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Drug discovery and development processes with a potential to benefit from biomarkers phase I, II and III refer to clinical trial phases. NDA, new drug application (FDA); BLA, biological license application (FDA); MAA, marketing authorisation application (EU).
Source publication
Biomarkers are widely used at every stage of drug discovery and development. Utilisation of biomarkers has a potential to make drug discovery, development and approval processes more efficient. An overview of the current global regulatory landscape is presented in this article with particular emphasis on the validation and qualification of biomarke...
Citations
... Furthermore, since the beginning of the twenty-first century, biomarkers have become increasingly significant in drug discovery, development, and approval. Identifying suitable biomarkers can contribute to a deeper understanding of a drug's mechanism of action, assist in selecting appropriate patients for clinical trials, facilitate monitoring and predicting toxicity issues, and offer guidance for regulatory and drug development decisions (Gromova et al. 2020). ...
Safety Pharmacology (SP) plays a critical role in assessing the potential adverse effects of drugs on vital organ systems during the early stages of drug discovery and development. The field of SP has evolved to incorporate various methodologies and testing strategies. In the era of Precision Medicine (PM), SP contributes to the development of PM drugs by ensuring their safety in specific subpopulations. However, it is noted that the SP considerations for PM therapies differ from those for conventional drug candidates. For cell therapies, SP studies must consider the unique characteristics of these products. SP in gene therapies focuses on the safety of genetic material transfer using viral vectors, while CAR-T cell therapies pose the challenges of human cellular products and genome editing vectors. PM also plays a role in SP by identifying robust biomarkers that aid in safety assessment, monitoring, and predicting toxicity. The PM-inspired biomarkers enhance our understanding of how a drug works, help select the right patients for clinical trials, and guide regulatory decisions. Moreover, PM enables the invention of new modalities for SP experiments, such as spheroids, organoids, and organ-on-a-chip models, which provide biologically relevant and stable in vitro systems. Personalized organ-on-a-chip models hold promise for individually assessing drug efficacy and safety, supporting personalized disease prevention and treatment strategies. Experts in both SP and PM recognize the importance of updating SP guidelines to incorporate the advancements of PM. Multidisciplinary efforts are expected to lead to remarkable advances in drug development, ultimately benefiting healthcare.
... Biomarkers play an essential role in diagnostics and drug development [24,25]. To quantify the bacterial load upon antibiotic treatment, we used CFU enumeration, RLU and OD 600 measurements, and quantification of 16S rRNA/IS2404 genes. ...
Background
Buruli ulcer (BU) is a skin neglected tropical disease (NTD) caused by Mycobacterium ulcerans . WHO-recommended treatment requires 8-weeks of daily rifampicin (RIF) and clarithromycin (CLA) with wound care. Treatment compliance may be challenging due to socioeconomic determinants. Previous minimum Inhibitory Concentration and checkerboard assays showed that amoxicillin/clavulanate (AMX/CLV) combined with RIF+CLA were synergistic against M . ulcerans . However, in vitro time kill assays (TKA) are a better approach to understand the antimicrobial activity of a drug over time. Colony forming units (CFU) enumeration is the in vitro reference method to measure bacterial load, although this is a time-consuming method due to the slow growth of M . ulcerans .
The aim of this study was to assess the in vitro activity of RIF, CLA and AMX/CLV combinations against M . ulcerans clinical isolates by TKA, while comparing four methodologies: CFU enumeration, luminescence by relative light unit (RLU) and optical density (at 600 nm) measurements, and 16S rRNA/IS 2404 genes quantification.
Methodology/Principal findings
TKA of RIF, CLA and AMX/CLV alone and in combination were performed against different M . ulcerans clinical isolates. Bacterial loads were quantified with different methodologies after 1, 3, 7, 10, 14, 21 and 28 days of treatment.
RIF+AMX/CLV and the triple RIF+CLA+AMX/CLV combinations were bactericidal and more effective in vitro than the currently used RIF+CLA combination to treat BU. All methodologies except IS 2404 quantitative PCR provided similar results with a good correlation with CFU enumeration. Measuring luminescence (RLU) was the most cost-effective methodology to quantify M . ulcerans bacterial loads in in vitro TKA.
