Sarepta Therapeutics : P1350 Mendell et al Pooled Analyses 3 year vs EC

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3-Year Functional Outcomes of Patients With Duchenne Muscular Dystrophy: Pooled Delandistrogene Moxeparvovec Clinical Trial Data vs External Controls

Jerry Mendell1; Anne M. Connolly2; John Day3; Craig McDonald4; Crystal Proud5; Perry Shieh6; Craig Zaidman7; Matthew Furgerson1; Sravya Ennamuri1; Kai Ding1; Carol Reid8; Alexander P. Murphy8; Louise Rodino-Klapac1 Objective

To compare 3-year functional outcomes of ambulatory patients treated in delandistrogene moxeparvovec clinical trials with those of propensity-score-weighted ECs to contextualize long-term treatment effects

Background

Delandistrogene moxeparvovec is an rAAVrh74 vector-based gene transfer therapy for DMD with high affinity for skeletal, respiratory, and cardiac muscles1-4 (Figure 1)
It delivers a transgene encoding delandistrogene moxeparvovec micro-dystrophin,1-4which is approved in the US and other select countries5-11
We previously compared 1-year functional data from patients with DMD who participated in delandistrogene moxeparvovec clinical trials with data from a cohort of well-matched EC patients that suggested a beneficial modification of the DMD disease trajectory in the patients who received treatment5

Figure 1. The unique delandistrogene moxeparvovec construct

′

4,12,13

*ITRs are required for genome replication and packaging. † PolyA signals the end of the transgene to the cellular machinery that transcribes (ie, copies) it.

Methods (cont.)

Statistical analyses

PSW was performed to ensure maximum comparability between the EC cohort and the delandistrogene moxeparvovec groups based on the following baseline parameters (Figure 4):

Age - RFF
NSAA total score - 10MWR

Height
Weight

- BMI

Following PSW, median regression and MMRM analyses were conducted for each of the following functional endpoints comparing delandistrogene moxeparvovec and EC cohorts:
- CFBL at year 3 in NSAA total score
- CFBL at year 3 in RFF (velocity and time)
- CFBL at year 3 in 10MWR (velocity and time)
MMRM was the primary analysis; median regression (shown here, because of the non-normal data distribution) was the sensitivity analysis

Figure 4. External controls cohort before and after PSW*

Before

After

Before PSW (n=83)

After excluding EC patients with non-overlapping propensity scores

(NSAA, n=73; TTR, n=72; 10MWR, n=72)

*PSW involves taking an EC group with similar age and function, but unequal distribution, and ensuring overlap after PSW.

Results (cont.)

Figure 5. 3-year median change from baseline in NSAA total score

Both MMRM (primary analysis; use QR code to access Appendix) and median regression (sensitivity analysis) showed long-term stabilization or slowing of disease progression at 3 years in the pooled treatment group vs the EC cohort, as measured via NSAA total score (Figure 5), RFF time and velocity (Figure 6), and

10MWR time and velocity (Figure 7)

-2

-4

-2.55

-6

-5.55

Delandistrogene moxeparvovec (n=50) EC cohort (n=73)

Figure 6. 3-year median change from baseline in RFF time and velocity

Median Δ (SE): -1.80 (0.32)

P<0.001

Median Δ (SE): 0.06 (0.01)

P<0.001

6 0.00

4.59

-0.04

2.79 -0.03

-0.08

-0.09

-0.12

Delandistrogene moxeparvovec (n=50) Delandistrogene moxeparvovec (n=50)

EC cohort (n=72) EC cohort (n=72)

Figure 7. 3-year median changes from baseline in 10MWR time and velocity

0.0

Median Δ (SE): 0.18 (0.07)

P=0.012

1.82

-0.1

1.42

-0.2

-0.3

-0.22

-0.4

-0.5

-0.40

Delandistrogene moxeparvovec (n=49) EC cohort (n=72)

Median Δ (SE): -0.40 (0.21)

P=0.059

Median Δ (SE): 3.00 (0.80)

P<0.001

RFF time: Median change from BL to year 3 (SE), s

Improvement

RFF velocity: Median change from BL to year 3 (SE), rise/s

NSAA total score: Median change from BL to year 3 (SE)

