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Clinical Trial
. 2025 Jul 1;82(7):734-744.
doi: 10.1001/jamaneurol.2025.0992.

Quantitative Muscle Magnetic Resonance Outcomes in Patients With Duchenne Muscular Dystrophy: An Exploratory Analysis From the EMBARK Randomized Clinical Trial

Krista Vandenborne  1 , Glenn A Walter  2 , Volker Straub  3 , Rebecca J Willcocks  1 , Sean C Forbes  1 , Eugenio M Mercuri  4 , Francesco Muntoni  5 , Kai Ding  6 , Sravya Ennamuri  6 , Carol Reid  7 , Alexander P Murphy  7 , Marianna Manfrini  8 , Jerry R Mendell  6   9   10 , Jacob S Elkins  6 , Louise R Rodino-Klapac  6
Affiliations
Clinical Trial

Quantitative Muscle Magnetic Resonance Outcomes in Patients With Duchenne Muscular Dystrophy: An Exploratory Analysis From the EMBARK Randomized Clinical Trial

Krista Vandenborne et al. JAMA Neurol. .

Abstract

Importance: Delandistrogene moxeparvovec is a recombinant adeno-associated virus rhesus isolate serotype 74 vector-based gene transfer therapy for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed pathogenic variant of the DMD gene. In a subset of patients in the EMBARK (A Gene Transfer Therapy Study to Evaluate the Safety and Efficacy of Delandistrogene Moxeparvovec [SRP-9001] in Participants With DMD) randomized clinical trial, changes in muscle health and pathology were assessed to evaluate the therapeutic impact of the treatment on disease progression.

Objective: To determine the effect of delandistrogene moxeparvovec on muscle quantitative magnetic resonance (QMR) measures of disease progression in patients in the EMBARK trial.

Design, setting, and participants: This was a phase 3, double-blind, placebo-controlled (October 2021-September 2023; week 52 cutoff date: September 13, 2023), multicenter randomized clinical trial that included 131 patients. Patients were randomized, and 125 were treated with either delandistrogene moxeparvovec (n = 63) or placebo (n = 62). The current study focused on a subset of patients who underwent muscle QMR imaging.

Intervention: Single-administration intravenous delandistrogene moxeparvovec (1.33 × 1014 vector genome/kg) or placebo.

Main outcomes and measures: Change from baseline to week 52 in muscle MR was a prespecified exploratory end point. Proton MR spectroscopy (MRS) and 8-point Dixon MR imaging (MRI) measured muscle fat fraction (FF); multislice spin echo MRI measured transverse relaxation time (T2). MRS FF was measured in the soleus and vastus lateralis. MRI FF and T2 were measured in 5 leg muscle locations important for ambulation. A post hoc global statistical test combining all muscles and modalities assessed overall treatment effect.

Results: In this exploratory EMBARK analysis, 39 male participants (delandistrogene moxeparvovec, n = 19; placebo, n = 20; mean [SD] age, 6.10 [1.04] years; mean [SD] baseline North Star Ambulatory Assessment total score, 22.99 [3.71] points) underwent muscle MRI. Treated patients showed less disease progression vs placebo on MR measures. Across muscles and modalities, magnitudes of FF change favored delandistrogene moxeparvovec; between-group differences in least-squares mean change ranged from -1.01 (95% CI, -2.79 to 0.77; soleus) to -0.71 (95% CI, -3.21 to 1.80; vastus lateralis) for MRS FF and -3.09 (95% CI, -7.62 to 1.45; vastus lateralis) to -0.44 (95% CI, -4.01 to 3.12; hamstrings) for MRI FF. T2 reductions (improvements; 4 of 5 muscles) were observed in treated patients vs increases (worsening; all muscles) in placebo patients; within-group differences in least-squares mean change ranged from -1.06 (95% CI, -2.10 to -0.02; soleus) to 0.17 (95% CI, -1.76 to 2.10; biceps femoris) in the delandistrogene moxeparvovec group and from 1.12 (95% CI, 0.08-2.16; soleus) to 2.94 (95% CI, 0.84-5.03; quadriceps) in the placebo group. The global statistical test supported treatment benefit (P = .03).

Conclusions and relevance: Results reveal that QMR outcomes consistently favored delandistrogene moxeparvovec across muscle groups, with treatment leading to decreased fat accumulation and improved T2 vs placebo over 52 weeks. Consistent with treatment effects on functional outcomes observed in the EMBARK trial, these results suggest stabilization or less progression of muscle pathology with delandistrogene moxeparvovec-adding to the totality of evidence supporting disease stabilization or slowing of disease progression with delandistrogene moxeparvovec.

