Genotype‐related respiratory progression in Duchenne muscular dystrophy—A multicenter international study

Trucco, Federica; Ridout, Deborah; Domingos, Joana; Maresh, Kate; Chesshyre, Mary; Munot, Pinki; Sárközy, Anna; Robb, Stephanie; Quinlivan, R.; Riley, Mollie; Wallis, Colin; Chan, Elaine; Abel, François; Lucia, Silvana De; Hogrel, Jean‐Yves; Niks, Erik H.; Groot, I. de; Servais, Laurent; Straub, Volker; Ricotti, Valeria; Muntoni, Francesco

doi:10.1002/mus.27427

Cited by 8 publications

(9 citation statements)

References 26 publications

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“…These results are consistent in both the main and sensitivity analyses with different patient samples. The estimated annualized slope of FVC%p decline for SoC patients in this analysis is similar to that estimated for patients aged 8 to 11 years in the study by Humbertclaude et al, who used the French Dystrophinophathy database,21 and that estimated for patients amenable to exon 51 skipping in the study by Trucco et al, who used the UK NorthStar and AFM Network databases 22.…”

supporting

confidence: 81%

Delays in pulmonary decline in eteplirsen‐treated patients with Duchenne muscular dystrophy

et al. 2022

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Introduction/Aims Pulmonary decline is a major issue in patients with Duchenne muscular dystrophy (DMD). Eteplirsen is a United States–approved treatment for patients with DMD and exon 51 skip‐amenable mutations. Previous analyses have shown that eteplirsen is associated with a statistically significant attenuation of pulmonary decline. In this study we evaluate the effect of eteplirsen treatment from newly available data sources on pulmonary function over time in patients with DMD. Methods We used a post hoc pooled analysis to compare the percentage of predicted forced vital capacity (FVC%p) and projected time with pulmonary function milestones in patients with DMD and exon 51 skip‐amenable mutations receiving eteplirsen (Studies 204 and 301) or standard of care (SoC; Cooperative International Neuromuscular Research Group Duchenne Natural History Study). A mixed model for repeated‐measures framework was applied to evaluate the impact of eteplirsen. Results An average annual rate of FVC%p decline for eteplirsen‐treated patients was estimated to be 3.47%, a statistically significant attenuation from the 5.95% rate of decline estimated in SoC patients (P = .0001). Using linear extrapolations of the model‐estimated decline in FVC%p, the attenuation in FVC%p decline for eteplirsen‐treated patients corresponded to a delay of 5.72 years in time to needing continuous ventilation, 3.31 years in time to needing nighttime ventilation, and 2.11 years in time to needing a cough assist device compared with SoC patients. Discussion The attenuation of FVC%p decline suggests that eteplirsen‐treated patients had statistically significant and clinically meaningful attenuations in pulmonary decline compared with SoC patients.

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confidence: 81%

Delays in pulmonary decline in eteplirsen‐treated patients with Duchenne muscular dystrophy

et al. 2022

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“…Alongside these challenges, though, are potentially good reasons for clinical trials to include genotypically matched control groups, as has been typical in DMD trials. 12,16,19 DMD genotype classes have shown clinically important associations with DMD disease progression, [22][23][24][25][26][27] including differences of up to 1 or more years of age at loss of functional milestones (e.g., for patients with deletions that would be reframed with exon 44 skipping). 7,25 Genotypically matched controls aim to ensure that genotype effects do not confound treatment effects.…”

Section: Discussionmentioning

confidence: 99%

“…To replicate known genotype-phenotype associations 7,[22][23][24][25] in our pooled database, we first studied associations between genotypes amenable to skipping of exons 44 or 51 and an ambulatory milestone (time to 10MWR >10 seconds). Specifically, we compared age at first recorded 10MWR >10 seconds using Kaplan-Meier curves stratified by genotype with comparisons based on a log-rank test.…”

Section: Genotype Associations With An Ambulatory Milestone From 2 Di...mentioning

confidence: 99%

“…The DMD Italian Group: Elena Mazzone (clinical evaluator; Child Neurology Unit e Centro Nemo, IRCCS Fondazione Policlinico Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy), Lavinia Fanelli (clinical evaluator; Child Neurology Unit e Centro Nemo, IRCCS Fondazione Policlinico Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy), Filippo Cavallaro (clinical evaluator; University of Messina, Italy), Adelina Carlesi (clinical evaluator; Bambino Gesù Children's Hospital, Rome, Italy), Maria Teresa Arnoldi (clinical evaluator; Instituto Neurologico "Besta" Milan, Italy), and Valentina Lanzillotta (clinical evaluator; G. Gaslini Institute, Genova, Italy). Part of the study materials was previously presented as a poster at the 26th International Annual Congress of the World Muscle Society, September [20][21][22][23][24]2021.…”