Improvement

1Sarepta Therapeutics, Inc., Cambridge, MA, USA; 2Chief of Neurology Division, Nationwide Children's Hospital, Columbus, OH, USA, and Professor of Pediatrics at The Ohio State University College of Medicine, Columbus, OH, USA; 3Professor, of Neurology and Neurological Sciences (Adult Neurology), of Pediatrics (Genetics) and, by courtesy, of Pathology, Stanford University, Palo Alto, CA, USA; 4Chair, Department of Physical Medicine & Rehabilitation and Professor, Departments of Pediatrics and Physical Medicine & Rehabilitation, UC Davis, Davis, CA, USA; 5Pediatric Neurologist and Director of Neurology, Children's Hospital of The King's Daughters, Norfolk, VA, USA; 6Neurologist, UCLA Health, Los Angeles, CA, USA; 7Professor of Neurology and of Pediatrics, Washington University in St. Louis, St. Louis, MO, USA; 8Roche Products Ltd, Welwyn Garden City, UK

		Delandistrogene moxeparvovec (n=50)	EC cohort before PSW (n=83)	EC cohort after PSW (n=73)	Standardized mean difference, treatment vs EC after PSW
Age, years	Mean (SD) Median (range)	6.4 (1.30) 6.3 (4.0-8.9)	6.5 (1.0) 6.5 (4.8-8.9)	6.5 (0.74) 6.5 (4.8-8.9)	-0.14
NSAA total score, points	Mean (SD) Median (range)	22.3 (3.7) 22 (13-30)	23.9 (4.4) 24 (13-30)	21.7 (4.0) 21 (13-30)	0.15
RFF time, s	Mean (SD) Median (range)	4.4 (1.8) 3.9 (2.4-10.4)	4.5 (1.6) 4.3 (2.0-10.2)	4.4 (1.2) 4.2 (2.0-10.2)	-0.05
10MWR time, s	Mean (SD) Median (range)	5.1 (1.1) 4.9 (3.5-9.1)	5.3 (1.0) 5.2 (3.6-7.9)	5.1 (0.8) 5.1 (3.6-7.9)	-0.04
Weight, kg	Mean (SD) Median (range)	22.7 (4.7) 22.0 (13.7-34.5)	21.3 (4.8) 20.3 (14.0-39.0)	23.3 (4.0) 22.6 (15.9-35.9)	-0.13
Height, cm	Mean (SD) Median (range)	111.8 (7.7) 113.1 (94.4-124.0)	111.9 (7.6) 111.3 (99.0-142.0)	112.9 (5.2) 113.0 (99.0-130.2)	-0.14
BMI, kg/m2	Mean (SD) Median (range)	18.1 (2.4) 17.5 (13.2-24.6)	16.8 (2.1) 16.4 (13.7-22.5)	18.2 (2.1) 17.5 (13.7-22.5)	-0.06

Acknowledgments

The authors would like to thank the patients, their families, the investigators, and trial staff for their participation in the

delandistrogene moxeparvovec studies. Studies 101 and 102 and ENDEAVOR are sponsored and funded by Sarepta Therapeutics, Inc., Cambridge, MA, USA. ENDEAVOR is also funded by

F. Hoffmann-La Roche Ltd, Basel, Switzerland. Medical writing and

editorial assistance were provided by Srividya Venkitachalam, PhD (HCG), in accordance with Good Publication Practice (GPP)

2022 guidelines (https://www.ismpp.org/gpp-2022) and were funded by Sarepta Therapeutics Inc., Cambridge, MA, USA, and F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Disclosures

JM has received study funding from Sarepta Therapeutics and has a service agreement with Sarepta Therapeutics to provide training on ongoing studies. JM is a co-inventor of AAVrh74.MHCK7.micro-dys technology. AMC has received study funding from Sarepta paid to Nationwide Children's Hospital and has served on advisory boards for Sarepta and Edgewise and DMSB for Avidity Biosciences. JD reports grants from AMO, Audentes, Avidity, Biogen, Cytokinetics, Ionis Pharmaceuticals, Novartis Gene Therapies, Roche Pharmaceuticals, Sanofi-Genzyme, Sarepta Therapeutics, and Scholar Rock. JD participates on advisory boards and is a consultant for Affinia Therapeutics, AMO Pharmaceuticals, Astellas Gene Therapies, Audentes Therapeutics, Avidity Therapeutics, Biogen, Cytokinetics, Epirium Bio, Ionis Pharmaceuticals,