Trial registration: ClinicalTrials.gov Identifier: NCT05096221.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Vandenborne reported receiving grants from Sarepta Therapeutics, Italfarmaco SPA, Astellas Pharma, Edgewise Therapeutics, Regenxbio, AskBio, Dyne Therapeutics, and the National Institutes of Health, all awarded to the University of Florida outside the submitted work. Dr Walter reported receiving funds for MR biomarker work from Sarepta Therapeutics to the University of Florida during the conduct of the study. Dr Straub reported receiving grants from Sarepta Therapeutics and advisory board/speaker honoraria from Pfizer outside the submitted work. Dr Willcocks reported receiving funding for data collection from Sarepta Therapeutics provided to the University of Florida during the conduct of the study. Dr Mercuri reported receiving advisory board/speaker fees from Sarepta Therapeutics outside the submitted work. Dr Muntoni reported receiving grants from Sarepta Therapeutics and Généthon and advisory board fees and/or symposia fees from Sarepta Therapeutics, Dyne Therapeutics, PTC Therapeutics, and Solid Bioscience outside the submitted work. Drs Ding, Ennamuri, and Elkins reported being employees of Sarepta Therapeutics Inc. Dr Reid reported owning stock options in F. Hoffmann-La Roche. Dr Murphy reported being employed by Roche Pharmaceuticals. Dr Mendell reported patients participating in the MRI study were treated at Nationwide Children’s Hospital during the conduct of the study, receiving personal fees from Sarepta Therapeutics outside the submitted work, having a patent for AAV delivery of microdystrophin issued, and serving multiple roles in developing the product, treating the patients, and serving as a senior advisor for Sarepta Therapeutics (delandistrogene moxeparvovec was developed under Dr Mendell’s supervision). Dr Rodino-Klapac reported receiving a patent for AAV delivery of muscle-specific micro-dystrophin to treat patients with muscular dystrophy licensed to Sarepta Therapeutics and being an employee of Sarepta Therapeutics. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Change in Magnetic Resonance (MR) End Points at Week 52 (EMBARK Part 1)
A, Change in MR spectroscopy (MRS) fat fraction (FF) at week 52 (EMBARK part 1). B, Change in MR imaging (MRI) FF at week 52 (EMBARK part 1); Dixon water images of the upper leg at baseline and week 52 in 2 patients (1 in the delandistrogene moxeparvovec group and 1 in the placebo group) who had similar FF values in the vastus lateralis at baseline. C, Arrowheads indicate new areas of fat deposition over 52 weeks. D, Change in MRI transverse relaxation time (T2) at week 52 (EMBARK part 1). Data are presented for patients with values at both baseline and week 52. Cutoff date: September 13, 2023.
Figure 2.
Figure 2.. Change in Magnetic Resonance Spectroscopy (MRS) Fat Fraction (FF) and MR Imaging (MRI) FF From Baseline to Week 52 (EMBARK Part 1) by Age Group
A, Change in MRS FF at week 52 by age group. B, Change in MRI FF (%) at week 52 by age group. Data are presented for patients with values at both baseline and week 52. Cutoff date: September 13, 2023.
Figure 3.
Figure 3.. Change in Magnetic Resonance Imaging (MRI) Transverse Relaxation Time (T2) From Baseline to Week 52 (EMBARK Part 1) by Age Group
A, Group aged 4 to 5 years. B, Group aged 6 to 7 years. Data are presented for patients with values at both baseline and week 52. Cutoff date: September 13, 2023.
See this image and copyright information in PMC

References

    1. Duan D, Goemans N, Takeda S, Mercuri E, Aartsma-Rus A. Duchenne muscular dystrophy. Nat Rev Dis Primers. 2021;7(1):13. doi: 10.1038/s41572-021-00248-3 - DOI - PMC - PubMed
    1. Johnson EK, Zhang L, Adams ME, et al. Proteomic analysis reveals new cardiac-specific dystrophin-associated proteins. PLoS One. 2012;7(8):e43515. doi: 10.1371/journal.pone.0043515 - DOI - PMC - PubMed
    1. Pessina P, Cabrera D, Morales MG, et al. Novel and optimized strategies for inducing fibrosis in vivo: focus on Duchenne muscular dystrophy. Skelet Muscle. 2014;4:7. doi: 10.1186/2044-5040-4-7 - DOI - PMC - PubMed
    1. Lechner A, Herzig JJ, Kientsch JG, et al. Cardiomyopathy as cause of death in Duchenne muscular dystrophy: a longitudinal observational study. ERJ Open Res. 2023;9(5):00176-02023. doi: 10.1183/23120541.00176-2023 - DOI - PMC - PubMed
    1. Erkut E, Yokota T. CRISPR therapeutics for Duchenne muscular dystrophy. Int J Mol Sci. 2022;23(3):1832. doi: 10.3390/ijms23031832 - DOI - PMC - PubMed

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