PRO38 Twenty Years of Clinical Trials in Duchenne Muscular Dystrophy: A Low Clinical Drug Development Success

Duchenne muscular dystrophy (DMD) is a devastating, rare disease. While clinically described in the 19th century, the genetic foundation of DMD was not discovered until more than 100 years later. This genetic understanding opened the door to the development of genetic treatments for DMD. Over the course of the last 30 years, the research that supports this development has moved into the realm of clinical trials and regulatory drug approvals. Exon skipping to therapeutically restore the frame of an out-of-frame dystrophin mutation has taken center stage in drug development for DMD. The research reviewed here focuses on the clinical development of exon skipping for the treatment of DMD. In addition to the generation of clinical treatments that are being used for patient care, this research sets the stage for future therapeutic development with a focus on increasing efficacy while providing safety and addressing the multi-systemic aspects of DMD.

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How clinical trials of myasthenia gravis can inform pre-clinical drug development

Experimental Neurology ◽

10.1016/j.expneurol.2014.12.022 ◽

2015 ◽

Vol 270 ◽

pp. 78-81 ◽

Cited By ~ 5

Author(s):

Anna Rostedt Punga ◽

Henry J. Kaminski ◽

David P. Richman ◽

Michael Benatar

Keyword(s):

Clinical Trials ◽

Drug Development ◽

Myasthenia Gravis ◽

Clinical Drug Development ◽

Clinical Drug

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MICRODOSING/MICROTRACING CLINICAL TRIALS USING ACCELERATED MASS SPECTROMETRY IN CLINICAL DRUG DEVELOPMENT

Proceedings for Annual Meeting of The Japanese Pharmacological Society ◽

10.1254/jpssuppl.wcp2018.0_or13-5 ◽

2018 ◽

Vol WCP2018 (0) ◽

pp. OR13-5

Author(s):

Mu Seong Ban ◽

Jun Gi Hwang ◽

Jae Hoon Shim ◽

Anhye Kim ◽

Joo-Youn Cho ◽

...

Keyword(s):

Mass Spectrometry ◽

Clinical Trials ◽

Drug Development ◽

Clinical Drug Development ◽

Clinical Drug

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Clinical Quality Considerations when Using Next-Generation Sequencing (NGS) in Clinical Drug Development

Therapeutic Innovation & Regulatory Science ◽

10.1007/s43441-021-00308-6 ◽

2021 ◽

Author(s):

Timothé Ménard ◽

Alaina Barros ◽

Christopher Ganter

Keyword(s):

Clinical Trials ◽

Next Generation Sequencing ◽

Drug Development ◽

Precision Medicine ◽

Service Providers ◽

Clinical Quality ◽

Clinical Drug Development ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing ◽

Clinical Drug

AbstractNext-generation sequencing (NGS) and decreased costs of genomic testing are changing the paradigm in precision medicine and continue to fuel innovation. Integration of NGS into clinical drug development has the potential to accelerate clinical trial conduct and ultimately will shape the landscape of clinical care by making it easier to identify patients who would benefit from particular therapy(ies) and to monitor treatment outcomes with less invasive tests. This has led to an increased use of NGS service providers by pharmaceutical sponsors: to screen patients for clinical trials eligibility and for patient stratification, expanded Companion Diagnostic (CDx) development for treatment recommendations and Comprehensive Genomic profiling (CGP). These changes are reshaping the face of clinical quality considerations for precision medicine. Although some clinical quality considerations do exist in Health Authorities (HA) guidances and regulations (e.g., International Conference of Harmonization Good Clinical Practices—GCP), there is currently no holistic GxP-like detailed framework for pharmaceutical sponsors using NGS service providers in clinical trials, or for the development of CDx and CGP. In this research, we identified existing and applicable regulations, guidelines and recommendations that could be translated into clinical quality considerations related to technology, data quality, patients and oversight. We propose these considerations as a basis for pharmaceutical sponsors using NGS service providers in clinical drug development to develop a set of guidelines for NGS clinical quality.

