Eteplirsen treatment for Duchenne muscular dystrophy

Charleston, Jay S.; Schnell, Frederick J.; Dworzak, J.; Donoghue, C.; Lewis, Sarah; Chen, Lei; Young, Gregory; Milici, Anthony J.; Voss, Jon; DeAlwis, U.; Wentworth, Bruce M.; Rodino‐Klapac, Louise R.; Sahenk, Zarife; Frank, Diane E.; Mendell, Jerry R.

doi:10.1212/wnl.0000000000005680

Cited by 199 publications

(157 citation statements)

References 34 publications

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“…To our knowledge, this is the longest period of exposure reported to an investigational drug in DMD outside that of GC use. Previously the longest follow-up time was 188 weeks (3.6 years) in drisapersen treated patients [23] and 180 weeks (3.5 years) in eteplirsen treated patients [24] ; with 12 subjects followed-up in both studies.…”

Section: Discussionmentioning

confidence: 99%

Long-term data with idebenone on respiratory function outcomes in patients with Duchenne muscular dystrophy

Servais

Straathof

Schara

et al. 2020

Neuromuscular Disorders

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Decline in respiratory function in patients with DMD starts during early teenage years and leads to early morbidity and mortality. Published evidence of efficacy for idebenone on respiratory function outcomes is currently limited to 12 months of follow-up time. Here we report data collected as retrospective cohort study (SYROS) from 18 DMD patients not using glucocorticoids who were treated with idebenone (900 mg/day) under Expanded Access Programs (EAPs). The objective was to assess the long-term respiratory function evolution for periods On-Idebenone compared to periods Off-Idebenone in the same patients. The mean idebenone exposure in the EAPs was 4.2 (range 2.4-6.1) years. The primary endpoint was the annual change in forced vital capacity percent of predicted (FVC%p) compared between Off-Idebenone and On-Idebenone periods. The annual rate of decline in FVC%p was reduced by approximately 50% from −7.4% (95% CI: −9.1, −5.8) for the Off-Idebenone periods to −3.8% (95% CI: −4.8, −2.8) for the On-Idebenone periods (N = 11). Similarly, annual change in peak expiratory flow percent of predicted (PEF%p) was −5.9% (95% CI: −8.0, −3.9) for the Off-Idebenone periods (N = 9) and reduced to −1.9% (95% CI: −3.2, −0.7) for the On-Idebenone periods during the EAPs. The reduced rates of decline in FVC%p and PEF%p were maintained for several years with possible beneficial effects on the rate of bronchopulmonary adverse events, time to 10% decline in FVC%p and risk of hospitalization due to respiratory cause. These long-term data provide Class IV evidence to further support the disease modifying treatment effect of idebenone previously observed in randomized, controlled trials.

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Section: Discussionmentioning

confidence: 99%

Long-term data with idebenone on respiratory function outcomes in patients with Duchenne muscular dystrophy

Servais

Straathof

Schara

et al. 2020

Neuromuscular Disorders

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“…This makes accurate quantification of dystrophin produced as a result of therapeutic intervention challenging via current conventional methods. This challenge is further compounded by the very low and variable expression of induced dystrophin that has been observed in recent trials involving antisense oligonucleotides [13,14,17,25,26,46] coupled with the observation that most DMD patient samples also have low level residual dystrophin expression at baseline, highlighting the necessity for a highly sensitive detection method capable of detecting dystrophin signal over a wide dynamic range to resolve even subtle differences between pre-and posttreatment biopsies [3]. The amount and distribution pattern of induced dystrophin needed for functional benefit in humans is not yet known although it is suggested that levels as low as 30% could be sufficient to completely avoid muscle weakness [33], while lower levels are expected to reduce the rate of muscle damage.…”

Section: Discussionmentioning

confidence: 99%

A high–throughput digital script for multiplexed immunofluorescent analysis and quantification of sarcolemmal and sarcomeric proteins in muscular dystrophies

Scaglioni

Ellis

Catapano

et al. 2020

acta neuropathol commun

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The primary molecular endpoint for many Duchenne muscular dystrophy (DMD) clinical trials is the induction, or increase in production, of dystrophin protein in striated muscle. For accurate endpoint analysis, it is essential to have reliable, robust and objective quantification methodologies capable of detecting subtle changes in dystrophin expression. In this work, we present further development and optimisation of an automated, digital, highthroughput script for quantitative analysis of multiplexed immunofluorescent (IF) whole slide images (WSI) of dystrophin, dystrophin associated proteins (DAPs) and regenerating myofibres (fetal/developmental myosin-positive) in transverse sections of DMD, Becker muscular dystrophy (BMD) and control skeletal muscle biopsies. The script enables extensive automated assessment of myofibre morphometrics, protein quantification by fluorescence intensity and sarcolemmal circumference coverage, colocalisation data for dystrophin and DAPs and regeneration at the single myofibre and whole section level. Analysis revealed significant variation in dystrophin intensity, percentage coverage and amounts of DAPs between differing DMD and BMD samples. Accurate identification of dystrophin via a novel background subtraction method allowed differential assessment of DAP fluorescence intensity within dystrophin positive compared to dystrophin negative sarcolemma regions. This enabled surrogate quantification of molecular functionality of dystrophin in the assembly of the DAP complex. Overall, the digital script is capable of multiparametric and unbiased analysis of markers of myofibre regeneration and dystrophin in relation to key DAPs and enabled better characterisation of the heterogeneity in dystrophin expression patterns

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“…Eteplirsen increased muscle dystrophin after 180 weeks of use in 11 treated DMD patients, compared with 13 controls. Dystrophin increased 100% when measured by real-time PCR techniques, 11.6 times by Western blot techniques (p < 0.007) and 7.4 to 15.5 times by immunohistochemistry (p < 0.001) 63 .…”

Section: Eteplirsenmentioning

confidence: 95%

Duchenne muscular dystrophy: an historical treatment review

Werneck

Lorenzoni

Ducci

et al. 2019

Arq. Neuro-Psiquiatr.

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In this review, we discuss the therapies used in the treatment of patients with Duchenne muscular dystrophy since the first description of the disease. A short description is given of the various theories based on disease pathogenesis, which give the substrates for the many therapeutic interventions. A brief review of the methods of evaluation used in therapeutic trials is made. Of all the treatments, the only drugs that are still considered able to modify the course of the disease are the corticosteroids (prednisone/prednisolone/deflazacort). Other drugs (coenzyme Q10 and creatine) have had a little effect in a few functions without adverse reactions. Idebenone seems to improve the respiratory function in the long term. The trials with mRNA transcription, through nonsense mutations or exon 51 skipping, show some beneficial results in a few functional tests, but they are limited to a small set of DMD patients.

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Eteplirsen treatment for Duchenne muscular dystrophy

Abstract: This study provides Class II evidence of the muscle cell penetration, exon skipping, and induction of novel dystrophin expression by eteplirsen, as confirmed by 4 assays.

Cited by 199 publications

References 34 publications

Long-term data with idebenone on respiratory function outcomes in patients with Duchenne muscular dystrophy

Long-term data with idebenone on respiratory function outcomes in patients with Duchenne muscular dystrophy

A high–throughput digital script for multiplexed immunofluorescent analysis and quantification of sarcolemmal and sarcomeric proteins in muscular dystrophies

Duchenne muscular dystrophy: an historical treatment review

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