Drug discovery and development for rare genetic disorders

Sun, Wei; Zheng, Wei; Simeonov, Anton

doi:10.1002/ajmg.a.38326

Cited by 70 publications

(52 citation statements)

References 107 publications

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“…Therapeutic approaches based on the development of small molecules are being successfully applied to genetic diseases such as cystic fibrosis and other genetic conditions [ 31 , 32 , 33 ]. However, the development of a drug starting from a potentially beneficial but newly identified molecule is a very long and expensive path.…”

Section: Translating the Results Of Basic Research Into The Develomentioning

confidence: 99%

“…However, the development of a drug starting from a potentially beneficial but newly identified molecule is a very long and expensive path. Drug repositioning, i.e., the use of known drugs and compounds to treat diseases different from those for which they were originally employed, provides a significant advantage in term of time and cost, compared to the development of new molecules [ 33 ].…”

Section: Translating the Results Of Basic Research Into The Develomentioning

confidence: 99%

See 1 more Smart Citation

The Horizon of a Therapy for Rare Genetic Diseases: A “Druggable” Future for Fibrodysplasia Ossificans Progressiva

Cappato

Giacopelli

Ravazzolo

et al. 2018

IJMS

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Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition characterized by progressive extra-skeletal ossification leading to cumulative and severe disability. FOP has an extremely variable and episodic course and can be induced by trauma, infections, iatrogenic harms, immunization or can occur in an unpredictable way, without any recognizable trigger. The causative gene is ACVR1, encoding the Alk-2 type I receptor for bone morphogenetic proteins (BMPs). The signaling is initiated by BMP binding to a receptor complex consisting of type I and II molecules and can proceed into the cell through two main pathways, a canonical, SMAD-dependent signaling and a p38-mediated cascade. Most FOP patients carry the recurrent R206H substitution in the receptor Glycine-Serine rich (GS) domain, whereas a few other mutations are responsible for a limited number of cases. Mutations cause a dysregulation of the downstream BMP-dependent pathway and make mutated ACVR1 responsive to a non-canonical ligand, Activin A. There is no etiologic treatment for FOP. However, many efforts are currently ongoing to find specific therapies targeting the receptor activity and the downstream aberrant pathway at different levels or targeting cellular components and/or processes that are important in modifying the local environment leading to bone neo-formation.

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Section: Translating the Results Of Basic Research Into The Develomentioning

confidence: 99%

Section: Translating the Results Of Basic Research Into The Develomentioning

confidence: 99%

The Horizon of a Therapy for Rare Genetic Diseases: A “Druggable” Future for Fibrodysplasia Ossificans Progressiva

Cappato

Giacopelli

Ravazzolo

et al. 2018

IJMS

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“…Gene replacement therapy (GRT) is a novel approach to cure diseases caused by monogenic genetic disorders which offers hope for lifelong improvement to patients suffering from inherited, incurable, and debilitating conditions[ 1 ]. Gene-based therapies use genes to treat diseases, but they can employ different techniques to repair a defect in an existing DNA[ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Health economic evaluation of gene replacement therapies: methodological issues and recommendations

Aballéa¹,

Thokagevistk

Velikanova

et al. 2020

Journal of Market Access & Health Policy

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Objective : To provide recommendations for addressing previously identified key challenges in health economic evaluations of Gene Replacement Therapies (GRTs), including: 1) the assessment of clinical effectiveness; 2) the valuation of health outcomes; 3) the time horizon and extrapolation of effects beyond trial duration; 4) the estimation of costs; 5) the selection of appropriate discount rates; 6) the incorporation of broader elements of value; and 7) affordability. Methods : A literature review on economic evaluations of GRT was performed. Interviews were conducted with 8 European and US health economic experts with experience in evaluations of GRT. Targeted literature reviews were conducted to investigate further potential solutions to specific challenges. Recommendations : Experts agreed on factors to be considered to ensure the acceptability of historical cohorts by HTA bodies. Existing prospective registries or, if not available, retrospective registries, may be used to analyse different disease trajectories and inform extrapolations. The importance of expert opinion due to limited data was acknowledged. Expert opinion should be obtained using structured elicitation techniques. Broader elements of value, beyond health gains directly related to treatment, can be considered through the application of a factor to inflate the quality-adjusted life years (QALYs) or a higher cost-effectiveness threshold. Additionally, the use of cost-benefit analysis and saved young life equivalents (SAVE) were proposed as alternatives to QALYs for the valuations of outcomes of GRT as they can incorporate broader elements of value and avoid problems of eliciting utilities for paediatric diseases. Conclusions : While some of the limitations of economic evaluations of GRT are inherent to limited clinical data and lack of experience with these treatments, others may be addressed by methodological research to be conducted by health economists.

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“…Three recent review articles in this journal have shared perspectives on important aspects of drug development for rare diseases. Sun, Zheng, and Simeonov () from the NIH described early stage drug development from in vitro screening, assay development, and lead optimization to preclinical proof of concept, pharmacology, and toxicity testing. Kempf, Goldsmith, and Temple () from the FDA discussed the challenges associated with running clinical trials for rare diseases as well as the regulatory programs that are intended to lend sponsors a helping hand.…”

Section: Introductionmentioning

confidence: 99%

The art and science of choosing efficacy endpoints for rare disease clinical trials

Cox

2018

American J of Med Genetics Pt A

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An important challenge in rare disease clinical trials is to demonstrate a clinically meaningful and statistically significant response to treatment. Selecting the most appropriate and sensitive efficacy endpoints for a treatment trial is part art and part science. The types of endpoints should align with the stage of development (e.g., proof of concept vs. confirmation of clinical efficacy). The patient characteristics and disease stage should reflect the treatment goal of improving disease manifestations or preventing disease progression. For rare diseases, regulatory approval requires demonstration of clinical benefit, defined as how a patient, feels, functions, or survives, in at least one adequate and well-controlled pivotal study conducted according to Good Clinical Practice. In some cases, full regulatory approval can occur using a validated surrogate biomarker, while accelerated, or provisional, approval can occur using a biomarker that is likely to predict clinical benefit. Rare disease studies are small by necessity and require the use of endpoints with large effect sizes to demonstrate statistical significance. Understanding the quantitative factors that determine effect size and its impact on powering the study with an adequate sample size is key to the successful choice of endpoints. Interpreting the clinical meaningfulness of an observed change in an efficacy endpoint can be justified by statistical methods, regulatory precedence, and clinical context. Heterogeneous diseases that affect multiple organ systems may be better accommodated by endpoints that assess mean change across multiple endpoints within the same patient rather than mean change in an individual endpoint across all patients.

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Drug discovery and development for rare genetic disorders

Cited by 70 publications

References 107 publications

The Horizon of a Therapy for Rare Genetic Diseases: A “Druggable” Future for Fibrodysplasia Ossificans Progressiva

The Horizon of a Therapy for Rare Genetic Diseases: A “Druggable” Future for Fibrodysplasia Ossificans Progressiva

Health economic evaluation of gene replacement therapies: methodological issues and recommendations

The art and science of choosing efficacy endpoints for rare disease clinical trials

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