Science Pool

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:

• Sequanamycins overcome Mtb’s inherent macrolide resistance.
• Lead compound   SEQ-9 is bactericidal when combined with other TB drugs.

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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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

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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.

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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 C_max: 100% specificity, 82% sensitivity, 86% accuracy; 25x C_max: 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.

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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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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..

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Cell line development at Just – Evotec Biologics is focused on lowering the cost of biologics development and manufacturing through the creation of highly productive engineered cell lines for our clients and partners. To achieve this, we leverage our own in-house GS knockout CHO host cell line, which has been shown to support cell densities up to 80 M cell/mL and productivities upwards of 5 g/L/day in our perfusion bioreactor platform. Additionally, we have implemented advanced instruments and liquid handling automation to increase the throughput of processes that are historically major bottlenecks. Examples of this include semi-automated, independent transfections of up to 32 different expression vectors or high throughput single-cell cloning/screening of up 1000 clones. Paired with our process development and manufacturing expertise, we continue to push the envelope on improving drug costs and have enabled many of our clients to file for INDs.

If you’d like to learn more about the benefits of a customized cell line development program, you can download our white paper here

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Patients around the world have limited or restricted access to biopharmaceutical medicines. Reducing production costs while still maintaining high quality standards will help increase the affordability of biologics and ensure more patients benefit from these life-saving medicines.

Traditional biomanufacturing facilities have failed to deliver biopharmaceutical products with sufficiently low Cost of Goods Manufactured (COGM) to allow greater patient access. These facilities have been built with fixed capacity and a focus on large-scale fed-batch manufacturing. Scaling-up processes to large-scale fed-batch manufacturing facilities involves considerable risk, resource, and upfront costs. Such facilities often lack flexibility which limits the products that can be produced within them and can leave valuable production assets idle for periods of time.

Manufacturing costs link directly to capacity utilization and product demand. There is a historical precedent within the biopharmaceutical industry of operating with excess capacity but we must recognise this comes with a financial penalty. We must address this challenge if we are to respond to global healthcare emergencies, changes in the way healthcare systems are managed and greater demand for global access to biotherapeutics.


Continuous Bioprocessing Platforms and Modular Facility Designs

The industry needs new flexible biomanufacturing concepts to quickly react to market fluctuations and achieve a higher predictability of costs. Modern biopharmaceutical productions facilities use building and manufacturing technologies, such as modular construction, to minimize clean room space utilization and reduce footprints. They allow faster speed to market with a lower upfront capital investment and are readily expandable when product demand is better understood. Continuous manufacturing platforms can be integrated into these facilities for low-cost bioprocessing using mammalian cell hosts in perfusion bioreactors linked to continuous downstream trains. Production costs remain low irrespective of facility mass output, the product quality attributes are consistent and manufacturing footprints are minimized.

Just-Evotec Biologics has developed a low-cost manufacturing facility design utilizing modular cleanroom pod technology that we call J.POD®. The J.POD facility design features individual pre-fabricated cleanroom pods arranged in a controlled, non-classified ballroom to minimize the cleanroom footprint of operations that would have previously taken place in a large ballroom. Media and buffer preparations, cell expansion, upstream, downstream and post viral are all housed in separate pods. The design minimizes fixed utility infrastructure and instead relies on single-use continuous upstream and downstream operations.

Biomanufacturing Facility Cost Comparisons

We developed process models for a fed-batch process in a traditional stainless-steel facility, a fed-batch process in a single-use facility and three continuous processes in a J.POD facility. The models were created using the Biosolve software (Biopharm Software Ltd) to show the benefit of the J.POD facility design on the COGM of an antibody biologic. We used Net Present Cost (NPC) to compare scenarios. NPC estimates cash flows by computing operational costs and discounting over time using a capital parameter. It does not include revenues in the accounting of cash flows and assumes capital costs are sunk costs incurred at the beginning of the project.



Figure 1 shows the expected costs from operating the different facility types and assumes their throughput increases at a rate of 250 kg/year up until a peak value. The range selected was representative of market demands for typical biopharmaceutical manufacturing facilities. Jumps in the NPC correspond to points when the capacity of a facility is reaches and new builds are needed.

We can draw the following conclusions from the results.

1. J.POD facilities achieve remarkable production outputs despite their small footprint because of the high productivity of the continuous perfusion process.
2. Fixed CapEx comprises a large proportion of the total costs in a stainless-steel facility. J.POD facilities apply single-use technologies resulting in a shift from fixed to variable costs.
3. The fully continuous J.POD facility gives the lowest costs with the stainless-steel facility returning the highest expenditure over the range.
4. The stainless-steel facility is not being operated at its optimum utilization rate over the production output range modelled that leads to inefficiencies.

Driving Up Access to Biotherapeutic Medicines

We believe that modern biomanufacturing facilities must have smaller processing spaces, higher production throughputs and lower production costs. Modelling shows how our J.POD facilities have the lowest initial build and operating costs as well as the ability to control operating costs. These facilities are outperforming older manufacturing platforms in terms of cost and utilization. They are becoming an essential component of strategies for reducing costs and driving up access to biotherapeutic medicines. 

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