Kate Therapeutics, Novartis, Novartis Gene Therapies, Pfizer, Roche/Genentech Pharmaceuticals, Sarepta Therapeutics, Scholar Rock, Shift Therapeutics, and Vertex. JD participated in the PepGen Scientific Advisory Board (2021). JD was a paid advisor to the Muscular Dystrophy

Association and an unpaid advisor to the Myotonic Dystrophy Foundation, Cure SMA, SMA Foundation, Parents Project Muscular Dystrophy, Foundation Building Strength for Nemaline Myopathy, Cure CMD, and Solve FSHD. JD holds patents licensed to Athena Diagnostics for genetic testing of myotonic dystrophy type 2 (US patent 7442782) and spinocerebellar ataxia type 5 (US patent 7527931). CM reports grants from Capricor, Catabasis, Edgewise, Epirium Bio, Italfarmaco, Pfizer, PTC Therapeutics, Santhera Pharmaceuticals, Sarepta Therapeutics; and other support from Capricor, Catabasis, PTC Therapeutics, Santhera Pharmaceuticals, and Sarepta Therapeutics. CP participates on an advisory board and is a consultant for Biogen, Sarepta Therapeutics, AveXis/Novartis Gene Therapies, Genentech/Roche, and Scholar Rock;

serves as a speaker for Biogen; is PI of studies sponsored by AveXis/Novartis Gene Therapies, AMO, Astellas, Biogen, CSL Behring, FibroGen, PTC Therapeutics, Pfizer, Sarepta Therapeutics, and Scholar Rock. PS reports being a consultant/independent contractor for AveXis, Biogen, Cytokinetics, and Sarepta Therapeutics and receiving grants/research support from AveXis, Biogen, Cytokinetics, Ionis Pharmaceuticals, Sanofi Genzyme, and Sarepta Therapeutics. CZ receives research support from Biogen and Novartis, serves on an advisory board for Biogen, receives speaker fees from Sarepta Therapeutics, and was a paid consultant for Optum. LRK is an employee of Sarepta Therapeutics and has received grant support from Sarepta Therapeutics and the Parent Project Muscular Dystrophy and financial consideration from Sarepta Therapeutics and Myonexus Therapeutics (now acquired by Sarepta Therapeutics). In addition, she is a co-inventor of AAVrh74.MHCK7.micro-dys technology. JM, MF, KD, and SE are employees of Sarepta Therapeutics Inc., and may own stock and / or stock options in the company. CR and APM are employees of F. Hoffmann-La Roche Ltd and may have stock options. Previously presented at the Muscular Dystrophy Association (MDA) Clinical and Scientific Conference; March 16-19, 2025; Dallas, TX, USA.

Abbreviations

10MWR, 10-meter walk/run; rAAVrh74, recombinant adeno-associated virus rhesus isolate serotype 74; BL, baseline; BMI, body mass index; CFBL, changes from baseline; CINRG, Cooperative International Neuromuscular Research Group;

DMD, Duchenne muscular dystrophy; DNHS, Duchenne Natural History Study;

EC, external control; FOR-DMD, Finding the Optimum Regimen for Duchenne Muscular Dystrophy; ITR, inverted terminal repeat; LSM, least-squares mean; MMRM, mixed-effects model for repeated measures; NSAA, North Star Ambulatory Assessment; NT, N-terminal; poly A, polyadenylation; PSW, propensity-score weighting; RFF, rise from floor; SD, standard deviation; SE, standard error;

ssDNA, single-stranded DNA; TTR, time to rise; vg, vector genome.

