Science Pool

The Covid-19 worldwide pandemic unveiled extraordinary resources within the scientific and pharmaceutical community delivering vaccines and therapeutic drug candidates within timelines never seen before. While the pandemic hit suddenly and the number of cases increased exponentially, the AMR crisis remained silent. Nevertheless, it is progressing and the emergency and spread of multidrug resistance is putting our existing antibiotic arsenal under increasing threat.

Is AMR our next pandemic?

Possibly, if we continue to consider antibiotics as fire-extinguishers: and only create novel therapeutics once we are face to face with the fire.

Innovation and collaboration are key in the preparedness, together with expertise and operational excellence. Evotec, with more than 200 scientists dedicated to antibacterial drug R&D, is at the forefront of AMR research and innovation. With infectious disease platforms spanning from in vitro biology to in vivo pharmacology and medicinal chemistry and benefiting from HTS platforms, ADME and toxicology expertise.

Innovative thinking and creativity to discover novel antibacterial compounds begins with designing a strategy to discover novel active compounds. By changing the paradigm in phenotypic screening and developing the Vivo Mimetic Media (VMM) concept for discovering novel Gram-negative antibacterials, Evotec has validated five alternative bacterial culture media that better mimic the conditions bacteria are facing during infections. These VMM conditions are affecting the physiology of growing bacteria by altering permeability (porins, efflux pumps and outer membrane) but mainly unveiling new targets and mechanisms of action (MoAs).

The cornerstone of innovation in antibacterial drug discovery is the application of machine learning to optimise chemical matter. By combining biological data, medicinal chemistry expertise and a deep learning approach, Evotec has enabled the prediction of antibacterial activities against 15 bacterial strains and provided de novo design of compounds, 76% of which were accurately predicted for their activity.

Validation of active compounds in appropriate pharmacodynamic models is crucial, while innovative approaches are needed for tailored design and improved readouts. By using luminescent or fluorescent bacteria, infection models with higher complexity have been developed to evaluate the spread of infection in real time and most importantly, measure the distribution of the active compound fluorescently labelled to the site of infection.

Innovation through collaboration and partnership is at the forefront of Evotec’s unique business model. Through a highly strategic partnership between Evotec, Resolute Therapeutics and CARB-X, a new antibacterial drug class termed TriBe is being advanced in the preclinical pipeline, with the objective to bring a candidate for the treatment of cUTI, cIAI and lung infections to clinical phase I. The TriBE series have unique properties with nanomolar bacterial topoisomerase inhibitors binding via the GyrB/ParE subunits, very broad bacterial spectrum, low potential to select for resistance, favourable PK and in vivo efficacy in multiple models of infection have been demonstrated.

While a consensus exists on the real and clear need for new antibacterials and approaches, the challenges are numerous and complex. Innovative thinking, creativity and novel approaches (target and technology) underpin anti-infective drug discovery at Evotec, enabling the redesigning of antibacterial discovery infrastructure to ensuring an integrated approach and foster collaboration, partnership, training and cross-interaction.

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Transient Receptor Potential Melastatin 5 (TRPM5) is an intracellular calcium-activated cation-selective ion channel which is expressed in a variety of cells and tissues. Dysfunction of the TRPM5 channel has been linked to a number of pathological conditions including diabetes, inflammatory responses, enteric infections and parasitic infections. Identifying sufficiently selective agonists or positive modulators of the TRPM5 channel has, to date, proved challenging which has limited its potential as a drug target.   

In this publication, we focus on:

• the development of a high throughput screen using a fluorescent membrane potential assay for primary hit identification screening and selectivity assessment of TRPM5 channel positive modulators 
• use of medium and high throughput electrophysiology assays (QPatch HTX and SyncroPatch 384PE) as follow-up screens to confirm activity and selectivity of identified hits
• the SyncroPatch 384PE assay for structure-activity relationship (SAR) expansion of the identified chemical series

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P2X3 receptors play an important role in the sensitisation of nerve fibres and pain pathways. Involvement in pathways triggering cough and contribution to the pathophysiology of endometriosis and overactive bladder have also been reported. Development of P2X antagonists have been hampered by off‑target effects which include severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer.  

