Towards regulatory endorsement of drug development tools to promote the application of model-informed drug development in Duchenne muscular dystrophy

Conrado, Daniela J.; Larkindale, Jane; Berg, Alexander; Hill, Martha; Burton, Jackson; Abrams, Keith R.; Abresch, Richard T.; Bronson, Abby; Chapman, Douglass; Crowther, Michael J.; Duong, Tina; Gordish‐Dressman, Heather; Harnisch, Lutz; Henricson, E.; Kim, Sarah; McDonald, Craig; Schmidt, Stephan; Vong, Camille; Wang, Xiaoxing; Wong, Brenda; Yong, Florence H.; Romero, Klaus

doi:10.1007/s10928-019-09642-7

Cited by 20 publications

(23 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DMD is a progressive degenerative disease, which shows age-dependent disease progression. As demonstrated recently, 24 disease progression of DMD in younger subjects < 7 years is in parallel with growth and development, which may result in a temporary net gain in strength or abilities, albeit to a lesser extent than in healthy children of the same age. This has also been confirmed by Lennie et al, 25 who applied an indirect response model to describe DMD disease progression as measured by the 6MWT over a wide pediatric age range and compared it with those of healthy subjects.…”

Section: Discussionmentioning

confidence: 64%

Exposure‐Response Analysis of Vamorolone (VBP15) in Boys With Duchenne Muscular Dystrophy

Conklin

Anker

et al. 2020

The Journal of Clinical Pharma

View full text Add to dashboard Cite

Exposure‐response relationships of vamorolone, a novel dissociative steroidal anti‐inflammatory drug, were investigated in clinical trials in boys with Duchenne muscular dystrophy. Variables were clinical outcome measures, Fridericia‐corrected QT (QTcF) duration, and pharmacodynamic (PD) biomarkers. Exposure metrics were area under the plasma concentration time curve (AUC) and maximum plasma concentration (Cmax), with a sigmoid Emax model applied. Significant improvement in clinical efficacy outcomes was observed after 24 weeks of daily dosing. The primary outcome, time to stand from supine velocity, exhibited the highest sensitivity to vamorolone, with the lowest AUC value providing 50% of maximum effect (E50 = 186 ng·h/mL), followed by time to climb 4 stairs (E50 = 478 ng·h/mL), time to run/walk 10 m (E50 = 1220 ng·h/mL), and 6‐minute walk test (E50 = 1770 ng·h/mL). Week 2 changes of proinflammatory PD biomarkers showed exposure‐dependent decreases. The E50 was 260 ng·h/mL for insulin‐like growth factor‐binding protein 2, 1200 ng·h/mL for matrix metalloproteinase 12, 1260 ng·h/mL for lymphotoxin α1/β2, 1340 ng·h/mL for CD23, 1420 ng·h/mL for interleukin‐22‐binding protein, and 1600 ng·h/mL for macrophage‐derived chemokine/C‐C motif chemokine 22. No relationship was found between QTcF interval changes from baseline and Cmax in week 2 or 24. This analysis showed that improvements in clinical efficacy end points in week 24 and PD biomarkers in week 2 were achieved at typical vamorolone exposure of 2 mg/kg daily dose with a median AUC dose of 6 mg/kg (3651 ng·h/mL), corresponding to approximately 95% of maximum effects for most response variables.

show abstract

Section: Discussionmentioning

confidence: 64%

Exposure‐Response Analysis of Vamorolone (VBP15) in Boys With Duchenne Muscular Dystrophy

Conklin

Anker

et al. 2020

The Journal of Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…These models will be used to develop a clinical trial simulation platform that will help optimize trial design by informing inclusion criteria and endpoint selection, and to inform how to optimize clinical trial protocols based on trial duration, numbers of subjects, predicted drug effect, and outcome assessments used. 15 An HD database with formats based upon the CDISC HD-TAUG is currently under development. It is anticipated to house data from over 10 registries, observational studies, and interventional clinical trials, resulting in an aggregate database of nearly 20,000 participants and covering the continuum of the disease in individuals over 18 years old.…”

