Review of Phase II and Phase III clinical trials for Duchenne muscular dystrophy

Scully, Michele A.; Pandya, Shree; Moxley, Richard T.

doi:10.1517/21678707.2013.746939

Cited by 15 publications

(8 citation statements)

References 103 publications

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“…The orphan disease Duchenne muscular dystrophy is caused by expression of a nonfunctional dystrophin protein due to deletion of a section of its corresponding gene [26]. As a result, a frame-shift occurs and a non-functional protein is expressed.…”

Section: Introduction -Oligonucleotide Therapeuticsmentioning

confidence: 99%

Going beyond the liver: Progress and challenges of targeted delivery of siRNA therapeutics

Lorenzer

Dirin

Winkler

et al. 2015

Journal of Controlled Release

253

204

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Therapeutic gene silencing promises significant progress in pharmacotherapy, including considerable expansion of the druggable target space and the possibility for treating orphan diseases. Technological hurdles have complicated the efficient use of therapeutic oligonucleotides, and siRNA agents suffer particularly from insufficient pharmacokinetic properties and poor cellular uptake. Intense development and evolution of delivery systems have resulted in efficient uptake predominantly in liver tissue, in which practically all nanoparticulate and liposomal delivery systems show the highest accumulation. The most efficacious strategies include liposomes and bioconjugations with N-acetylgalactosamine. Both are in early clinical evaluation stages for treatment of liver-associated diseases. Approaches for achieving knockdown in other tissues and tumors have been proven to be more complicated. Selective targeting to tumors may be enabled through careful modulation of physical properties, such as particle size, or by taking advantage of specific targeting ligands. Significant barriers stand between sufficient accumulation in other organs, including endothelial barriers, cellular membranes, and the endosome. The brain, which is shielded by the blood-brain barrier, is of particular interest to facilitate efficient oligonucleotide therapy of neurological diseases. Transcytosis of the blood-brain barrier through receptor-specific docking is investigated to increase accumulation in the central nervous system. In this review, the current clinical status of siRNA therapeutics is summarized, as well as innovative and promising preclinical concepts employing tissue- and tumor-targeted ligands. The requirements and the respective advantages and drawbacks of bioconjugates and ligand-decorated lipid or polymeric particles are discussed.

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Section: Introduction -Oligonucleotide Therapeuticsmentioning

confidence: 99%

Going beyond the liver: Progress and challenges of targeted delivery of siRNA therapeutics

Lorenzer

Dirin

Winkler

et al. 2015

Journal of Controlled Release

253

204

View full text Add to dashboard Cite

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“…4 Each approach is aimed at a small subset of less than 13% of the DMD population. 5 The potential for utrophin to functionally replace dystrophin has been recognized for some time. [6][7][8][9] The utrophin gene is the autosomal homolog of dystrophin; they share similar structural organizational motifs and protein binding properties.…”

mentioning

confidence: 99%

“…A limited number of disease modifying drugs are in clinical trials including: Ataluren (directed against stop‐codon mutations, PTC Therapeutics) and both drisapersen (Prosensa) and eteplirsen (Sarepta) targeting skipping of dystrophin exons 53, 51, 45, and 44 . Each approach is aimed at a small subset of less than 13% of the DMD population …”

mentioning

confidence: 99%

Safety, tolerability, and pharmacokinetics of SMT C1100, a 2‐arylbenzoxazole utrophin modulator, following single‐ and multiple‐dose administration to healthy male adult volunteers

Tinsley

Robinson

Davies

2015

The Journal of Clinical Pharmacology

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SMT C1100 is a small molecule utrophin modulator in development to treat Duchenne muscular dystrophy. This study evaluated the safety, tolerability, and pharmacokinetics of SMT C1100 in healthy volunteers. This double‐blind, placebo‐controlled Phase 1 study comprised: Part 1, an escalating, single‐dose with/without fasting involving 50 mg/kg, 100 mg/kg, 200 mg/kg, and 400 mg/kg doses; and Part 2, a multiple 10 day dose evaluation involving 100 mg/kg bid and 200 mg/kg bid doses. Adverse events were recorded. SMT C1100 was absorbed rapidly following single and multiple oral doses, with median tmax attained within 2–3.5 hour across all doses. Considerable variability of pharmacokinetic parameters was noted among subjects. Following single doses, systemic exposure increased in a sub‐proportional manner, with the 8.0‐fold dose increment resulting in 2.7‐ and 2.4‐fold increases in AUC0‐∞ and Cmax, respectively. AUC0‐∞ and Cmax were estimated as 4.2‐ and 4.8‐fold greater, respectively, following food. Systemic exposure reduced upon repeat dosing with steady‐state concentrations achieved within 3–5 days of multiple bid dosing. No serious or severe adverse events were reported. SMT C1100 was safe and well tolerated with plasma concentrations achieved sufficient to cause a 50% increase in concentrations of utrophin in cells in vitro.

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“…Management: Currently, DMD has no curative treatment although corticosteroids is the gold standard therapy that can delay DMD progression but associated with several adverse effects (weight gain, nervous system disturbance, gastrointestinal symptoms, metabolic disorders or osteoporosis), which can be reduced by finding an optimal standard regimen [49,50]. Since DMD can lead to multisystem complications, a multidisciplinary approach is essential for effective treatment.…”

Section: Duchenne Muscular Dystrophymentioning

confidence: 99%

Familial neuromuscular cardiomyopathy: A review and pooled analysis of pathophysiology, diagnosis and clinical management

Albakri¹

2019

Clin Med Invest

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The role of genetic mutation in the pathogenesis of cardiomyopathies (CM) has been long-established. In contrast, the involvement of familial (hereditary) neuromuscular diseases (NDs) in the development of CM remains under-researched. Little attention has been paid to better characterize and understand myocardial involvement in NDs. There is evidence that early diagnosis may improve therapeutic response in ND patients with CM. However, diagnosis can be easily missed because signs and symptoms of cardiac dysfunction are non-specific or can overlap with that of muscular wasting (reduced physical activity) and respiratory failure due to the underlying ND. Diagnosis can also be delayed because of the late manifestations of the traditional non-invasive imaging markers of cardiac dysfunction particularly left ventricular (LV) systolic function and LV volumes or dimensions on echocardiography and late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMRI). For these reasons, a better understanding of longitudinal progress, cardiac complications and long-term cardiac outcomes is warranted. The clinician should also be familiar with the therapeutic options in CM associated with NDs. Thus, this review discusses important clinical and diagnostic features of CM in patients with NDs as well as emerging diagnostic and therapeutic options.

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Review of Phase II and Phase III clinical trials for Duchenne muscular dystrophy

Cited by 15 publications

References 103 publications

Going beyond the liver: Progress and challenges of targeted delivery of siRNA therapeutics

Going beyond the liver: Progress and challenges of targeted delivery of siRNA therapeutics

Safety, tolerability, and pharmacokinetics of SMT C1100, a 2‐arylbenzoxazole utrophin modulator, following single‐ and multiple‐dose administration to healthy male adult volunteers

Familial neuromuscular cardiomyopathy: A review and pooled analysis of pathophysiology, diagnosis and clinical management

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