Eteplirsen Treatment Attenuates Respiratory Decline in Ambulatory and Non-Ambulatory Patients with Duchenne Muscular Dystrophy

Khan, Navid; Eliopoulos, Helen; Han, Lixin; Kinane, T. Bernard; Lowes, Linda; Mendell, Jerry R.; Gordish‐Dressman, Heather; Henricson, E.; McDonald, Craig

doi:10.3233/jnd-180351

Cited by 77 publications

(98 citation statements)

References 33 publications

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“…With regard to idebenone, according to our results, this agent exerts a clear beneficial effect on PEF (increase, stabilization, or attenuation of the decline), while improvement in FVC has been identified in fewer studies and is subtler . A positive impact on inspiratory muscle function was also identified by Buyse et al Available literature evidence about eteplirsen demonstrates stabilization, attenuation of the decrease or even slight increase in % predicted expiratory or inspiratory spirometric values (FVC, MEP, and maximal inspiratory pressure [MIP]) . In one study about the effect of stem‐cell therapy, we identified an increase in FVC and forced expiratory volume in the 1st second (FEV1) was noted.…”

Section: Resultssupporting

confidence: 64%

“…In general, the studies identified in the literature and included in our review displayed a beneficial effect of eteplirsen on the lung function of Duchenne patients . Moreover, no significant differences were detected between ambulatory and nonambulatory patients …”

Section: Discussionmentioning

confidence: 74%

“…Assessment of risk bias in our studies is thoroughly presented in Tables and . With respect to studies by Khan, Kinane, and Mendell risk bias was separately analyzed and presented for their first (randomized) and second (nonrandomized) phase. The terms unclear and unknown were not applicable to the evaluation of the studies included in our review.…”

Section: Resultsmentioning

confidence: 99%

“…Available literature evidence about the role of eteplirsen in Duchenne muscular dystrophy is mainly drawn from a randomized controlled trial including administration of eteplirsen (30 or 50 mg/kg/wk) or placebo for 24 weeks (STUDY 201) followed by an open‐label phase extension phase during which patients originally randomized to receive placebo were randomized to eteplirsen 30 or 50 mg/kg (STUDY 202). The total follow‐up period lasted for approximately 4 years (3‐5 years) . As the final number of patients enrolled was relatively small (12 in total), historical control groups were used by the authors to facilitate comparisons with the natural course of the disease .…”

Section: Discussionmentioning

confidence: 99%

“…As the final number of patients enrolled was relatively small (12 in total), historical control groups were used by the authors to facilitate comparisons with the natural course of the disease . Two more recent open‐label studies with larger sample sizes and the inclusion of a significant number of placebo‐treated patients (STUDIES 204 and 301) provided additional information to the data supplied by studies 201 and 202 and served further to underscore the difference in respiratory outcomes between eteplirsen and control group …”

Section: Discussionmentioning

confidence: 99%

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Therapies that are available and under development for Duchenne muscular dystrophy: What about lung function?

Γώγου

Pavlou

Haidopoulou

2019

Pediatric Pulmonology

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Background Respiratory failure is the principal source of morbidity and mortality among patients with Duchenne muscular dystrophy exerting a negative influence on their total quality of life. The aim of this review is to provide systematically current literature evidence about the effects of different treatment options (available or under development) for Duchenne muscular dystrophy on the pulmonary function of these patients. Methods A comprehensive search was undertaken using multiple health‐related databases, while two independent reviewers assessed the eligibility of studies. A third person addressed any disagreements between reviewers. The quality of the methodology of the included studies was also assessed. Results A total of 19 original research papers (nine evaluating the role of steroids, six idebenone, three eteplirsen, one stem‐cell therapy, and one ataluren) were found to fulfill our selection criteria with the majority of them (14 of 19) being prospective studies, not always including a control group. Endpoints mainly used in these studies were values of pulmonary function tests. Current and under development treatments proved to be safe and no significant adverse events were reported. A beneficial impact on pulmonary function was described by authors in the majority of these studies. The principal effect was slowing of lung disease progress, as expressed by spirometric values. However, the risk of bias was introduced in many of the above studies, while high heterogeneity in terms of treatment protocols and outcome measures limits the comparability of the results. Conclusion Glucocorticoids remain the best‐studied pharmacologic therapy for Duchenne muscular dystrophy and very likely delay the expected decline in lung function. With regard to new therapeutic agents, initial study results are encouraging. However, larger clinical trials are needed that minimize the risk of study bias, optimize the comparability of treatment groups, examine clinically meaningful pulmonary outcome measures, and include long‐term follow up.

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Section: Resultssupporting

confidence: 64%

Section: Discussionmentioning

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Therapies that are available and under development for Duchenne muscular dystrophy: What about lung function?

