in motor function compared to placebo after 1 year, despite previous optimism.¹

The randomized, placebo-controlled study included 125 boys with DMD aged 4 to 8 years. Participants received delandistrogen moxeparvovec or placebo, with changes in North Star Ambulatory Assessment (NSAA) scores as the primary endpoint. NSAA measures motor functions such as walking, running, and getting up from the ground in children with DMD. However, the difference in NSAA scores between the treatment and placebo groups was only 0.65 points, and this difference was neither statistically nor clinically significant.

Both trials aimed to restore levels of dystrophin, a protein critical for muscle function. Image source: RFBSIP –stock.adobe.com

Although the primary endpoint was not met, some secondary measures indicated potential benefits. Children treated with delandystrogen moxeparvovec performed better on tasks such as getting up from the ground and completing a 10-meter walk or run, and showed higher expression of micro-dystrophin, a biomarker associated with the intended effect of the treatment. Additionally, no new safety concerns were raised in the study, with adverse events effectively managed through monitoring and treatment. But the modest gains did not meet high expectations for the trial.

“In this early outpatient population, NSAA may not have been sensitive enough to detect a statistically significant difference at 52 weeks,” EMBARK researchers said. They cited natural variability in motor development among boys ages 4 to 7 as a significant challenge that complicates efforts to separate treatment effects from normal developmental progression.

To add to the complexity, children in the trial were also given high doses of corticosteroids to reduce potential immune reactions from the gene therapy. These steroids may temporarily increase muscle function and possibly contribute to improved performance in both treatment and placebo groups. The researchers acknowledged that the use of steroids, although necessary, may have masked the true effect of the treatment during the short duration of the trial.

While other clinical trials continue to examine the use of delandystrogen moxeparvovec in other age groups, experts and patients alike remain hopeful for positive results. However, the insignificant increase in NSAA scores in boys aged 4 to 7 years has raised concerns, especially among failures in other DMD trials.

“This not only caused disappointment in the DMD community, but also triggered debate about the effectiveness of microdystrophy and raised questions about how best to evaluate the effectiveness of gene therapy in DMD,” the researchers said. response piece According to EMBARK results.² “Indeed, the positive results achieved on all remaining predefined key secondary clinical endpoints suggest that this drug has a positive effect on various muscle functions in treated patients and therefore deserves more in-depth evaluation.”

Outputs from CIFFREO

In parallel, Pfizer’s CIFFREO trial it also failed to meet its primary endpoint.³ CIFFREO aimed to evaluate another investigational gene therapy, fordadistrogen movaparvovec, for ambulatory boys with DMD aged 4 to 7 years. Like EMBARK, this study measured changes in NSAA scores over a year but found no significant improvement compared to placebo. Secondary endpoints such as walking/running speed and time to rise from the ground also failed to show significant differences between the treatment and placebo groups.

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

Pfizer encountered further complications after a boy in the phase 2 DAYLIGHT study was included in CIFFREO’s crossover trial design.died of heart attackIt led to dosing being paused in the CIFFREO trial.⁴ While the safety profile of fordadistrogen movaparvovec was considered manageable, the earlier incident highlighted the risks inherent in gene therapy trials, especially for complex conditions such as DMD.

Pfizer after CIFFREO trial failure layoffs announced At its manufacturing facility in Sanford, North Carolina, where the company has invested heavily in gene therapy production.⁵ In October 2024, 75 employees were laid off; This marked the second wave of layoffs this year, after 150 positions were cut in July. Pfizer originally purchased the new manufacturing facility in Sanford to support commercial production of gene therapies, but those plans have now been canceled for months and the facility is up for sale. Operations will continue at the main facility in the same town.

These layoffs come at a time of wider financial difficulties for Pfizer, which has embarked on cost-cutting measures after poor returns on research and development investments. Activist investor Starboard Value recently called on Pfizer’s board to “hold management accountable” for the company’s financial performance, increasing pressure on leadership to reevaluate its strategic priorities.

What Does This Mean for DMD Research?

Disappointing results from 2 anticipated studies highlight significant challenges in developing gene therapy for DMD, a rare disease with complex progression. Both trials aimed to restore levels of dystrophin, the protein critical for muscle function, but their failure to meet primary endpoints raised questions about microdystrophin gene therapies and how best to measure effectiveness in DMD clinical trials.

For patients and families affected by DMD, these setbacks are especially disheartening. Many people had pinned their hopes on gene therapy’s potential to increase mobility and improve quality of life, especially under the impression that Sarepta’s drug had been approved by the FDA. “quite likely” to estimate a benefit.⁶

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

References

1. Mendell JR, Muntoni F, McDonald CM, et al. AAV gene therapy for Duchenne muscular dystrophy: EMBARK phase 3 randomized trial. NatMed. 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. Gen Ther. Published online October 23, 2024. doi:10.1038/s41434-024-00494-6
3. Pfizer provides updates on the phase 3 study of its investigational gene therapy for ambulatory boys with Duchenne muscular dystrophy. Newsletter. Pfizer. June 12, 2024. Access date: October 28, 2024. https://investors.pfizer.com/Investors/News/news-details/2024/Pfizer-Provides-Update-on-Phase-3-Study-of-Investigational-Gene -Duchenne-Muscular-Dystrophy-Ambulatory-Therapy for Boys/default.aspx
4. Masson G. UPDATE: Pfizer’s phase 3 gene therapy trial fails to improve function in boys with Duchenne muscular dystrophy. Newsletter. Violent Biotechnology. June 12, 2024. Access date: 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 laid off 75 more workers in North Carolina after its late-stage DMD trial failed. Newsletter. Violent 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 is expanding approval of gene therapy for patients with Duchenne muscular dystrophy. Newsletter. FDA. 20 June 2024. Access date: 28 October 2024.