Conclusions/Significance
Our study suggests that alternative and faster TKA methodologies can be used in BU research instead of the cumbersome CFU quantification method. These results provide an in vitro microbiological support to of the BLMs4BU clinical trial ( NCT05169554 , PACTR202209521256638 ) to shorten BU treatment.
... Biomarkers are powerful tools to enable confidence in decisionmaking along the drug development lifecycle for diverse applications, including diagnosis, patient stratification, pharmacodynamic response, and surrogates of efficacy. Importantly, the rate of drug approvals across diseases is known to increase when biomarkers are utilized in trials (Gromova et al., 2020). The use of pharmacodynamic biomarkers to demonstrate target engagement in early clinical development is key to assuring proof of pharmacology in target tissue. ...
A rich pipeline of therapeutic candidates is advancing for Parkinson’s disease, many of which are targeting the underlying pathophysiology of disease. Emerging evidence grounded in novel genetics and biomarker discoveries is illuminating the true promise of precision medicine-based therapeutic strategies for PD. There has been a growing effort to investigate disease-modifying therapies by designing clinical trials for genetic forms of PD - providing a clearer link to underlying pathophysiology. Leading candidate genes based on human genetic findings that are under active investigation in an array of basic and translational models include SNCA, LRRK2, and GBA. Broad investigations across mechanistic models show that these genes signal through common molecular pathways, namely, autosomal lysosomal pathways, inflammation and mitochondrial function. Therapeutic clinical trials to date based on genetically defined targets have not yet achieved approvals; however, much is to be learned from such pioneering trials. Fundamental principles of drug development that include proof of pharmacology in target tissue are critical to have confidence in advancing such precision-based therapies. There is a clear need for downstream biomarkers of leading candidate therapies to demonstrate proof of mechanism. The current regulatory landscape is poised and primed to support translational modeling strategies for the effective advancement of PD disease-modifying therapeutic candidates. A convergence of rich complex data that is available, the regulatory framework of model informed drug development (MIDD), and the new biological integrated staging frameworks when combined are collectively setting the stage for advancing new approaches in PD to accelerate progress. This perspective review highlights the potential of quantitative systems pharmacology (QSP) modeling in contributing to the field and hastening the pace of progress in advancing collaborative approaches for urgently needed PD disease-modifying treatments.
... In that context, identifying biomarkers predictive of response is crucial to refine patient selection, improve treatment efficacy, and prolong survival in patient subpopulations. Biomarker discovery is leading to a paradigm shift in cancer treatment by providing powerful information to improve diagnostic accuracy, predict treatment response and determine prognosis [15]. ...
We recently discovered a putative paclitaxel response predictive biomarker for glioblastoma and breast cancer using the whole genome CRISPR knockout screen. The biomarker candidate was validated in two independent breast cancer patient cohorts that received taxane treatment. To further evaluate the potential application of this biomarker in the clinic for patients with glioblastoma, a prospective validation in cohorts of patients with glioblastoma is essential and will be performed as part of our ongoing phase II clinical trial (NCT04528680). The validation of novel biomarkers of susceptibility to therapy is critical to elucidate the efficacy signal of therapeutic agents. This is especially important in the context of glioblastoma, where therapeutic benefit is variable and unpredictable, leading to negative trials, yet the outcome of subset of patients has outperformed expectations.
... Among various methods, biomarkers are widely used in the diagnosis of pathological conditions. It is also applicable in many research fields such as drug discovery and the monitoring of specific medication (Gromova et al., 2020). Although some previous research have been conducted to identify biomarkers specific to T. spiralis, most of them were focused on the protein-based biomarkers Wang et al., 2014;Thawornkuno et al., 2022). ...
