Challenges in drug development for central nervous system disorders: a European Medicines Agency perspective

Butlen-Ducuing, Florence; Pétavy, Frank; Guizzaro, Lorenzo; Zienowicz, Małgorzata; Haas, Manuel; Alteri, Enrica; Salmonson, Tomas

doi:10.1038/nrd.2016.237

Cited by 34 publications

(22 citation statements)

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“…Current AD management is only symptomatic and a global goal of finding an effective treatment or a way to prevent AD has been set to year 2025 3 . Early and precise diagnosis of AD, as well as appropriate clinical trial designs with sufficient justification for the choice of dose, are key aspects of successful drug development 4 . Proper dose selection in clinical trials is exceptionally challenging and it requires a knowledge-based confidence in processes governing pharmacological effect throughout CNS drug development.…”

Section: Introductionmentioning

confidence: 99%

Heterogeneous drug tissue binding in brain regions of rats, Alzheimer’s patients and controls: impact on translational drug development

Gustafsson

Sehlin

Lampa

et al. 2019

Sci Rep

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For preclinical and clinical assessment of therapeutically relevant unbound, free, brain concentrations, the pharmacokinetic parameter fraction of unbound drug in brain (f u,brain ) is commonly used to compensate total drug concentrations for nonspecific brain tissue binding (BTB). As, homogenous BTB is assumed between species and in health and disease, rat BTB is routinely used. The impact of Alzheimer’s disease (AD) on drug BTB in brain regions of interest (ROI), i.e., f u,brain,ROI , is yet unclear. This study for the first time provides insight into regional drug BTB and the validity of employing rat f u,brain,ROI as a surrogate of human BTB, by investigating five marketed drugs in post-mortem tissue from AD patients (n = 6) and age-matched controls (n = 6). Heterogeneous drug BTB was observed in all within group comparisons independent of disease and species. The findings oppose the assumption of uniform BTB, highlighting the need of case-by-case evaluation of f u,brain,ROI in translational CNS research.

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Section: Introductionmentioning

confidence: 99%

Heterogeneous drug tissue binding in brain regions of rats, Alzheimer’s patients and controls: impact on translational drug development

Gustafsson

Sehlin

Lampa

et al. 2019

Sci Rep

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“…Butlen-Ducuing et al . had access to applications of this type and found 46 applications in psychiatry between 1995 and 2014 (Butlen-Ducuing et al ., 2016). We were unable to compare the applications that resulted in an approval with refused applications.…”

Section: Discussionmentioning

confidence: 99%

The evidence base for psychotropic drugs approved by the European Medicines Agency: a meta-assessment of all European Public Assessment Reports

Erhel

Scanff

Naudet

2020

Epidemiol Psychiatr Sci

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Aims To systematically assess the level of evidence for psychotropic drugs approved by the European Medicines Agency (EMA). Methods Cross-sectional analysis of all European Public Assessment Reports (EPARs) and meta-analyses of the many studies reported in these EPARs. Eligible EPARs were identified from the EMA's website and individual study reports were requested from the Agency when necessary. All marketing authorisation applications (defined by the drug, the route of administration and given indications) for psychotropic medications for adults (including drugs used in psychiatry and addictology) were considered. EPARs solely based on bioequivalence studies were excluded. Our primary outcome measure was the presence of robust evidence of comparative effectiveness, defined as at least two ‘positive’ superiority studies against an active comparator. Various other features of the approvals were assessed, such as evidence of non-inferiority v. active comparator and superiority v. placebo. For studies with available data, effect sizes were computed and pooled using a random effect meta-analysis for each dose of each drug in each indication. Results Twenty-seven marketing authorisations were identified. For one, comparative effectiveness was explicitly considered as not needed in the EPAR. Of those remaining, 21/26 (81%) did not provide any evidence of superiority against an active comparator, 2/26 (8%) were based on at least two trials showing superiority against active comparator and three (11%) were based on one positive trial; 1/26 provided evidence for two positive non-inferiority analyses v. active comparator and seven (26%) provided evidence for one. In total, 20/27 (74%) evaluations reported evidence of superiority v. placebo with two or more trials. Among the meta-analyses of initiation studies against active comparator (57 available comparisons), the median effect size was 0.051 (range −0.503; 0.318). Twenty approved evaluations (74%) reported evidence of superiority v. placebo on the basis of two or more initiation trials and seven based on a single trial. Among meta-analyses of initiation studies against placebo (125 available comparisons), the median effect size was −0.283 (range −0.820; 0.091). Importantly, among the 89 study reports requested on the EMA website, only 19 were made available 1 year after our requests. Conclusions The evidence for psychiatric drug approved by the EMA was in general poor. Small to modest effects v. placebo were considered sufficient in indications where an earlier drug exists. Data retrieval was incomplete after 1 year despite EMA's commitment to transparency. Improvements are needed.

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“…Confounding factors include the complexity of brain physiology and pathology, as well as inadequate translational preclinical models to evaluate experimental therapeutics [ 1 ]. Despite significant progress in brain imaging surrogates for assessing therapeutic efficacy, more accessible brain-specific molecular biomarkers for early diagnosis and patient stratification for clinical trials remain sparse [ 1 ]. In addition, the delivery of therapeutics across the blood–brain barrier (BBB) remains one of the prime challenges in CNS drug development.…”

Section: The Blood–brain Barrier: a Challenge Solved?mentioning

confidence: 99%

Emerging Technologies for Delivery of Biotherapeutics and Gene Therapy Across the Blood–Brain Barrier

2018

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Antibody, immuno- and gene therapies developed for neurological indications face a delivery challenge posed by various anatomical and physiological barriers within the central nervous system (CNS); most notably, the blood–brain barrier (BBB). Emerging delivery technologies for biotherapeutics have focused on trans-cellular pathways across the BBB utilizing receptor-mediated transcytosis (RMT). ‘Traditionally’ targeted RMT receptors, transferrin receptor (TfR) and insulin receptor (IR), are ubiquitously expressed and pose numerous translational challenges during development, including species differences and safety risks. Recent advances in antibody engineering technologies and discoveries of RMT targets and BBB-crossing antibodies that are more BBB-selective have combined to create a new preclinical pipeline of BBB-crossing biotherapeutics with improved efficacy and safety. Novel BBB-selective RMT targets and carrier antibodies have exposed additional opportunities for re-targeting gene delivery vectors or nanocarriers for more efficient brain delivery. Emergence and refinement of core technologies of genetic engineering and editing as well as biomanufacturing of viral vectors and cell-derived products have de-risked the path to the development of systemic gene therapy approaches for the CNS. In particular, brain-tropic viral vectors and extracellular vesicles have recently expanded the repertoire of brain delivery strategies for biotherapeutics. Whereas protein biotherapeutics and bispecific antibodies enabled for BBB transcytosis are rapidly heading towards clinical trials, systemic gene therapy approaches for CNS will likely remain in research phase for the foreseeable future. The promise and limitations of these emerging cross-BBB delivery technologies are further discussed in this article.

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Challenges in drug development for central nervous system disorders: a European Medicines Agency perspective

Cited by 34 publications

References 0 publications

Heterogeneous drug tissue binding in brain regions of rats, Alzheimer’s patients and controls: impact on translational drug development

Heterogeneous drug tissue binding in brain regions of rats, Alzheimer’s patients and controls: impact on translational drug development

The evidence base for psychotropic drugs approved by the European Medicines Agency: a meta-assessment of all European Public Assessment Reports

Emerging Technologies for Delivery of Biotherapeutics and Gene Therapy Across the Blood–Brain Barrier

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