Γώγου

Pavlou

Haidopoulou

2019

Pediatric Pulmonology

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Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy

et al. 2020

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IMPORTANCE Micro-dystrophin gene transfer shows promise for treating patients with Duchenne muscular dystrophy (DMD) using recombinant adeno-associated virus serotype rh74 (rAAVrh74) and codon-optimized human micro-dystrophin driven by a skeletal and cardiac muscle-specific promoter with enhanced cardiac expression (MHCK7). OBJECTIVE To identify the 1-year safety and tolerability of intravenous rAAVrh74.MHCK7.micro-dystrophin in patients with DMD. DESIGN, SETTING, AND PARTICIPANTS This open-label, phase 1/2a nonrandomized controlled trial was conducted at the Nationwide Children's Hospital in Columbus, Ohio. It began on November 2, 2017, with a planned duration of follow-up of 3 years, ending in March 2021. The first 4 patients who met eligibility criteria were enrolled, consisting of ambulatory male children with DMD without preexisting AAVrh74 antibodies and a stable corticosteroid dose (Ն12 weeks). INTERVENTIONS A single dose of 2.0 × 10 14 vg/kg rAAVrh74.MHCK7.micro-dystrophin was infused through a peripheral limb vein. Daily prednisolone, 1 mg/kg, started 1 day before gene delivery (30-day taper after infusion). MAIN OUTCOMES AND MEASURES Safety was the primary outcome. Secondary outcomes included micro-dystrophin expression by Western blot and immunohistochemistry. Functional outcomes measured by North Star Ambulatory Assessment (NSAA) and serum creatine kinase were exploratory outcomes. RESULTS Four patients were included (mean [SD] age at enrollment, 4.8 [1.0] years). All adverse events (n = 53) were considered mild (33 [62%]) or moderate (20 [38%]), and no serious adverse events occurred. Eighteen adverse events were considered treatment related, the most common of which was vomiting (9 of 18 events [50%]). Three patients had transiently elevated γ-glutamyltransferase, which resolved with corticosteroids. At 12 weeks, immunohistochemistry of gastrocnemius muscle biopsy specimens revealed robust transgene expression in all patients, with a mean of 81.2% of muscle fibers expressing micro-dystrophin with a mean intensity of 96% at the sarcolemma. Western blot showed a mean expression of 74.3% without fat or fibrosis adjustment and 95.8% with adjustment. All patients had confirmed vector transduction and showed functional improvement of NSAA scores and reduced creatine kinase levels (posttreatment vs baseline) that were maintained for 1 year. CONCLUSIONS AND RELEVANCE This trial showed rAAVrh74.MHCK7.micro-dystrophin to be well tolerated and have minimal adverse events; the safe delivery of micro-dystrophin transgene; the robust expression and correct localization of micro-dystrophin protein; and improvements in creatine kinase levels and NSAA scores. These findings suggest that rAAVrh74.MHCK7.micro-dystrophin can provide functional improvement that is greater than that observed under standard of care. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03375164

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Genetic modifiers of respiratory function in Duchenne muscular dystrophy

Bello

D'Angelo

Villa

et al. 2020

Ann Clin Transl Neurol

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Objective: Respiratory insufficiency is a major complication of Duchenne muscular dystrophy (DMD). Its progression shows considerable interindividual variability, which has been less thoroughly characterized and understood than in skeletal muscle. We collected pulmonary function testing (PFT) data from a large retrospective cohort followed at Centers collaborating in the Italian DMD Network. Furthermore, we analyzed PFT associations with different DMD mutation types, and with genetic variants in SPP1, LTBP4, CD40, and ACTN3, known to modify skeletal muscle weakness in DMD. Genetic association findings were independently validated in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). Methods and Results: Generalized estimating equation analysis of 1852 PFTs from 327 Italian DMD patients, over an average follow-up time of 4.5 years, 786 estimated that forced vital capacity (FVC) declined yearly by À4.2%, forced expiratory volume in 1 sec by À5.0%, and peak expiratory flow (PEF) by À2.9%. Glucocorticoid (GC) treatment was associated with higher values of all PFT measures (approximately + 15% across disease stages). Mutations situated 3' of DMD intron 44, thus predicted to alter the expression of short dystrophin isoforms, were associated with lower (approximately À6%) PFT values, a finding independently validated in the CINRG-DNHS. Deletions amenable to skipping of exon 51 and 53 were independently associated with worse PFT outcomes. A meta-analysis of the two cohorts identified detrimental effects of SPP1 rs28357094 and CD40 rs1883832 minor alleles on both FVC and PEF. Interpretation: These findings support GC efficacy in delaying respiratory insufficiency, and will be useful for the design and interpretation of clinical trials focused on respiratory endpoints in DMD.

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Eteplirsen Treatment Attenuates Respiratory Decline in Ambulatory and Non-Ambulatory Patients with Duchenne Muscular Dystrophy

Cited by 77 publications

References 33 publications

Therapies that are available and under development for Duchenne muscular dystrophy: What about lung function?

Therapies that are available and under development for Duchenne muscular dystrophy: What about lung function?

Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy

Genetic modifiers of respiratory function in Duchenne muscular dystrophy

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