Clinical Perspectives on Targeting Therapies for Personalized Medicine

Abstract

Expected benefits from new technology include more efficient patient selection for clinical trials, more cost-effective treatment pathways for patients and health services and a more profitable accelerated approach for drug developers. Regulatory authorities expect the pharmaceutical and biotechnology industries to accelerate their development of companion diagnostics and companion therapeutics toward the goal of safer and more effective personalized medicine, and expect health services to fund and prescribers to adopt these new therapeutic technologies. This review discusses the importance of a range of new approaches to developing new and reprofiled medicines to treat common and serious diseases, and rare diseases: new network pharmacology approaches, adaptive trial designs with enriched populations more likely to respond safely to treatment, as assessed by companion diagnostics for response and toxicity risk and use of "real world" data. Case studies are described of single and multiple protein drug targets in several important therapeutic areas. These case studies also illustrate the value and complexity of use of selective biomarkers of clinical response and risk of adverse drug effects, either singly or in combination.

Pharmacogenomics of Multifactorial Diseases: A Focus on Psoriatic Arthritis

“…Consequently, the PGx research exploits the individual genetic makeup to stratify the patients into different subgroups that will be treated according to the precision medicine approach. In fact, a personalized therapy will be designed for patients subgroups with the purpose of achieving the optimal effectiveness and safety [7,8]. In this context, an excellent example of precision medicine is the screening for HLA-B*57:01, which has been associated with a high risk for hypersensitivity reaction to abacavir treatment (a very efficient antiretroviral drug) [9,10].…”

“…These indicators can be engaged as PGx biomarkers (PGBMs) for the development of genetic tests for the prediction of the response degree and/or the risk for ADRs to particular drugs [47]. The clinical utility of PGBMs has been extensively demonstrated by the reduction of ADRs incidence and the improvement of drugs efficacy in different pathological conditions [8][9][10][11][12][13]. Concerning the drugs in use for the treatment of PsA, the PGx research has been described only few 'genetic modifiers' (DHFR, MTHFR, FCGR2A, TNFRSF1A and TNFRSF10A) of the drug response and the susceptibility to ADRs [24].…”

Translating Knowledge Into Therapy for Acute Kidney Injury

“…More comprehensive, systems-based network analyses will be necessary to untangle and properly organize these data to identify common molecular networks and cellular phenotypes that influence cell function and disease phenotypes. 29,30 Systems-based analyses provide much stronger support for the choice of a molecular target (or targets) driving complex cellular responses because they account for higher-order interactions, downstream responses, and compensatory pathways that may not be identified using reductionist approaches for single target discovery. 31 In addition, systems-based analyses allow for the identification of common pathogenic or reparative cellular phenotypes that might be exploited in phenotype-driven discovery efforts.…”

From Personalized to Precision Medicine

“…По их утверждению точный, персонализированный подход -это «воз-можность классифицировать индивидуумов в субпо-пуляции, которые отличаются по своей подверженно-сти конкретному заболеванию или ответу на специ-фическое лечение. Профилактические или терапевти-ческие вмешательства могут быть сосредоточены на тех, кому они достоверно пойдут на пользу, избавляя от не-нужных расходов и побочных эффектов тех, кто от их применения достоверно не выиграет» [4].…”

“…Нередко пациенты не желают предоставлять ис-следователям свои личные данные, опасаясь негатив-ного влияния результатов на свое финансовое и соци-альное положение (возможность устроиться на рабо-ту, получить кредит, застраховаться) [4].…”