Section: Resultsmentioning

confidence: 99%

“…The models and platform have been accepted into review programs by the FDA and EMA for potential regulatory endorsement. 15 By developing the CDISC TAUG for DMD, a process and structure has been laid out for standardized collection of prospective data across studies, and through which results of different studies can be compared. This will lead to valuable new insights in both treating disease and developing new therapies.…”

Section: Discussionmentioning

confidence: 99%

Standardized Data Structures in Rare Diseases: CDISC User Guides for Duchenne Muscular Dystrophy and Huntington’s Disease

Mullin

Corey

Turner

et al. 2020

Clinical Translational Sci

Self Cite

View full text Add to dashboard Cite

Interest in drug development for rare diseases has expanded dramatically since the Orphan Drug Act was passed in 1983, with 40% of new drug approvals in 2019 targeting orphan indications. However, limited quantitative understanding of natural history and disease progression hinders progress and increases the risks associated with rare disease drug development. Use of international data standards can assist in data harmonization and enable data exchange, integration into larger datasets, and a quantitative understanding of disease natural history. The US Food and Drug Administration (FDA) requires the use of Clinical Data Interchange Consortium (CDISC) Standards in new drug submissions to help the agency efficiently and effectively receive, process, review, and archive submissions, as well as to help integrate data to answer research questions. Such databases have been at the core of biomarker qualification efforts and fit-for-purpose models endorsed by the regulators. We describe the development of CDISC therapeutic area user guides for Duchenne muscular dystrophy and Huntington's disease through Critical Path Institute consortia. These guides describe formalized data structures and controlled terminology to map and integrate data from different sources. This will result in increased standardization of data collection and allow integration and comparison of data from multiple studies. Integration of multiple data sets enables a quantitative understanding of disease progression, which can help overcome common challenges in clinical trial design in these and other rare diseases. Ultimately, clinical data standardization will lead to a faster path to regulatory approval of urgently needed new therapies for patients.

show abstract

“…Only then can a slower decline be picked up reliably. Two collaborative initiatives (the collaborative trajectory analysis project (cTAP) and the Duchenne muscular dystrophy regulatory science consortium (D-RSC)) are generating models to facilitate optimize patient selection for clinical trials [119][120][121][122].…”

Section: Expert Opinionmentioning

confidence: 99%

Developments in reading frame restoring therapy approaches for Duchenne muscular dystrophy

Schneider

Aartsma‐Rus

2020

Expert Opinion on Biological Therapy

View full text Add to dashboard Cite

Introduction: Exon skipping compounds restoring the dystrophin transcript reading frame have received regulatory approval for Duchenne muscular dystrophy (DMD). Recently, focus shifted to developing compounds to skip additional exons, improving delivery to skeletal muscle, and to genome editing, to restore the reading frame on DNA level. Areas covered: We outline developments for reading frame restoring approaches, challenges of mutation specificity, and optimizing delivery. Also, we highlight ongoing efforts to better detect exon skipping therapeutic effects in clinical trials. Searches on relevant terms were performed, focusing on recent publications (<3 years). Expert opinion: Currently, 3 AONS are approved. Whether dystrophin levels are sufficient to slowdown disease progression needs to be confirmed. Enhancing AON uptake by muscles is currently under investigation. Gene editing is an alternative, but one that involves practical and ethical concerns. Given the field's momentum, we believe the efficiency of frame-restoring approaches will improve.

show abstract

Towards regulatory endorsement of drug development tools to promote the application of model-informed drug development in Duchenne muscular dystrophy

Cited by 20 publications

References 27 publications

Exposure‐Response Analysis of Vamorolone (VBP15) in Boys With Duchenne Muscular Dystrophy

Exposure‐Response Analysis of Vamorolone (VBP15) in Boys With Duchenne Muscular Dystrophy

Standardized Data Structures in Rare Diseases: CDISC User Guides for Duchenne Muscular Dystrophy and Huntington’s Disease

Developments in reading frame restoring therapy approaches for Duchenne muscular dystrophy

Contact Info

Product

Resources

About