References

Mendell JR, et al. JAMA Neurol. 2020;77:1122-1131. 8. ClinicalTrials.gov identifier: NCT04626674. Updated August 26, 2024. Accessed February 23, 2025.
Asher DR, et al. Expert Opin Biol Ther. 2020;20:263-274. https://www.clinicaltrials.gov/study/NCT04626674.
Zheng C and Baum BJ. Methods Mol Biol. 2008;434:205-219. 9. ClinicalTrials.gov identifier: NCT01603407. Updated August 12, 2022. Accessed February 23, 2025.
Mendell JR, et al. Pediatr Neurol. 2024;153:11-18. https://clinicaltrials.gov/study/NCT01603407. https://clinicaltrials.gov/study/NCT01603407.
Proud CM, et al. Poster presented at: Muscular Dystrophy Association (MDA) Clinical and 10. ClinicalTrials.gov identifier: NCT01865804. Updated December 8, 2017. Accessed Scientific Conference 2023; March19-22, 2023; Dallas, TX. Poster 106. February 23, 2025. https://clinicaltrials.gov/study/NCT01753804.
ClinicalTrials.gov identifier NCT03375164. Updated November 14, 2024. Accessed 11. ClinicalTrials.gov identifier: NCT00468832. Updated April 21, 2016. Accessed February 23, 2025.
February 23, 2025. https://www.clinicaltrials.gov/study/NCT03375164. https://clinicaltrials.gov/study/NCT00468832.
ClinicalTrials.gov identifier: NCT03769116. Updated November 14, 2024. Accessed 12. Duan D. Mol Ther. 2018;26:2337-2356.

February 23, 2025. https://www.clinicaltrials.gov/study/NCT03769116. 13. Deng J, et al. Front Pharmacol. 2022;13:950651.

The QR code is intended to provide scientific information for individual reference, and the information should not be altered or reproduced in any way.

Methods

Analysis set

Functional outcomes data were pooled from 50 patients with DMD enrolled in 3 studies (Figure 2)

Figure 2. Sources of clinical trial data

Study 101 (NCT03375164, n=4)6

Study 102 (NCT03769116, n=26)7

ENDEAVOR Cohort 1 (NCT04626674, n=20)8

Delandistrogene moxeparvovec (n=50)

EC cohort, before PSW, included 83 patients with DMD pooled from 3 natural history and clinical trial studies (Figure 3)

Figure 3. Sources of external control data

FOR-DMD (NCT01603407, n=68)9,*

BioMarin PRO-DMD-01 (NCT01753804, n=12)10,*

CINRG DNHS (NCT00468832, n=3)11,*

EC (n=83)

*Only the patients who were receiving a stable corticosteroid regimen were included in the EC cohort. † May also be referred to as TTR.

Prospective natural history study

Prospective natural history study in ambulatory/ non-ambulatory patients with DMD

Phase 3 randomized trial in ambulatory patients with DMD on corticosteroid regimens

Phase1b study of delandistrogene moxeparvovec in ambulatory patients with DMD

Phase 2 study of delandistrogene moxeparvovec in ambulatory patients with DMD

Phase 1/2 study of delandistrogene moxeparvovec in ambulatory patients with DMD

Entry criteria

Age at baseline: ≥4 to <9 years
NSAA total score: ≥13 and ≤30 points
RFF† time: ≤10.4 s
10MWR time: ≤9.1 s
Stable corticosteroid dose: ≥12 weeks
Had both a baseline value and a year 3

post-baseline value

Entry criteria

Target dose: 1.33×1014 vg/kg
Age at dosing: ≥4 to <9 years
Had both a baseline value and a year 3

post-baseline value

Results

Pooled treatment group and EC cohort had similar baseline covariate values after PSW (Table 1)

Table 1. Baseline covariates before and after propensity-score weighting (3-year total analysis sets)

Conclusions

At 3 years, patients treated with delandistrogene moxeparvovec demonstrated long-term stabilization or slowing of disease progression compared with a well-matched EC cohort, as measured via NSAA total score, RFF time and velocity, and 10MWR time and velocity, and analyzed using MMRM and median regression
These data suggest that delandistrogene moxeparvovec has a clinically meaningful long-term impact on the disease course of DMD, modifying its trajectory relative to the natural history of the disease

10MWR time: Median change from BL to year 3 (SE), s

Improvement

10MWR velocity: Median change from BL to year 3 (SE), m/s

Improvement

Presented at the American Society of Gene and Cell Therapy (ASGCT) 28th Annual Meeting; May 13-17, 2025; New Orleans, LA, USA.