In this publication, we focus on:

• how eliapixant (BAY 1817080), a P2X3 receptor antagonist, is both highly potent and selective for P2X3 over other P2X subtypes in vitro including P2X2/3
• how eliapixant reduces inflammatory pain in relevant animal models
• experimental evidence that P2X3 antagonism reduces neurogenic inflammation and vaginal pain, and demonstration of the potential use of eliapixant in endometriosis

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The key to de-risking and expediting the development and approval of new antimicrobials lies in the detailed understanding of the PK/PD relationship. Understanding this relationship informs the development of optimal human dosing, maximising efficacy while minimising the potential to antimicrobial resistance.

This white paper describes and appraises today's most versatile in vitro system for the determination of in vitro PK/PD relationships between antimicrobial compounds and bacteria, fungi and viruses - the Hollow Fibre Infection Model (HFIM)

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Alastair Parkes, Ph.D, Group Leader, Discovery Chemistry, Evotec UK

As part of our ongoing efforts at Evotec to tackle AMR through the design of novel antibiotics we have been working with Boston-based X-Biotix in a collaboration focussed on targeting priority Gram-negative pathogens. We are now able to share the story of our work on inhibitors of UDP-N-Acetylglucosamine Acyltransferase (LpxA), a key enzyme in the biosynthetic pathway of the outer membrane lipopolysaccharide of Gram-negative bacteria. Building on hit-finding work at X-Biotix we put together a multi-disciplinary team including Medicinal Chemistry, Computational Chemistry, Structural Biology and DMPK at our Abingdon UK site, in vitro and in vivo Microbiology and PK at our Alderley Park UK site, and in vitro Biology at our site in Hamburg, Germany. Through structure and property-based optimisation we were able to design highly potent inhibitors of Pseudomonas aeruginosa LpxA that were active against multi-drug resistant clinical isolates. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa bacteria. In our paper in the Journal of Medicinal Chemistry we share the optimisation story, along with a significant quantity of activity data that we hope will be useful for other teams working on small molecule strategies to tackle P. aeruginosa and other Gram-negative bacteria.

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The challenge of neurodegenerative diseases

In the context of an aging population, neurodegenerative conditions such as Parkinson´s disease or Alzheimer´s disease have become a major health problem in Western countries.
The global market size for neurodegenerative diseases drugs was estimated at USD 35 billion in 2018 and is projected to reach USD 63 billion by the end of 2026, exhibiting a CAGR of 7.2% (source: Fortune Business Insights).

Developing treatments for neurodegenerative diseases comes with a number of challenges: The underlying causes, diseases mechanisms and progression of disorders affecting the central nervous system have not yet been fully understood. This results in much higher drug failure rates as compared to other fields, making the development of novel therapeutics for neurodegenerative disease very time and cost intensive. Approved drugs only offer short-term improvement of the patients’ symptoms, so there is a huge unmet medical need for innovative therapies that slow down or ideally revert disease progression.

New treatment approaches urgently needed

In response to the high attrition rates, R&D efforts to unveil the mechanism of neurodegenerative diseases have gained increasing attention. Evotec has a strong commitment to developing novel therapeutic options in neurodegeneration for more than a decade. In our long-standing collaboration with Celgene (now Bristol Myers Squibb) we have set out to establish human induced pluripotent stem cell-based disease models to discover novel disease-modifying treatments for a broad range of neurodegenerative diseases.

What are induced pluripotent stem cells?
Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from the patient’s somatic cells through reprogramming. They can be propagated indefinitely and give rise to almost every cell type in the body (such as neurons, heart, pancreatic and liver cells) thereby presenting unprecedented opportunities to model human disease pathology.

Over the past decade, Evotec has built an industrialised iPSC infrastructure that represents one of the largest and most sophisticated iPSC platforms in the industry. It comprises multiple different cell types to investigate disease-relevant phenotypes, translatable biomarkers and therapeutic targets. Evotec’s iPSC platform has continuously been optimized for increased throughput, reproducibility and robustness to provide large-scale cultures of iPSC derived cells for disease modeling, drug discovery and cell therapy. Moreover, it is closely connected with our PanOmics and PanHunter platforms to determine molecular disease signatures that may aid in stratification of patients and clinical trial success.

