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. 2019;21(2):177-191.
doi: 10.31887/DCNS.2019.21.2/hhampel.

Blood-based systems biology biomarkers for next-generation clinical trials in Alzheimer's disease

Harald Hampel  1 , Andrea Vergallo  1 , Mohammad Afshar  1 , Leyla Akman-Anderson  1 , Joaquín Arenas  1 , Norbert Benda  1 , Richard Batrla  1 , Karl Broich  1 , Filippo Caraci  1 , A Claudio Cuello  1 , Enzo Emanuele  1 , Marion Haberkamp  1 , Steven J Kiddle  1 , Alejandro Lucía  1 , Mark Mapstone  1 , Steven R Verdooner  1 , Janet Woodcock  1 , Simone Lista  1
Affiliations

Blood-based systems biology biomarkers for next-generation clinical trials in Alzheimer's disease

Harald Hampel et al. Dialogues Clin Neurosci. 2019.

Abstract
in English, Spanish, French

Alzheimer's disease (AD)-a complex disease showing multiple pathomechanistic alterations-is triggered by nonlinear dynamic interactions of genetic/epigenetic and environmental risk factors, which, ultimately, converge into a biologically heterogeneous disease. To tackle the burden of AD during early preclinical stages, accessible blood-based biomarkers are currently being developed. Specifically, next-generation clinical trials are expected to integrate positive and negative predictive blood-based biomarkers into study designs to evaluate, at the individual level, target druggability and potential drug resistance mechanisms. In this scenario, systems biology holds promise to accelerate validation and qualification for clinical trial contexts of use-including proof-of-mechanism, patient selection, assessment of treatment efficacy and safety rates, and prognostic evaluation. Albeit in their infancy, systems biology-based approaches are poised to identify relevant AD "signatures" through multifactorial and interindividual variability, allowing us to decipher disease pathophysiology and etiology. Hopefully, innovative biomarker-drug codevelopment strategies will be the road ahead towards effective disease-modifying drugs. .

La Enfermedad de Alzheimer (EA) es una enfermedad compleja que presenta múltiples alteraciones patomecánicas, que se desencadena por interacciones dinámicas no lineales de factores de riesgo genéticos / epigenéticos y ambientales, los que, en definitiva, convergen en una enfermedad biológicamente heterogénea. Para hacer frente a la carga de la EA durante las etapas preclínicas tempranas, actualmente se están desarrollando biomarcadores sanguíneos de fácil accesibilidad. Específicamente, se espera que los ensayos clínicos de próxima generación integren biomarcadores sanguíneos predictivos tanto positivos como negativos en los diseños de los estudios para evaluar, a nivel individual, la capacidad de la droga objetivo y los posibles mecanismos de resistencia a los medicamentos. En este contexto, la biología de sistemas promete acelerar la validación y la calificación de su empleo en los ensayos clínicos, incluida la prueba del mecanismo, la selección de pacientes, la evaluación de la eficacia del tratamiento y los porcentajes de seguridad, y la evaluación pronóstica. A pesar de estar en sus comienzos, los enfoques basados en la biología de sistemas están preparados para identificar “firmas” de EA relevantes a través de la variabilidad multifactorial e interindividual, lo que nos permite descifrar la fisiopatología y la etiología de la enfermedad. Ojalá, las estrategias innovadoras conjuntas del desarrollo de biomarcadores y de medicamentos sean el camino adecuado para conseguir fármacos eficaces que modifiquen la enfermedad.

La maladie d’Alzheimer (MA) — maladie complexe présentant des altérations nombreuses pathomécaniques — est déclenchée par des interactions dynamiques non linéaires entre des facteurs de risques génétiques et épigénétiques et environnementaux qui, au bout du compte, aboutissent à une maladie biologiquement hétérogène. Pour réduire la charge de morbidité de la MA durant ses premiers stades précliniques, des biomarqueurs sanguins sont actuellement développés. Spécifiquement, la prochaine génération d’essais cliniques devrait intégrer ces biomarqueurs sanguins positifs ou négatifs prédictifs de la maladie dans des études qui auront pour but d’évaluer, à un niveau individuel, des cibles pouvant être traitées par des candidats médicaments et de potentiels mécanismes de résistance à ces médicaments. Dans ce contexte, la biologie des systèmes devrait permettre d’accélérer la validation et la qualification de leur utilisation dans les études cliniques – incluant la preuve du mécanisme d’action, la sélection des patients, la confirmation de l’efficacité du traitement et son niveau de sécurité, ainsi que l’évaluation pronostique. Bien que nous en soyons au tout début, les approches reposant sur la biologie des systèmes sont sur le point d’identifier des « signatures » pertinentes de la MA grâce à des variables multifactorielles et interindividuelles, qui nous permettront d’élucider la pathophysiologie et l’étiologie de la maladie. Avec un peu de chance, les stratégies innovantes de codéveloppement de biomarqueurs et de médicaments nous mèneront vers des médicaments efficaces pour lutter contre la maladie.

Keywords: Alzheimer’s disease; biomarker-drug codevelopment; blood-based biomarker; clinical trial; context of use; pathophysiology; precision medicine; predictive biomarker; systems biology.

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Figures

Figure 1.
Figure 1.. Potential collaboration points between academia and industry. Academic and industrial approaches to biomarker development are inherently different, but combining these approaches could be extremely useful. Close collaboration 
between industry and academia would allow sharing of expertise in product testing, access to cohorts and clinical data, 
and sharing of ideas and theories with regard to clinical end points and context. By merging the two approaches, a method whereby the context of use is the primary focus throughout the process can be established. This model enabled synergistic development of a new biomarker between academics and industrial partners, sharing a wealth of experience.
Figure 2.
Figure 2.. Conceptual framework for biomarker-drug codevelopment strategies. Biomarkers should go through all the phases of drug development and should be validated and qualified with regulatory guidance. Here, a “regulatory” setting for a 
single test that would be used together with a single drug in the clinical management of a patient is shown. The figure 
emphasizes key events for both the diagnostic test and drug regulation with coordination of the regulatory processes 
governing them, with the purpose of launching the products in parallel. Blue arrows, Drug development; orange rectangles, biomarker discovery, validation, and qualification.
See this image and copyright information in PMC

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