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Clinical Drug Development in Thromboembolic Diseases: Regulatory and Methodological Approach

Current Drug Discovery Technologies ◽

10.2174/1570163811209020105 ◽

2012 ◽

Vol 9 (2) ◽

pp. 105-118 ◽

Cited By ~ 2

Author(s):

Gonzalo Calvo-Rojas ◽

Antonio Gomez-Outes

Keyword(s):

Drug Development ◽

Methodological Approach ◽

Clinical Drug Development ◽

Clinical Drug

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Genotype characterization and delayed loss of ambulation by glucocorticoids in a large cohort of patients with Duchenne muscular dystrophy

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01837-x ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Shu Zhang ◽

◽

Dongdong Qin ◽

Liwen Wu ◽

Man Li ◽

...

Keyword(s):

Clinical Trials ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Hazard Ratio ◽

Large Cohort ◽

Muscle Disease ◽

Clinical Progression ◽

Large Deletions ◽

The Mean ◽

Lower Hazard

Abstract Background Duchenne muscular dystrophy (DMD) is the most common genetic muscle disease in human. We aimed to describe the genotype distribution in a large cohort of Chinese DMD patients and their delayed loss of ambulation by glucocorticoid (GC) treatments. This is to facilitate protocol designs and outcome measures for the emerging DMD clinical trials. Results A total of 1163 patients with DMD were recruited and genotyped. Genotype variations were categorized as large deletions, large duplications, and small mutations. Large deletions were further analyzed for those amenable to exon-skipping therapies. Participants aged 5 years or older were grouped into GC-treated and GC-naïve groups. Clinical progression among different genotypes and their responses to GC treatments were measured by age at loss of ambulation (LOA). Among the mutation genotypes, large deletions, large duplications, and small mutations accounted for 68.79%, 7.14%, and 24.07%, respectively. The mean age at diagnosis was 4.59 years; the median ages at LOA for the GC-naïve, prednisone/prednisolone-treated, and deflazacort-treated groups were 10.23, 12.02, and 13.95 years, respectively. The “deletion amenable to skipping exon 44” subgroup and the nonsense-mutation subgroup had older ages at LOA than the “other deletions” subgroup. Subgroups were further analyzed by both genotypes and GC status. All genotypes showed significant beneficial responses to GC treatment. Deletions amenable to skipping exon 44 showed a lower hazard ratio (0.155). The mean age at death was 18.57 years in this DMD group. Conclusion Genotype variation influences clinical progression in certain DMD groups. Beneficial responses to GC treatment were observed among all DMD genotypes. Compared with other genotypes, deletions amenable to skipping exon 44 had a lower hazard ratio, which may indicate a stronger protective effect of GC treatments on this subgroup. These data are valuable for designing future clinical trials, as clinical outcomes may be influenced by the genotypes.

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Has molecular imaging delivered to drug development?

Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences ◽

10.1098/rsta.2017.0112 ◽

2017 ◽

Vol 375 (2107) ◽

pp. 20170112 ◽

Cited By ~ 2

Author(s):

Philip S. Murphy ◽

Neel Patel ◽

Timothy J. McCarthy

Keyword(s):

Molecular Imaging ◽

Drug Development ◽

Clinical Studies ◽

Pharmaceutical Research ◽

Whole Body ◽

Drug Candidate ◽

Clinical Drug Development ◽

Target Binding ◽

The Brain ◽

Clinical Drug

Pharmaceutical research and development requires a systematic interrogation of a candidate molecule through clinical studies. To ensure resources are spent on only the most promising molecules, early clinical studies must understand fundamental attributes of the drug candidate, including exposure at the target site, target binding and pharmacological response in disease. Molecular imaging has the potential to quantitatively characterize these properties in small, efficient clinical studies. Specific benefits of molecular imaging in this setting (compared to blood and tissue sampling) include non-invasiveness and the ability to survey the whole body temporally. These methods have been adopted primarily for neuroscience drug development, catalysed by the inability to access the brain compartment by other means. If we believe molecular imaging is a technology platform able to underpin clinical drug development, why is it not adopted further to enable earlier decisions? This article considers current drug development needs, progress towards integration of molecular imaging into studies, current impediments and proposed models to broaden use and increase impact. This article is part of the themed issue ‘Challenges for chemistry in molecular imaging’.

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