Systemic Administration of PRO051 in Duchenne's Muscular Dystrophy

Goemans, Nathalie; Tulinius, M.; Akker, Johanna T van den; Burm, Brigitte E; Ekhart, Peter F.; Heuvelmans, Niki; Holling, Tjadine M.; Janson, A. A. M.; Platenburg, Gerard; Sipkens, Jessica A.; Sitsen, J. M. A.; Aartsma‐Rus, Annemieke; Ommen, Gert‐Jan B. van; Buyse, Gunnar; Darín, Niklas; Verschuuren, Jan J.; Campion, G.; Kimpe, Sjef J. De; Deutekom, Judith C. van

doi:10.1056/nejmoa1011367

Cited by 626 publications

(546 citation statements)

References 25 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%

See 1 more Smart Citation

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

Mendell

Goemans²,

Lowes

et al. 2016

Annals of Neurology

439

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%

“…The 6MWT33 was administered once, or twice on consecutive days, according to predetermined schedules outlined in the protocol, with each patient following the same schedule. When the 6MWT was administered on 2 consecutive days, the day 1 results were used for this analysis for comparison to matched controls who had 1 value for each time point.…”

Section: Methodsmentioning

confidence: 99%

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

Mendell

Goemans²,

Lowes

et al. 2016

Annals of Neurology

439

392

View full text Add to dashboard Cite

show abstract

“…Average life expectancy in DMD patients has shifted from adolescence in the 70s of last century to third and fourth decade of life, with some patients surviving now even in their forties [3,4,32], mainly because of improved supportive treatment of cardiac, respiratory and orthopedic complications [5,6]. As a reference center for DMD we were alarmed by few recent publications suggesting that renal function might be compromised by this disorder [8][9][10]. Moreover, the emergence of new therapeutic strategies moving into clinical development has highlighted the need for safe and robust tools to monitor renal safety of new compounds.…”

Section: Discussionmentioning

confidence: 99%

“…Among these, RNA modulating approaches such as antisense mediated exon skipping and nonsense codon suppression aim to restore the production of partially functional or full length dystrophin protein [7]. A recent phase 1-2a study of local intramuscular administration of the antisense oligonucleotide PRO051 showed a modest improvement in the 6-minute walk test after 12 weeks of extended treatment, but variable proteinuria was an adverse event in all patients [8]. However, in general, little is known about renal function in DMD patients.…”

Section: Introductionmentioning

confidence: 99%

Renal function in children and adolescents with Duchenne muscular dystrophy

Braat

Hoste

Waele

et al. 2015

Neuromuscular Disorders

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Improved life expectancy and the need for robust tools to monitor renal safety of emerging new therapies have fueled the interest in renal function in Duchenne muscular dystrophy (DMD) patients. We aimed to establish a methodology to accurately assess their renal function. Twenty DMD patients (5-22 years) were included in this prospective study. After obtaining medical history, all patients underwent a clinical examination, 24-hour ambulatory blood pressure monitoring, ultrasound of the kidneys, direct GFR measurement ( 51 Cr-EDTA, mGFR), complete blood and urine analysis. Seventeen of 20 patients were treated with corticosteroids and 5/20 with angiotensin converting enzyme inhibitor (lisinopril). No patient suffered from urinary tract infections or other renal diseases. Hypertension (systolic or diastolic blood pressure >P95) was found in 9/20 patients (8/9 patients were on steroid treatment) and a non-dipping blood pressure profile in 13/20 subjects (10/13 patients were on steroid treatment). Urinary protein to creatinine ratio was elevated in 17/18 patients, whereas 24-hour urine protein excretion was normal in all subjects. Median interquartile range (IQR) mGFR was 130.4 (29.1) mL/min/1.73 m 2 . Hyperfiltration (mGFR >150 mL/min/1.73 m 2 ) was found in 5/20 patients. Inverse correlation between mGFR and age was observed (R 2 = 0.45, p = 0.001). Serum creatinine based estimated GFR (eGFR) equations overestimated mGFR up to 300%. eGFR based on cystatin C Filler equation was closest to the mGFR (median eGFR (IQR) of 129.5 (39.7) mL/min/1.73 m 2 ). Our study demonstrates a high prevalence of hyperfiltration and hypertension in children and adolescents with DMD. Because the majority of hypertensive patients were under corticosteroid treatment, the iatrogenic cause of hypertension cannot be excluded. Serum or urine creatinine measurements are of no value to evaluate renal function in DMD patients due to the reduced skeletal muscle mass.

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“…[8][9][10][11][12] Exon skipping, which rectifies the aberrant reading frame, aims to treat patients with large deletions; yet, to achieve this, the selection of appropriate patients with detailed genetic diagnosis is very important.…”

Section: Introductionmentioning

confidence: 99%

Targeted next-generation sequencing as a comprehensive test for patients with and female carriers of DMD/BMD: a multi-population diagnostic study

Wei

Dai

et al. 2013

Eur J Hum Genet

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Duchenne and Becker muscular dystrophies (DMD/BMD) are the most commonly inherited neuromuscular disease. However, accurate and convenient molecular diagnosis cannot be achieved easily because of the enormous size of the dystrophin gene and complex causative mutation spectrum. Such traditional methods as multiplex ligation-dependent probe amplification plus Sanger sequencing require multiple steps to fulfill the diagnosis of DMD/BMD. Here, we introduce a new single-step method for the genetic analysis of DMD patients and female carriers in real clinical settings and demonstrate the validation of its accuracy. A total of 89 patients, 18 female carriers and 245 non-DMD patients were evaluated using our targeted NGS approaches. Compared with traditional methods, our new method yielded 99.99% specificity and 98.96% sensitivity for copy number variations detection and 100% accuracy for the identification of single-nucleotide variation mutations. Additionally, this method is able to detect partial deletions/duplications, thus offering precise personal DMD gene information for gene therapy. We detected novel partial deletions of exons in nine samples for which the breakpoints were located within exonic regions. The results proved that our new method is suitable for routine clinical practice, with shorter turnaround time, higher accuracy, and better insight into comprehensive genetic information (detailed breakpoints) for ensuing gene therapy.

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Systemic Administration of PRO051 in Duchenne's Muscular Dystrophy

Cited by 626 publications

References 25 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

Renal function in children and adolescents with Duchenne muscular dystrophy

Targeted next-generation sequencing as a comprehensive test for patients with and female carriers of DMD/BMD: a multi-population diagnostic study

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