Human trichinellosis is a parasitic infection caused by roundworms belonging to the genus Trichinella, especially Trichinella spiralis. Early and accurate clinical diagnoses of trichinellosis are required for efficacious prognosis and treatment. Current drug therapies are limited by antiparasitic resistance, poor absorption, and an inability to kill the encapsulating muscle-stage larvae. Therefore, reliable biomarkers and drug targets for novel diagnostic approaches and anthelmintic drugs are required. In this study, metabolite profiles of T. spiralis adult worms and muscle larvae were obtained using mass spectrometry-based metabolomics. In addition, metabolite-based biomarkers of T. spiralis excretory–secretory products and their related metabolic pathways were characterized. The metabolic profiling identified major, related metabolic pathways involving adenosine monophosphate (AMP)-dependent synthetase/ligase and glycolysis/gluconeogenesis in T. spiralis adult worms and muscle larvae, respectively. These pathways are potential drug targets for the treatment of the intestinal and muscular phases of infection. The metabolome of larva excretory–secretory products was characterized, with amino acid permease and carbohydrate kinase being identified as key metabolic pathways. Among six metabolites, decanoyl-l-carnitine and 2,3-dinor-6-keto prostaglandin F1α-d9 were identified as potential metabolite-based biomarkers that might be related to the host inflammatory processes. In summary, this study compared the relationships between the metabolic profiles of two T. spiralis growth stages. Importantly, the main metabolites and metabolic pathways identified may aid the development of novel clinical diagnostics and therapeutics for human trichinellosis and other related helminthic infections.
... The ultimate goal is to improve patient outcomes by preventing missed treatment opportunities and reducing undesirable side effects. 18 In this article, we present recent advancements in the identification of predictive markers for therapeutic response and toxicity to single chemotherapeutic drugs and their combinations, which can be used to inform treatment decisions. We then discuss the challenges and prospects of biomarker discovery. ...
During the last few decades, the treatment options available for patients with metastatic colorectal cancer (mCRC) have undergone continuous improvements, transitioning from conventional chemotherapy to targeted therapy. These therapeutic innovations have led to significant improvements in patient clinical outcomes. However, there remains a need to improve the outcome for many CRC patients. Chemotherapy remains a cornerstone of CRC treatment, but the wide variability in tumour response and adverse reactions to chemotherapy poses a challenge to cancer treatment management. As a result, there is an unmet need to identify predictive biomarkers of chemotherapeutic response to guide treatment decisions. In this review, we summarise the conventional biomarkers used to predict chemotherapy responses in CRC and provide an overview of emerging predictive biomarkers based on the current understanding of the molecular biology of treatment response. Finally, we explore the challenges and future prospects of biomarker discovery to improve the prediction of patient response and ensure optimal treatment management for patients with metastatic CRC.
... Biomarkers are customarily hired in each phase of drug discovery; the use of biomarkers has the potential to speed up the drug discovery process and approval procedures [21]. The ability of biomarkers is exploited during preclinical studies, to distinguish disease models, and investigate the consequence and mechanism of action of the lead drug candidates in vivo models [20]. ...
The application of biotechnology in drug discovery has been discovered to be a promising and resourceful approach for the discovery of novel therapeutic candidates that comes with less time and cost than the traditional ways of drug discovery. This has additionally endowed researchers with the necessary understanding of diseases, which offers exceptional methods for treating patients. Additionally, diagnosis and treatment are becoming increasingly intertwined with the help of biotechnology. Today, researchers in biotechnology deal with the root of diseases and find solutions through therapeutic agents, hence, improving quality of life. The discovery of drugs in recent days
is practically challenging without good modeling in biotechnology, this wonderful technique is now being adopted in the discovery of new and effective classes of drugs which include but are not limited to gene therapy, cancer vaccines, proteins, and even enzymes. In this current review, we review the efforts so far in the usage of this approach in drug discovery. The review targets the biotechnological application and design implementation in drug discovery. It explains the use of proteins, genes, in-silico, and stem cells in designing models for enhanced drug discovery, the chemical similarity network for drug discovery, and future recommendations on the integration of AI in biotechnology
... [35][36][37] Biomarkers have also contributed to the approval of new therapeutic strategies. 38 Nab-paclitaxel, the first prototypical member of albumin-bound chemotherapy, is widely used in clinical practice; however, not all patients benefit from nab-paclitaxel. Therefore, specific biomarkers that predict patient outcomes from this class of treatment are lacking. ...
