Expression of SRP-9001 dystrophin and stabilization of motor function up to 2 years post-treatment with delandistrogene moxeparvovec gene therapy in individuals with Duchenne muscular dystrophy
Copyright © 2023 Mendell, Shieh, McDonald, Sahenk, Lehman, Lowes, Reash, Iammarino, Alfano, Sabo, Woods, Skura, Mao, Staudt, Griffin, Lewis, Wang, Potter, Singh and Rodino-Klapac..
Introduction: Delandistrogene moxeparvovec (SRP-9001) is an investigational gene transfer therapy designed for targeted expression of SRP-9001 dystrophin protein, a shortened dystrophin retaining key functional domains of the wild-type protein. Methods: This Phase 2, double-blind, two-part (48 weeks per part) crossover study (SRP-9001-102 [Study 102]; NCT03769116) evaluated delandistrogene moxeparvovec in patients, aged ≥4 to <8 years with Duchenne muscular dystrophy. Primary endpoints (Part 1) were change from baseline (CFBL) in SRP-9001 dystrophin expression (Week 12), by Western blot, and in North Star Ambulatory Assessment (NSAA) score (Week 48). Safety assessments included treatment-related adverse events (TRAEs). Patients were randomized and stratified by age to placebo (n = 21) or delandistrogene moxeparvovec (n = 20) and crossed over for Part 2. Results: SRP-9001 dystrophin expression was achieved in all patients: mean CFBL to Week 12 was 23.82% and 39.64% normal in Parts 1 and 2, respectively. In Part 1, CFBL to Week 48 in NSAA score (least-squares mean, LSM [standard error]) was +1.7 (0.6) with treatment versus +0.9 (0.6) for placebo; p = 0.37. Disparity in baseline motor function between groups likely confounded these results. In 4- to 5-year-olds with matched baseline motor function, CFBL to Week 48 in NSAA scores was significantly different (+2.5 points; p = 0.0172), but not significantly different in 6-to-7-year-olds with imbalanced baseline motor function (-0.7 points; p = 0.5384). For patients treated with delandistrogene moxeparvovec in Part 2, CFBL to Week 48 in NSAA score was +1.3 (2.7), whereas for those treated in Part 1, NSAA scores were maintained. As all patients in Part 2 were exposed to treatment, results were compared with a propensity-score-weighted external control (EC) cohort. The LSM difference in NSAA score between the Part 2 treated group and EC cohort was statistically significant (+2.0 points; p = 0.0009). The most common TRAEs were vomiting, decreased appetite, and nausea. Most occurred within the first 90 days and all resolved. Discussion: Results indicate robust expression of SRP-9001 dystrophin and overall stabilization in NSAA up to 2 years post-treatment. Differences in NSAA between groups in Part 1 were not significant for the overall population, likely because cohorts were stratified only by age, and other critical prognostic factors were not well matched at baseline.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
Frontiers in cell and developmental biology - 11(2023) vom: 01., Seite 1167762 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mendell, Jerry R [VerfasserIn] |
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| Links: |
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| Themen: |
AAVrh74 |
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| Anmerkungen: |
Date Revised 28.07.2023 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.3389/fcell.2023.1167762 |
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| Förderinstitution / Projekttitel: |
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NLM359974880 |
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| 100 | 1 | |a Mendell, Jerry R |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Expression of SRP-9001 dystrophin and stabilization of motor function up to 2 years post-treatment with delandistrogene moxeparvovec gene therapy in individuals with Duchenne muscular dystrophy |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Revised 28.07.2023 | ||
