Ambulatory capacity and disease progression as measured by the 6-minute-walk-distance in Duchenne muscular dystrophy subjects on daily corticosteroids

Goemans, Nathalie; Hauwe, M. van den; Wilson, Rosamund; Impe, Annelies van; Klingels, Katrijn; Buyse, Gunnar

doi:10.1016/j.nmd.2013.05.006

Cited by 63 publications

(89 citation statements)

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“…The previously reported age dichotomy15, 26 observed for the general DMD population was confirmed for the subpopulation of patients with genotypes amenable to exon skipping (see Fig 3A). Consistent with previous reports, patients <7 years of age showed improvement over the first 2 years of observation, followed by a decline (although remaining above the baseline value by 25m) between months 24 and 36.…”

Section: Resultssupporting

confidence: 78%

“…It has been previously suggested that disease severity may be affected by mutation type,25 and multiple publications have demonstrated an age‐dependent change in disease trajectory, showing that when younger than 7 years, boys with DMD experience a steady increase in 6MWT distance, whereas boys aged ≥7 years experience progressive decline 15, 26. In the current study, the pooled historical control data set was analyzed to further elucidate the effect of mutation type and age on disease progression to further the field's understanding of DMD disease progression and to identify the most comparable patient subset for comparison to the eteplirsen‐treated cohort.…”

Section: Resultsmentioning

confidence: 99%

“…Patient‐level historical control data were provided by E.M. on behalf of the Italian DMD Registry database,26 and N.G 15…”

Section: Methodsmentioning

confidence: 99%

“…Understanding of DMD disease progression as measured by 6MWT has increased in recent years with publications of natural history data14, 15, 16, 17, 18, 19 as well as placebo‐arm reporting from DMD trials 20, 21, 22. Published data support that on average, 6MWT distance is stable or increases in patients <7 years of age, whereas it declines in older patients 15, 17, 18, 23, 24. Evidence also suggests that DMD genotype may influence disease severity 25…”

mentioning

confidence: 99%

“…Given that there is no control group in the open label, long‐term extension study, eteplirsen's effect on disease progression as measured by 6MWT was evaluated by comparison to matched historical controls from 2 DMD natural history cohorts: the Leuven Neuromuscular Reference Center (LNMRC) and the Italian Telethon registry 15, 26. These 2 investigator‐initiated studies are the only DMD natural history data sets that have prospectively and consistently collected 6MWT assessments for a substantial number of patients for 36 months or longer.…”

mentioning

confidence: 99%

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Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

Mendell

Goemans²,

Lowes

et al. 2016

Annals of Neurology

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392

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ObjectiveTo continue evaluation of the long‐term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy (DMD). Three‐year progression of eteplirsen‐treated patients was compared to matched historical controls (HC).MethodsAmbulatory DMD patients who were ≥7 years old and amenable to exon 51 skipping were randomized to eteplirsen (30/50mg/kg) or placebo for 24 weeks. Thereafter, all received eteplirsen on an open‐label basis. The primary functional assessment in this study was the 6‐Minute Walk Test (6MWT). Respiratory muscle function was assessed by pulmonary function testing (PFT). Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use, and genotype.ResultsAt 36 months, eteplirsen‐treated patients (n = 12) demonstrated a statistically significant advantage of 151m (p < 0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (n = 13) amenable to exon 51 skipping. PFT results remained relatively stable in eteplirsen‐treated patients. Eteplirsen was well tolerated. Analysis of HC confirmed the previously observed change in disease trajectory at age 7 years, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable. The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping.InterpretationOver 3 years of follow‐up, eteplirsen‐treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC. Ann Neurol 2016;79:257–271

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Section: Resultssupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

“…Patient‐level historical control data were provided by E.M. on behalf of the Italian DMD Registry database,26 and N.G 15…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

Mendell

Goemans²,

Lowes

et al. 2016

Annals of Neurology

Self Cite

453

392

View full text Add to dashboard Cite

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Placebo‐controlled Phase 2 Trial of Drisapersen for Duchenne Muscular Dystrophy

McDonald

Wong

Flanigan

et al. 2018

Ann Clin Transl Neurol

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ObjectiveThis double‐blind, randomized, placebo‐controlled Phase 2 study (NCT01462292) assessed the 24‐week efficacy, safety, tolerability, and pharmacokinetics of two different subcutaneous drisapersen doses, and the 24‐week off‐dose persistent effect, in ambulant Duchenne muscular dystrophy (DMD) patients.MethodsMale DMD patients (≥5 years; time to rise from floor ≤15 s) were randomized to drisapersen 3 mg/kg/week, 6 mg/kg/week or placebo. The primary efficacy endpoint was change from baseline in 6‐minute walking distance (6MWD) at week 24. Secondary endpoints included changes in timed function tests, muscle strength, and pulmonary function tests.ResultsFifty‐one patients were randomized to placebo (N = 16), drisapersen 3 mg/kg/week (N = 17) or 6 mg/kg/week (N = 18). All but 2 patients had baseline rise from floor time <7 s. This study was exploratory and not prospectively powered; however, a difference in mean 6MWD versus placebo in favor of drisapersen 6 mg/kg/week was observed at week 24 (27.1 m; P = 0.069) and maintained 24 weeks off‐treatment (27.9 m; P = 0.177). The 3 mg/kg/week group showed no statistically significant difference in mean 6MWD versus placebo. For some secondary endpoints, a more positive response in favor of drisapersen 6 mg/kg/week compared to placebo was shown. Drisapersen had a long half‐life with steady state reached after approximately 36 weeks. Most common adverse events in both drisapersen groups were related to injection site reactions and subclinical proteinuria.InterpretationDrisapersen 6 mg/kg/week for 24 weeks resulted in a treatment benefit in 6MWD, largely maintained 24 weeks off‐treatment. This study provided insights for further studies to optimize dosage regimen.

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Seeking a better landscape for therapy development in neuromuscular disorders

Larkindale

Porter

2017

Muscle and Nerve

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Although the neuromuscular field has seen accelerated approval of a drug for Duchenne muscular dystrophy (DMD) and full approval of one for spinal muscular atrophy, these experiences have shown that objective data and an adequate level of effect are essential for drug approval and reimbursement. The appropriateness and validity of biomarkers and clinically meaningful endpoints and an understanding of disease progression rates all played essential roles in the levels of evidence for these drugs. Such tools are best developed through integration of clinical data. The siloing of clinical data for rare neuromuscular diseases represents a considerable barrier to achieving better care and novel therapies for patients living with neuromuscular diseases. We discuss a data-sharing model implemented for DMD and urge cultural changes in the ways natural history and clinical trial data are collected and shared across all neuromuscular diseases in order to benefit the primary stakeholder, the patient.

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Ambulatory capacity and disease progression as measured by the 6-minute-walk-distance in Duchenne muscular dystrophy subjects on daily corticosteroids

Cited by 63 publications

References 13 publications

Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

Placebo‐controlled Phase 2 Trial of Drisapersen for Duchenne Muscular Dystrophy

Seeking a better landscape for therapy development in neuromuscular disorders

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