By leveraging intensification, minimization, and simplification in bioprocessing workflows, Just-Evotec Biologics can achieve higher productivity, better resource utilization and lower facility costs. Collectively, these benefits contribute to reducing the COGM of biotherapeutics.
Continuous biomanufacturing arrives in Europe:
Nick Hutchinson, Head of Market Development at Just – Evotec Biologics, explains the benefits of this new approach, why the company’s new cGMP manufacturing facility, J.POD® Toulouse, France (EU), is the first of its kind in Europe and what this means for the industry.
Tags: Articles & Whitepapers, Formulation & CMC, Biologics, Immunology & Inflammation, Clinical Development
4’-Phosphopantetheinyl transferase (PptT) is a crucial enzyme for the survival and virulence of Mycobacterium tuberculosis (Mtb), making it an attractive target for tuberculosis treatment. In recent research, our collaborators at University of North Carolina (UNC ); Weill Cornell Medical College, Texas Agricultural and Mechanical University (TAMU) explored ways to replace the amidinourea moiety in the previously known PptT inhibitor AU 8918. These findings hold promise for developing new drugs to combat mycobacterial infections.
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Evotec and Sanofi scientists, together with TBAlliance and Tuberculosis Drug Accelerator (TBDA) partners, have been involved in the discovery of sequanamycins, a class of compounds that combat drug-resistant tuberculosis. The original compound , the SEQ-503 was a macrolide from the Sanofi Natural Product patrimony, discovered in 1962 in Vitry-sur Seine and named after sequana, the seine goddess in the Gallo-Roman religion. Optimization of SEQ-503 has given rise to SEQ9 with a remarkable efficacy against Mycobacterium tuberculosis (Mtb).
Key findings:
Promising prospects for TB clinical candidates!
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We are honoured to be part of the TBDA consortium and would like to congratulate our colleagues on the release of their new publication
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Our recent publication, "Crystal structure of human peptidylarginine deiminase type VI (PAD6) provides insights into its inactivity", written in collaboration with our partners the Bill & Melinda Gates Foundation, has been accepted and released by the IUCr Journal. You can freely access it below.
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Tags: Articles & Whitepapers
Biomarkers are very useful tools for drug developers as well as for clinicians. In drug research and development, they add value as they improve the success rate of clinical trials. In the clinic, they validate the eligibility of patients as well as the efficacy of an approved treatment. In the recent Evotec webinar on aging, Elizabeth van der Kam, SVP, Translational Biomarkers and Human Sample Management, gave an overview on biomarkers in general and the role of biomarkers in aging.
In fact, the success rate of clinical studies can by doubled by introducing biomarkers early on, that can predict efficacy and potential safety issues. Biomarkers also may be important to reduce costs by running smarter trails in smaller groups of patients and if translated to companion diagnostics, biomarkers enhance the readiness of payers to reimburse a novel drug, but they also enable higher profits as the drug can be sold together with a diagnostic test. Therefore, Evotec´s strategy is to develop a biomarker as early as possible during the R&D process.
Types of biomarkers
There are several types of biomarkers. Useful for early studies are biomarkers that demonstrate target engagement, meaning they show that a drug candidate hits the target in the relevant organ and triggers a response. However, target engagement not necessarily means that this is relevant for the disease.
Another classification consists of surrogate biomarkers, which exhibit correlations with the disease or its progression and could hold relevance in the context of the disease More useful are efficacy markers which are not just correlated but causative for the disease. Another important class of biomarkers are safety biomarkers which, as an example, alert a clinical trial leader or a physician that the drug also hits another target and could potentially cause an issue. Then there are stratification markers indicating the likelihood of a patient to respond to treatment. This is important as non-responders should not be included in trials or prescribed an ineffective treatment. Last but not least, there are diagnostic and prognostic biomarkers that help to better understand the disease and its progression, to establish the right dosage, assess efficacy and predict disease progression and monitor the patients.
In any case, a biomarker needs to be translatable and relevant, and its measurement should be feasible, robust, reliable, and durable.
Biomarkers in aging
The situation is complex in aging. Chronological age is not the best inclusion criterium for clinical trials of medicines trying to improve the health span of elderly patients as chronological age can be very different from biological age.
But how to define biological age? What markers are out there? Of course, there are a lot of markers of biological age, e.g., body composition, body fat, physical appearance and function, muscle mass, grip strength, walking speed, balance, wrinkles, grey hair, but also blood-based changes in terms of hormone and vitamin levels and progressing diseases such as poor eyesight, osteoporosis, declining kidney function, and many more.
However, none of these markers is sufficient as a stand-alone data point. Some of the changes observed in elderly people can also be found in younger people or in patients with non-age-related diseases. The best biomarkers are the ones that can be established without subjective assessments.
The situation is further complicated by the fact that aging is not a disease, and that any intervention should be made early before the onset of typical signs of aging. Ideally, one would have biomarkers that can tell which category of older people will develop certain diseases. At present however, there are biomarkers indicating changes in many pathways and targets, but these often only indicate a certain chance of getting a disease.
The challenge
At present, biomedicine does not have access to markers that can predict certain biological deteriorations, let alone predict potential success of a treatment. And how to define a subpopulation and forecast treatment success without waiting for years to see an effect?
