Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study

Voït, Thomas; Topaloğlu, Haluk; Straub, Volker; Muntoni, Francesco; Deconinck, Nicolas; Campion, Giles; Kimpe, Sjef J Sj De; Eagle, Michelle; Guglieri, Michela; Hood, Steve S; Liefaard, Lia; Lourbakos, Afrodite; Morgan, Allison A; Nakielny, Joanna; Quarcoo, Naashika; Ricotti, Valeria; Rolfe, Katie K; Servais, Laurent; Wardell, C.; Wilson, Rosamund; Wright, Pádraig; Kraus, John E.

doi:10.1016/s1474-4422(14)70195-4

Cited by 280 publications

(254 citation statements)

References 32 publications

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“…Notably, adverse events frequently seen with other RNA analogs, including administration site reactions, flulike symptoms, coagulopathies, inflammatory response, and renal or hepatic toxicity,20, 33 were observed rarely, if at all 20, 33. This is consistent with the safety profile and tolerability of eteplirsen and other PMO‐based oligomers seen in animals41, 42, 43 and in other human studies 44.…”

Section: Discussionsupporting

confidence: 76%

“…The 6MWT is an ambulatory outcome measure that has been utilized in clinical trials for 3 DMD therapeutics (eteplirsen, drisapersen, and ataluren) and has been shown to be accurate and reproducible 13. 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.…”

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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

453

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: Discussionsupporting

confidence: 76%

mentioning

confidence: 99%

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

Mendell

Goemans²,

Lowes

et al. 2016

Annals of Neurology

453

392

View full text Add to dashboard Cite

show abstract

“…Phosphorothioate oligonucleotides (PS, Drisapersen) and morpholino phosphorodiamidate oligomers (PMO, Eteplirsen) are useful for patients carrying the mutation in exon 51; they can be injected locally or delivered systemically [33]. During phase II and III clinical trials, Drisapersen has not shown the expected results, and it is now under investigation in younger patients [19,34]. Instead, patients treated with Eteplirsen revealed an increased number of dystrophin-positive myofibers compared with placebo-treated patients, and improvement in functional tests [35] so that the US FDA accelerated the approval of this drug on September 2016.…”

Section: Exon Skippingmentioning

confidence: 99%

Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy

Chiappalupi

Salvadori

Luca

et al. 2017

JFMK

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Duchenne muscular dystrophy (DMD) is a lethal X-linked pathology due to lack of dystrophin and characterized by progressive muscle degeneration, impaired locomotion and premature death. The chronic presence of inflammatory cells, fibrosis and fat deposition are hallmarks of DMD muscle tissue. Many different therapeutic approaches to DMD have been tested, including cell-based and gene-based approaches, exon skipping, induction of expression of the dystrophin paralogue, utrophin, and, most recently the application of the CASPR/Cas9 genome editing system. However, corticosteroid treatment remains the gold standard therapy, even if corticosteroids have shown multiple undesirable side effects. Sertoli cells (SeC) have long been known for their ability to produce immunomodulatory and trophic factors, and have been used in a plethora of experimental models of disease. Recently, microencapsulated porcine SeC (MC-SeC) injected intraperitoneally in dystrophic mice produced morphological and functional benefits in muscles thanks to their release into the circulation of anti-inflammatory factors and heregulin β1, a known inducer of utrophin expression, thus opening a new avenue in the treatment of DMD. In order to stress the potentiality of the use of MC-SeC in the treatment of DMD, here, we examine the principal therapeutic approaches to DMD, and the properties of SeC (either nude or encapsulated into alginate-based microcapsules) and their preclinical and clinical use. Finally, we discuss the potential and future development of this latter approach.Keywords: Duchenne muscular dystrophy; therapeutic approaches; Sertoli cell; muscle inflammation; myopathies; encapsulation; biomaterials Duchenne Muscular Dystrophy (DMD)Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy. Muscular dystrophies are a group of inherited muscle diseases characterized by mutations in specific genes and resulting in muscle degeneration, impaired locomotion and premature death [1,2]. DMD is an X-linked recessive pathology caused by mutations in the dystrophin gene (DMD) usually resulting in the complete absence of this protein. Dystrophin is an essential component of the dystrophin-associated protein complex (DAPC) at the sarcolemma, a complex that ensures the structural and functional integrity of the myofibers during contraction representing a mechanical link between the intracellular cytoskeleton and the extracellular matrix. Absence of dystrophin or other components of the DAPC compromises the integrity of the DAPC itself leading to a susceptibility of myofibers to degeneration

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“…[19][20][21] Even very small quantities of dystrophin, hardly detectable by immunohistochemistry (IHC) or Western blot (WB), might ameliorate the disease and delay LoA by several years. This is particularly relevant for the development of dystrophin-restoring treatments, such as exon skipping by antisense oligonucleotides (AONs) [22][23][24][25][26][27][28][29][30] and stop codon readthrough, [31][32][33] as variation in baseline levels of dystrophin may confound evaluations of efficacy in clinical trials.…”

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confidence: 99%

DMD genotypes and loss of ambulation in the CINRG Duchenne natural history study

Bello

Morgenroth

Gordish‐Dressman

et al. 2016

Neuromuscular Disorders

101

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Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study

Cited by 280 publications

References 32 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

Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy

DMD genotypes and loss of ambulation in the CINRG Duchenne natural history study

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