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| 520 | |a Copyright © 2023 Mendell, Shieh, McDonald, Sahenk, Lehman, Lowes, Reash, Iammarino, Alfano, Sabo, Woods, Skura, Mao, Staudt, Griffin, Lewis, Wang, Potter, Singh and Rodino-Klapac. | ||
| 520 | |a Introduction: Delandistrogene moxeparvovec (SRP-9001) is an investigational gene transfer therapy designed for targeted expression of SRP-9001 dystrophin protein, a shortened dystrophin retaining key functional domains of the wild-type protein. Methods: This Phase 2, double-blind, two-part (48 weeks per part) crossover study (SRP-9001-102 [Study 102]; NCT03769116) evaluated delandistrogene moxeparvovec in patients, aged ≥4 to <8 years with Duchenne muscular dystrophy. Primary endpoints (Part 1) were change from baseline (CFBL) in SRP-9001 dystrophin expression (Week 12), by Western blot, and in North Star Ambulatory Assessment (NSAA) score (Week 48). Safety assessments included treatment-related adverse events (TRAEs). Patients were randomized and stratified by age to placebo (n = 21) or delandistrogene moxeparvovec (n = 20) and crossed over for Part 2. Results: SRP-9001 dystrophin expression was achieved in all patients: mean CFBL to Week 12 was 23.82% and 39.64% normal in Parts 1 and 2, respectively. In Part 1, CFBL to Week 48 in NSAA score (least-squares mean, LSM [standard error]) was +1.7 (0.6) with treatment versus +0.9 (0.6) for placebo; p = 0.37. Disparity in baseline motor function between groups likely confounded these results. In 4- to 5-year-olds with matched baseline motor function, CFBL to Week 48 in NSAA scores was significantly different (+2.5 points; p = 0.0172), but not significantly different in 6-to-7-year-olds with imbalanced baseline motor function (-0.7 points; p = 0.5384). For patients treated with delandistrogene moxeparvovec in Part 2, CFBL to Week 48 in NSAA score was +1.3 (2.7), whereas for those treated in Part 1, NSAA scores were maintained. As all patients in Part 2 were exposed to treatment, results were compared with a propensity-score-weighted external control (EC) cohort. The LSM difference in NSAA score between the Part 2 treated group and EC cohort was statistically significant (+2.0 points; p = 0.0009). The most common TRAEs were vomiting, decreased appetite, and nausea. Most occurred within the first 90 days and all resolved. Discussion: Results indicate robust expression of SRP-9001 dystrophin and overall stabilization in NSAA up to 2 years post-treatment. Differences in NSAA between groups in Part 1 were not significant for the overall population, likely because cohorts were stratified only by age, and other critical prognostic factors were not well matched at baseline | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a AAVrh74 | |
| 650 | 4 | |a Duchenne muscular dystrophy | |
| 650 | 4 | |a SRP-9001 | |
| 650 | 4 | |a dystrophin | |
| 650 | 4 | |a gene therapy | |
| 700 | 1 | |a Shieh, Perry B |e verfasserin |4 aut | |
| 700 | 1 | |a McDonald, Craig M |e verfasserin |4 aut | |
| 700 | 1 | |a Sahenk, Zarife |e verfasserin |4 aut | |
| 700 | 1 | |a Lehman, Kelly J |e verfasserin |4 aut | |
| 700 | 1 | |a Lowes, Linda P |e verfasserin |4 aut | |
| 700 | 1 | |a Reash, Natalie F |e verfasserin |4 aut | |
| 700 | 1 | |a Iammarino, Megan A |e verfasserin |4 aut | |
| 700 | 1 | |a Alfano, Lindsay N |e verfasserin |4 aut | |
| 700 | 1 | |a Sabo, Brenna |e verfasserin |4 aut | |
| 700 | 1 | |a Woods, Jeremy D |e verfasserin |4 aut | |
| 700 | 1 | |a Skura, Christy L |e verfasserin |4 aut | |
| 700 | 1 | |a Mao, Howard C |e verfasserin |4 aut | |
| 700 | 1 | |a Staudt, Loretta A |e verfasserin |4 aut | |
| 700 | 1 | |a Griffin, Danielle A |e verfasserin |4 aut | |
| 700 | 1 | |a Lewis, Sarah |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Shufang |e verfasserin |4 aut | |
| 700 | 1 | |a Potter, Rachael A |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Teji |e verfasserin |4 aut | |
| 700 | 1 | |a Rodino-Klapac, Louise R |e verfasserin |4 aut | |
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