Quantitative Magnetic Resonance Outcomes Suggest Gene Therapy Slows DMD Progression

Delandistrogene moxeparvovec (Elevidys; Sarepta Therapeutics) appeared to slow disease progression vs a placebo in patients with Duchenne muscular dystrophy (DMD) based on muscle quantitative magnetic resonance (QMR) measures in an exploratory analysis of the phase 3 EMBARK clinical trial (NCT05096221).¹ The findings were published in JAMA Neurology.  

Quantitative magnetic resonance imaging seemed to show that delandistrogene moxeparvovec protects muscle from progressive damage in DMD. | Image credit: OlegKachura - stock.adobe.com

The double-blind, placebo-controlled EMBARK trial included 63 patients treated with delandistrogene moxeparvovec and 62 given a placebo.² Delandistrogene moxeparvovec, a recombinant adeno-associated virus (AAV) vector–based gene therapy, is indicated for ambulatory and nonambulatory patients with DMD aged 4 years and older.³ Its approval for nonambulatory patients is an accelerated approval based on micro-dystrophin expression.

For the exploratory analysis, researchers identified 19 participants in the treatment group and 20 in the placebo group who had undergone QMR imaging.¹ The prespecified exploratory end point was change in muscle MR from baseline to week 52, with proton MR spectroscopy (MRS) and MRI measuring muscle fat fraction and multislice spin echo MRI measuring transverse relaxation time (T₂). The mean (SD) baseline North Star Ambulatory Assessment (NSAA) score was 22.99 (3.71) points.

Patients who received gene therapy demonstrated less disease progression compared with the placebo group based on QMR measurements. Treated patients showed a smaller mean increase in muscle fat fraction based on MRS in the soleus and vastus lateralis muscles. The mean (SE) changes in the soleus from baseline to week 52 were 0.28% (0.28%) in the treatment group and 1.17% (0.80%) in the placebo group. Changes in the vastus lateralis group were 0.86% (0.83%) in the gene therapy cohort and 2.07% (0.97%) in the placebo group. Between-group differences in least-squares mean (LSM) change based on MRS ranged from −1.01 (95% CI, −2.79 to 0.77) in the soleus to −0.71 (95% CI, −3.21 to 1.80) in the vastus lateralis.

MRI measures of muscle fat fraction also showed less progression with delandistrogene moxeparvovec from baseline to week 52, with smaller increases across 5 leg muscle locations important to ambulation. The mean (SE) changes were 1.67% (1.44%) compared with 3.67% (1.85%) in the biceps femoris; 0.76% (1.23%) vs 1.17% (1.15%) in the hamstrings; 0.55% (0.91%) vs 3.32% (1.99%) in the quadriceps; −0.65% (0.82%) vs 0.45% (0.91%) in the soleus; and 0.72% (0.93%) compared with 3.89% (2.14%) in the vastus lateralis. Between-group differences in LSM change ranged from −3.09 (95% CI, −7.62 to 1.45) in the vastus lateralis to −0.44 (95% CI, −4.01 to 3.12) in the hamstrings.

T₂ improvements were seen in 4 of 5 muscles in treated patients, while all muscles in placebo group patients showed worsened T₂ measurements.The within-group differences in LSM changes ranged from −1.06 (95% CI, −2.10 to −0.02) for the soleus to 0.17 (95% CI, −1.76 to 2.10) for the biceps femoris in the gene therapy cohort. In the placebo group, LSM changes ranged from 1.12 (95% CI, 0.08-2.16) in the soleus to 2.94 (95% CI, 0.84-5.03) in the quadriceps.

The QMR findings were exploratory and hypothesis-generating, the authors noted, adding that they require confirmation in a randomized controlled trial testing a clinically relevant end point. However, considering that muscle fat fraction has been linked with loss of ambulation and the findings align with differences in progression to the 5-second TTR threshold indicative of significant loss of ambulation between the cohorts, there could be implications for ambulation preservation with gene therapy.

“Findings were congruent with results for secondary functional outcomes in the EMBARK trial; MR results were generally consistent across muscle locations and MR sequences, suggesting that delandistrogene moxeparvovec may sustain muscle health and reduce muscle wasting,” the authors concluded. “This work adds to the totality of evidence supporting stabilization or slowing of disease progression with delandistrogene moxeparvovec.”

References

1. Vandenborne K, Walter GA, Straub V, et al. Quantitative muscle magnetic resonance outcomes in patients with Duchenne muscular dystrophy: an exploratory analysis from the EMBARK randomized clinical trial. JAMA Neurol. Published online May 12, 2025. doi:10.1001/jamaneurol.2025.0992
2. Mendell JR, Muntoni F, McDonald CM, et al. AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial. Nat Med. 2025;31(1):332-341. doi:10.1038/s41591-024-03304-z
3. Elevidys. Prescribing information. Sarepta Therapeutics; 2024. Accessed May 14, 2025. https://www.elevidyshcp.com/pi