Currently one of the best overall indicators of biological aging is inflammaging. It demonstrates changes in the immune system, inflammation, and an imbalance in the innate or the adaptive immune system, thereby predicting a high risk of unhealthy aging. However, inflammaging can also be caused by lifestyle and gender, so it is not an ideal biomarker. Recently, under review of the U.S. National Institute for Aging, the TAME BIO (Targeted Ageing with MEtformin) project tried to establish a basis for future biomarker discovery and validation and accelerate the pace of ageing-research.
The project started out with more than 200 potential biomarker candidates that were screened for feasibility, dependency on gender, and environmental factors, etc., bringing down the list of candidates to less than 90. Then they were assessed for disease-relation, robustness, their association to multi-morbidity and the usefulness to clinical trials, leaving a final set of eight candidates. This was, however, a purely theoretical exercise and whether these candidates are useful in real life needs to be proven. At present, the jury is still out on useful biomarkers for trials and therapies to prolong health span and quality and duration of life.
Learn more in the webinar "A Spotlight on Ageing" by Elizabeth van der Kam, SVP, Translational Biomarkers and Human Sample Management at Evotec
Tags: Articles & Whitepapers, Blog, In vitro Biology, Proteomics, Metabolomics & Biomarkers, Age-Related Diseases, Clinical Development
This review explores patient-centric omics mining strategies for target identification in disease mechanism-centric medicine. Using chronic kidney disease (CKD) as an illustrative example, the paper proposes a data-driven and unbiased patient stratification approach to support traditional classification based on observable clinical symptoms and diagnoses. Advocating for state-of-the-art systems biology, the paper suggests integrating transcriptomic, clinical, and morphological data to construct verifiable models of diseases like CKD. These models can provide a framework for mechanistic analysis and for the identification of potential therapeutic targets in the context of precision medicine.
Tags: Articles & Whitepapers, Proteomics, Metabolomics & Biomarkers
Cardiotoxicity is one of the most reported adverse effects that leads to pre-clinical and clinical drug failure. To tackle this, the International Conference of Harmonization (ICH) S7B guideline in 2005, proposed a non-clinical assessment of new drug entities using in vitro electrophysiology studies (typically hERG ion channel) and in vivo telemetry in animal models. Although these are very sensitive approaches, they may have also led to unwarranted drug attrition of many potentially valuable therapeutics due to the low specificity nature of the assays.
More recently, the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative was proposed by experts in the field and was established to move safety pharmacology towards in silico and in vitro approaches utilising new and emerging technologies such as stem-cell-derived cardiomyocytes. Building on this new safety paradigm, colleagues from Evotec and Cyprotex have worked collaboratively to develop a non-clinical model using cutting-edge techniques with improved predictive power to de-risk cardiotoxicity in early drug discovery. We have presented the output of this work in a research article titled “In-depth mechanistic analysis including high-throughput RNA sequencing in the prediction of functional and structural cardiotoxicants using hiPSC cardiomyocytes” published in a recent edition of Expert Opinion on Drug Metabolism and Toxicology.
In this article, we describe the use of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as an in vitro model system together with three high-throughput technologies incorporating structural assays (high-content imaging, HCI), functional assays (Ca2+ transience, CaT) and high-throughput RNA-sequencing (ScreenSeq) for the pre-clinical risk assessment of novel compounds. The transcriptional responses of hiPSC-CMs to 24 h treatment with 33 cardiotoxicants (12 structural cardiotoxicants, 14 functional cardiotoxicants, 7 structural/functional cardiotoxicants) and 9 non-cardiotoxicants of mixed therapeutic indications were investigated and compound-induced differential gene expression (DEG) was calculated in comparison with vehicle treated controls. Likewise, the hiPSC-CMs responses to six structural readouts (cell count, cellular ATP, mitochondrial mass, mitochondrial membrane potential, calcium content, DNA structure and nuclear size) and four functional readouts (amplitude, frequency, peak width and decay time) were analysed. In summary, hiPSC-CMs recapitulated expected structural and functional toxicity mechanisms, validating their use as in vitro model system to detect and characterize modes of toxicity. ScreenSeq identified several molecular mechanisms of toxicity such as alterations in cardiac pathways, genotoxicity, ER stress and mitochondrial toxicity. Together, HCI, CaT and ScreenSeq provided the best cardiotoxicity prediction metrics (10x Cmax: 100% specificity, 82% sensitivity, 86% accuracy; 25x Cmax: 89% specificity, 91% sensi-tivity, 90% accuracy).
This study not only provides invaluable cardiotoxic mechanistic information of the drugs tested, but it also demonstrates the potential of this mechanism-driven risk assessment approach in predicting drug-induced cardiotoxicity in hiPSC-CMs.
Read the paper.
Read more about our Cardiotox Screen assay consisting of both a functional assay (examining the mechanical function of the cardiomyocytes) and a structural assay (assessing morphological changes and loss of viability).
In addition, discover more about our transcriptomics offerings here.
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Tags: Toxicology, Articles & Whitepapers, Blog, Toxicology & Safety
Target identification is a fundamental first step in drug discovery, involving the discovery and validation of disease-associated molecular mechanism that can be modulated by a drug. In this whitepaper we introduce Evotec's PanOmics TargetID Framework developed by the Bioinformatics and Computational Biology teams. It is a modular system that uses computational tools coupled with expert assessments to identify and rank potential drug targets. Our framework delivers a comprehensive report with a list of disease-relevant targets, their scores, annotations, rankings, and detailed information on their druggability, biology, safety, competition, and efficacy..
Tags: Articles & Whitepapers, Proteomics, Metabolomics & Biomarkers