Albumin is an attractive candidate carrier for the development of novel therapeutic drugs. Gemcitabine has been FDA approved for the treatment of solid tumors; however, new drugs that optimize gemcitabine delivery are not available for clinical use. The aim of this study was to test the efficacy of a novel albumin-encapsulated gemcitabine prodrug, JNTX-101, and investigate whether Cav-1 expression predicts the therapeutic efficacy of JNTX-101. We first determined the treatment efficacy of JNTX-101 in a panel of pancreatic/lung cancer cell lines and found that increases in Cav-1 expression resulted in higher uptake of albumin, while Cav-1 depletion attenuated the sensitivity of cells to JNTX-101. In addition, decreased Cav-1 expression markedly reduced JNTX-101-induced apoptotic cell death in a panel of cells, particularly in low-serum conditions. Furthermore, we tested the therapeutic efficacy of JNTX-101 in xenograft models and the role of Cav-1 in JNTX-101 sensitivity using a Tet-on-inducible tumor model in vivo. Our data suggest that JNTX-101 effectively inhibits cell viability and tumor growth, and that Cav-1 expression dictates optimal sensitivity to JNTX-101. These data indicate that Cav-1 correlates with JNTX-101 sensitivity, especially under nutrient-deprived conditions, and supports a role for Cav-1 as a predictive biomarker for albumin-encapsulated therapeutics such as JNTX-101.
... Schon von den in den Jahren von 2015 bis 2019 von der European Medicines Agency (EMA) und der amerikanischen Food and Drug Administration (FDA) neu zugelassenen Medikamenten waren rund zwei Drittel (65 %) unter Zuhilfenahme von Biomarkern entwickelt worden (vgl. Gromova et al. 2020 ...
Die Studie untersucht den gegenwärtigen und zukünftig zu erwartenden Nutzen von Laboranalysen aus der Perspektive von Patientinnen und Patienten und der Gesellschaft. Nach Expertenmeinung gilt die Labormedizin als ausschlaggebend für etwa 70 Prozent aller klinischen Entscheidungen; sie wird jedoch hinsichtlich ihrer Kosten und des Kosten-Nutzen-Verhältnisses diagnostischer Verfahren kritisch betrachtet.
Die Autoren publizieren mit diesem Buch eine wissenschaftliche Untersuchung, die für die Schweiz massgebliche Krankheitsbilder identifiziert und innerhalb dieser Gruppen die Bedeutung der Labordiagnostik anhand exemplarischer Analysen und Tests explizit herausstellt. Darüber hinaus werden die Zukunftspotenziale der Labormedizin eingehend beleuchtet.
... Schon von den in den Jahren von 2015 bis 2019 von der European Medicines Agency (EMA) und der amerikanischen Food and Drug Administration (FDA) neu zugelassenen Medikamenten waren rund zwei Drittel (65 %) unter Zuhilfenahme von Biomarkern entwickelt worden (vgl. Gromova et al. 2020 ...
Zusammenfassung
In der Gesamtbetrachtung zeichnet sich das Gesundheitssystem der Schweiz im internationalen Vergleich gleichermassen durch seine grosse Leistungsfähigkeit ( pars pro toto : die Lebenserwartung der Schweizer wird nur von derjenigen der Japaner übertroffen) wie durch seine hohen Kosten aus.
Vor dem Hintergrund steigender Ansprüche an den Nachweis der Wirksamkeit und der Wirtschaftlichkeit medizinischer Massnahmen ist es das Ziel der vorliegenden Arbeit, den Nutzen der Laboratoriumsmedizin aus patientenbezogener und gesellschaftlicher Perspektive anhand exemplarischer Testverfahren zu dokumentieren.
