A novel clinical trial design to evaluate the efficacy and safety of two exon-skipping PMOs, SRP-4045 and SRP-4053, in patients with Duchenne muscular dystrophy

2015 ◽  
Vol 25 ◽  
pp. S263-S264
Author(s):  
G. Laforet ◽  
E. Kaye ◽  
J. Saoud
Keyword(s):  
Clinical Trial ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Exon Skipping ◽  
Efficacy And Safety

scholarly journals Corticosteroid Treatment Impact on Spinal Deformity in Duchenne Muscular Dystrophy

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Ilaria Sanzarello ◽  
Luciano Merlini ◽  
Francesco Traina ◽  
Michele Attilio Rosa ◽  
Cesare Faldini
Keyword(s):  
Clinical Trial ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Spinal Deformity ◽  
Trial Design ◽  
Progressive Disease ◽  
Clinical Trial Design ◽  
Corticosteroid Treatment ◽  
Surgical Interventions ◽  
History Of

Duchenne muscular dystrophy is a progressive disease with loss of ambulation at around 9-10 years of age, followed, if untreated, by development of scoliosis, respiratory insufficiency, and death in the second decade of life. This review highlights the natural history of the disease, in particular, with regard to the development of the spinal deformity and how this complication has been modified by surgical interventions and overall by corticosteroid treatment. The beneficial effect of corticosteroids may have also an impact on the clinical trial design of the new emerging causative therapies.

scholarly journals INTEREST GROUP SESSION—GEROSCIENCE: METHODS FROM BENCH TO POPULATION SCIENCE TO INFORM CONSTRUCTION OF GEROSCIENCE CLINICAL TRIALS

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S745-S745
Author(s):  
Jason L Sanders ◽  
Anne B Newman
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Biological Pathway ◽  
Efficacy And Safety ◽  
Population Science ◽  
Multiple Levels ◽  
Aging Mechanisms

Abstract We are on the cusp of a revolution in aging science. It has matured to the point where geroscience trials will test interventions in humans which alter aging mechanisms to lengthen healthspan and possibly lifespan. This goal is unprecedented in clinical trial design, and it requires retooling the clinical trial toolbox. Traditionally, trials are constructed around a single disease; interventions target a narrow part of a defined biological pathway involving only one molecule, tissue, or organ; events are well known intermediate endpoints and clinically-defined hard outcomes; and follow up may be short and historically informed based on prior trials. Geroscience trials by design target aging mechanisms which, when altered, are likely to have pleiotropic effects that modify several biologic pathways; efficacy and safety signals may require integration across multiple levels of biologic organization; intermediate endpoints are not agreed upon; and follow up timelines are undefined. In this symposium, we provide guidance on the design of geroscience trials using examples that span from bench to population science. Dr. LeBrasseur will discuss screening senolytic compounds across models of age-associated decline and advancing their candidacy as interventions. Dr. Justice will detail a framework for biomarker selection in geroscience trials, focusing on a trial of metformin as an example. Dr. Sanders will illustrate how observational data can inform phenotype use in clinical trials. Dr. Levine will explain translating omics data for use in geroscience trials, focusing on epigenomics. We expect additional discussion to hasten development of well-designed geroscience trials.

Systemic administration of the antisense oligonucleotide NS-065/NCNP-01 for skipping of exon 53 in patients with Duchenne muscular dystrophy

2018 ◽  
Vol 10 (437) ◽  
pp. eaan0713 ◽  
Author(s):  
Hirofumi Komaki ◽  
Tetsuya Nagata ◽  
Takashi Saito ◽  
Satoru Masuda ◽  
Eri Takeshita ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Protein ◽  
Phase 1 ◽  
Exon Skipping ◽  
Muscle Disease ◽  
Dependent Manner ◽  
Reading Frame ◽  
Dystrophin Expression

Duchenne muscular dystrophy (DMD) is a lethal hereditary muscle disease caused by mutations in the gene encoding the muscle protein dystrophin. These mutations result in a shift in the open reading frame leading to loss of the dystrophin protein. Antisense oligonucleotides (ASOs) that induce exon skipping correct this frame shift during pre-mRNA splicing and partially restore dystrophin expression in mouse and dog models. We conducted a phase 1, open-label, dose-escalation clinical trial to determine the safety, pharmacokinetics, and activity of NS-065/NCNP-01, a morpholino ASO that enables skipping of exon 53. Ten patients with DMD (6 to 16 years old), carrying mutations in the dystrophin gene whose reading frame would be restored by exon 53 skipping, were administered NS-065/NCNP-01 at doses of 1.25, 5, or 20 mg/kg weekly for 12 weeks. The primary endpoint was safety; the secondary endpoints were pharmacokinetics and successful exon skipping. No severe adverse drug reactions were observed, and no treatment discontinuation occurred. Muscle biopsy samples were taken before and after treatment and compared by reverse transcription polymerase chain reaction (RT-PCR), immunofluorescence, and Western blotting to assess the amount of exon 53 skipping and dystrophin expression. NS-065/NCNP-01 induced exon 53 skipping in dystrophin-encoding mRNA in a dose-dependent manner and increased the dystrophin/spectrin ratio in 7 of 10 patients. Furthermore, the amount of exon skipping correlated with the maximum drug concentration in plasma (Cmax) and the area under the concentration-time curve in plasma (AUC0-t). These results indicate that NS-065/NCNP-01 has a favorable safety profile and promising pharmacokinetics warranting further study in a phase 2 clinical trial.

Ataluren: Clinical Trial Results in Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)

2016 ◽  
Vol 47 (S 01) ◽  
Author(s):  
U. Schara ◽  
C. McDonald ◽  
K. Bushby ◽  
M. Tulinius ◽  
R. Finkel ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Nonsense Mutation ◽  
Clinical Trial Results

Integrating radiomics into clinical trial design

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Jessica J. Waninger ◽  
Michael D. Green ◽  
Catherine Cheze Le Rest ◽  
Benjamin Rosen ◽  
Issam El Naqa
Keyword(s):  
Clinical Trial ◽  
Trial Design ◽  
Clinical Trial Design
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