Evotec’s iPSC platform has been developed in collaboration with top-tier academic and industrial partners such as the CHDI Foundation, the Harvard Stem Cell Institute, Centogene, CENSO Biotechnologies (now Axol Bioscience), Fraunhofer IME-SP, Reprocell, Pancella, the University of Tübingen – and more recently - Sartorius and Curexsys. The Company´s goal is to build a proprietary pipeline of first-in-class therapeutic agents for a broad range of different diseases with high medical need, including neurodegenerative disorders, to ultimately extend and improve the lives of millions of patients and their families worldwide.

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Mutant huntingtin (mHTT) protein has been implicated in neuronal degeneration in Huntington's Disease.

In this publication, we focus on:

• a background to the inherited neurodegenerative disorder, Huntington's Disease, including the impact of the mutant huntingtin (mHTT) gene
• a discussion of the use of positron emission tomography (PET) to monitor disease progression
• the identification of a novel ligand CHDI-626 which binds to mHTT aggregates

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Huntington's Disease is caused a mutation in the huntingtin (mHTT) gene which codes for the huntingtin (HTT) protein.

In this publication, we focus on:

• a background to link between Huntington's Disease and the mutant huntingtin gene (mHTT)
• the development of PET tracers for imaging mHTT aggregates
• characterisation of these PET tracers including pharmacological investigation of their binding affinities and selectivity

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The Hollow Fibre Infection Model (HFIM) is a dynamic in vitro system for the determination of  PK/PD relationships between antimicrobial compounds and bacteria, fungi or viruses.

Evotec has developed its own dedicated state-of-the-art BSL2 facility offering it partners a bespoke in vitro PK/PD service tailored to advance their individual antimicrobial development programs.

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The journey from a bacteria defence mechanism to a leading tool in modern biomedical research is often a long one. One exception to this has been the development of CRISPR-Cas9 technology. Originally discovered in its components as early as 1987, it reached the realms of a technology tool at the beginning of the last decade and was awarded the Nobel Prize in 2020.

Looking through the eyes of a drug hunter, it is fantastic to know that, finally, fast genetic modifications no longer have to be limited to yeast systems. Indeed, CRISPR Cas9 is greatly advancing the generation of model systems, the validation of drug targets and also the identification of new targets in previously inaccessible biological systems. Even therapeutic applications are possible with the promise of correcting faulty genes in patients. Furthermore, the tool is still evolving and almost daily, the attention of the scientific community is drawn to new exciting uses of this technology. It seems that with CRISPR creativity has no limits.

The CRISPR Cas9 system is a molecular scissor with the possibility of being directed to a precise location in the genome. So far, it has been shown to work very efficiently in knocking out a gene, both via cuts of major or minor part of its DNA or via insertion of stop cassettes. This process can offer a powerful tool to validate the effects of a drug or the effects of the absence of a target in a cell system. It can also boost or shut down the expression of a drug target, simulate pathologic conditions and better model a disease. Furthermore, with its handful of components, it is a versatile tool, which can cut and edit the genome to: knock out, overexpress, create base pair mutations, insert sequences at precise locations and interfere with gene expression. The fast and precise outcome, added to the speed by which this technology can perform, make it a valuable tool to add to the wide-spectrum of technologies already available.

At Evotec CRISPR Cas9 is widely used. Different licensing agreements are in place enabling use of the technology commercially. This adds important advantages when combined with the other myriad of technologies that the company offers. Evotec uses the technology to drive its target identification and validation platforms as well as aid the deconvolution of targets from phenotypic screening or in disease model generation. As an example, with the application of genome-wide CRISPR libraries into Evotec’s screening platforms, Evotec is harnessing the power of gene deletion and human cell-based disease models, to identify novel targets for downstream drug discovery programs and this helps the company’s research engine to move swiftly across the R&D Autobahn.

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