Section: Study Fundingmentioning

confidence: 99%

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DMD Genotypes and Motor Function in Duchenne Muscular Dystrophy

et al. 2023

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Background and Objectives:Clinical trials of genotype-targeted treatments in Duchenne muscular dystrophy (DMD) traditionally compare treated patients to untreated patients with the sameDMDgenotype class. This avoids confounding of drug efficacy by genotype effects but also shrinks the pool of eligible controls, increasing challenges for trial enrollment in this already rare disease. To evaluate the suitability of genotypically unmatched controls in DMD, we quantified effects of genotype class on 1-year changes in motor function endpoints used in clinical trials.Methods:Over 1,600 patient-years of follow-up (>700 patients) were studied from six real-world/natural history data sources (UZ Leuven, PRO-DMD-01 shared by CureDuchenne, iMDEX, North Star UK, Cincinnati Children’s Hospital Medical Center, and the DMD Italian Group), with genotypes classified as amenable to skipping exons 44, 45, 51 or 53, other skippable, nonsense, and other mutations. Associations between genotype class and 1-year changes in North Star Ambulatory Assessment total score (ΔNSAA) and in 10-meter walk/run velocity (Δ10MWR) were studied in each data source with and without adjustment for baseline prognostic factors.Results:The studied genotype classes accounted for approximately 2% of variation in ΔNSAA outcomes after 12 months, whereas other prognostic factors explained >30% of variation in large data sources. Based on a meta-analysis across all data sources, pooled effect estimates for the studied skip-amenable mutation classes were all small in magnitude (<2 units in ΔNSAA total score in 1-year follow up), smaller than clinically important differences in NSAA, and were precisely estimated with standard errors <1 unit after adjusting for non-genotypic prognostic factors.Discussion:These findings suggest viability of trial designs incorporating genotypically mixed or unmatched controls for up to 12 months in duration for motor function outcomes, which would ease recruitment challenges and reduce numbers of patients assigned to placebos. Such trial designs, including multi-genotype platform trials and hybrid designs, should ensure baseline balance between treatment and control groups for the most important prognostic factors, while accounting for small remaining genotype effects quantified in the present study.

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“…Additionally, owing to the non-existence of a comparator population including a correspondingly large number of patients with nmDMD, a limitation of these analyses is that the STRIDE and CINRG DNHS patients were not matched based on mutation type or location, which have been reported to affect DMD progression [ 28 – 30 ]. Therefore, the best possible alternatives of the most routinely captured disease progression predictor data were used as covariates.…”

Section: Discussionmentioning

confidence: 99%

Safety and effectiveness of ataluren in patients with nonsense mutation DMD in the STRIDE Registry compared with the CINRG Duchenne Natural History Study (2015–2022): 2022 interim analysis

Osorio¹,

Muntoni²,

Buccella³

et al. 2023

J Neurol

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Objective Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, international, multicenter registry of real-world ataluren use in individuals with nonsense mutation Duchenne muscular dystrophy (nmDMD) in clinical practice. This updated interim report (data cut-off: January 31, 2022), describes STRIDE patient characteristics and ataluren safety data, as well as the effectiveness of ataluren plus standard of care (SoC) in STRIDE versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS). Methods Patients are followed up from enrollment for at least 5 years or until study withdrawal. Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established predictors of disease progression. Results As of January 31, 2022, 307 patients were enrolled from 14 countries. Mean (standard deviation [SD]) ages at first symptoms and at genetic diagnosis were 2.9 (1.7) years and 4.5 (3.7) years, respectively. Mean (SD) duration of ataluren exposure was 1671 (56.8) days. Ataluren had a favorable safety profile; most treatment-emergent adverse events were mild or moderate and unrelated to ataluren. Kaplan–Meier analyses demonstrated that ataluren plus SoC significantly delayed age at loss of ambulation by 4 years (p < 0.0001) and age at decline to %-predicted forced vital capacity of < 60% and < 50% by 1.8 years (p = 0.0021) and 2.3 years (p = 0.0207), respectively, compared with SoC alone. Conclusion Long-term, real-world treatment with ataluren plus SoC delays several disease progression milestones in individuals with nmDMD. NCT02369731; registration date: February 24, 2015.

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Genotype‐related respiratory progression in Duchenne muscular dystrophy—A multicenter international study

Cited by 8 publications

References 26 publications

Delays in pulmonary decline in eteplirsen‐treated patients with Duchenne muscular dystrophy

Delays in pulmonary decline in eteplirsen‐treated patients with Duchenne muscular dystrophy

DMD Genotypes and Motor Function in Duchenne Muscular Dystrophy

Safety and effectiveness of ataluren in patients with nonsense mutation DMD in the STRIDE Registry compared with the CINRG Duchenne Natural History Study (2015–2022): 2022 interim analysis

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