3-Year Functional Outcomes of Patients With Duchenne Muscular Dystrophy: Pooled Delandistrogene Moxeparvovec Clinical Trial Data vs External Controls

Supplementary Information

Appendix:

Changes in NSAA Total Score, RFF Time and Velocity, and 10MWR Time and Velocity (MMRM)

NSAA Total Score RFF Time RFF Velocity 10MWR Time 10MWR Velocity

LSM Δ (SE): 2.96 (1.40)

P=0.038

NSAA total score: LSM change from BL to year 3 (SE) 0 -2

-1.36

-4 -6

Improvement

-4.32

LSM Δ (SE): -3.99 (1.62)

P=0.016

RFF time: LSM change from BL to year 3 (SE), s 10 8

6 4.63

4 2 0

Improvement

8.62

0.00 RFF velocity: LSM change from BL to year 3 (SE), rise/s -0.04 -0.08 -0.12

-0.04

-0.10

6 10MWR time: LSM change from BL to year 3 (SE), s

3.53

4 2 0

LSM Δ (SE): 0.32 (0.12)

P=0.009

LSM Δ (SE): -1.26 (1.30)

P=0.335

LSM Δ (SE): 0.06 (0.02)

P=0.001

4.79

0.0 10MWR velocity: LSM change from BL to year 3 (SE), m/s -0.2 -0.4 -0.6

-0.23

-0.55

Delandistrogene moxeparvovec (n=50)

EC cohort (n=73)

Delandistrogene moxeparvovec (n=50)

EC cohort (n=72)

Delandistrogene moxeparvovec (n=50)

EC cohort (n=72)

Delandistrogene moxeparvovec (n=49)

EC cohort (n=72)

Delandistrogene moxeparvovec (n=49)

EC cohort (n=72)

Acknowledgments

The authors would like to thank the patients, their families, the investigators, and trial staff for their participation in the

delandistrogene moxeparvovec studies. Studies 101 and 102 and ENDEAVOR are sponsored and funded by Sarepta Therapeutics, Inc., Cambridge, MA, USA. ENDEAVOR is also funded by

F. Hoffmann-La Roche Ltd, Basel, Switzerland. Medical writing and

editorial assistance were provided by Srividya Venkitachalam, PhD (HCG), in accordance with Good Publication Practice (GPP)

2022 guidelines (https://www.ismpp.org/gpp-2022) and were funded by Sarepta Therapeutics Inc., Cambridge, MA, USA, and F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Disclosures

Abbreviations

DMD, Duchenne muscular dystrophy; DNHS, Duchenne Natural History Study;

ssDNA, single-stranded DNA; TTR, time to rise; vg, vector genome.

References

Mendell JR, et al. JAMA Neurol. 2020;77:1122-1131. 8. ClinicalTrials.gov identifier: NCT04626674. Updated August 26, 2024. Accessed February 23, 2025.
Asher DR, et al. Expert Opin Biol Ther. 2020;20:263-274. https://www.clinicaltrials.gov/study/NCT04626674.
Zheng C and Baum BJ. Methods Mol Biol. 2008;434:205-219. 9. ClinicalTrials.gov identifier: NCT01603407. Updated August 12, 2022. Accessed February 23, 2025.
Mendell JR, et al. Pediatr Neurol. 2024;153:11-18. https://clinicaltrials.gov/study/NCT01603407. https://clinicaltrials.gov/study/NCT01603407.
Proud CM, et al. Poster presented at: Muscular Dystrophy Association (MDA) Clinical and 10. ClinicalTrials.gov identifier: NCT01865804. Updated December 8, 2017. Accessed Scientific Conference 2023; March19-22, 2023; Dallas, TX. Poster 106. February 23, 2025. https://clinicaltrials.gov/study/NCT01753804.
ClinicalTrials.gov identifier NCT03375164. Updated November 14, 2024. Accessed 11. ClinicalTrials.gov identifier: NCT00468832. Updated April 21, 2016. Accessed February 23, 2025.
February 23, 2025. https://www.clinicaltrials.gov/study/NCT03375164. https://clinicaltrials.gov/study/NCT00468832.
ClinicalTrials.gov identifier: NCT03769116. Updated November 14, 2024. Accessed 12. Duan D. Mol Ther. 2018;26:2337-2356.

February 23, 2025. https://www.clinicaltrials.gov/study/NCT03769116. 13. Deng J, et al. Front Pharmacol. 2022;13:950651.

The QR code is intended to provide scientific information for individual reference, and the information should not be altered or reproduced in any way.

Presented at the American Society of Gene and Cell Therapy (ASGCT) 28th Annual Meeting; May 13-17, 2025; New Orleans, LA, USA.

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