Science Pool

Molecular profiling of cancer patients is a great success story: A single test can analyse a patient’s genome to identify genetic alterations from the four main classes that are known to drive cancer growth: base mutations, gene insertions and deletions, copy number alterations, and rearrangements or fusions. In addition to retrieving information on these common oncogenic drivers, it is also possible to obtain new information on complex or rare biomarkers from the same test. Based on this knowledge, oncologists can select the most suitable cancer therapy, often a combination of increasingly targeted drugs that address a specific cancer mechanism. As a result, molecular profiling approaches have been integrated to mainstream clinical oncology, and targeted therapies have become standard of care for patients known to express certain mutations in their tumours.

Molecular profiling – suitable for many indications

This success has fueled interest in the molecular profiling of other complex indications as well and has also expanded the profiling process: not only the sequence is analysed, but also methylation and expression patterns. The profiling toolbox also includes proteomics to analyse the proteins expressed in a cell or tissue and metabolomics to study the metabolism of diseased cells, tissue, organs, and patients.

The wealth of data generated by these approaches is now being analysed by artificial intelligence linking these data to individual patient information to identify biomarkers that provide insights into the genesis and course of the disease and that may help to stratify patients, predict outcome, and select therapies. The goal of these efforts is the development of precision medicines for complex diseases not only in cancer, but also in autoimmune or other chronic diseases – a clear departure from the old paradigm of “one-drug-fits-all.”

By systematically integrating data science across its discovery and development platform, Evotec aims to lead this paradigm change towards highly effective personalised medicine of the future. It has industrialised the generation of genomics, transcriptomics, proteomics and metabolomics data with its EVOpanOmics platform and has built a strong complementary data analytics platform driven by artificial intelligence and machine learning with EVOpanHunter. This platform makes use of molecular patient databases, bioinformatics and the data generated by EVOpanOmics.

Integrated approach

The company is in a unique position as these platforms are complemented by Evotec’s multimodality expertise spanning from small molecules and chemistry to biologicals, antisense molecules to cell and gene therapy. Moreover, with its iPSC platform Evotec’s scientists can design and test patient-derived disease models for comprehensive compound profiling in the treatment development process, focusing on disease relevance throughout the entire pre-clinical and clinical steps.

Already, Evotec has closed a number of collaborations in this field. In 2020, it joined forces with Indivumed GmbH for the discovery and development of first-in-class therapeutics for the treatment of non-small cell lung cancer (NSCLC). The collaboration combines Evotec’s bioinformatics, advanced analytics and AI capabilities as well as its small molecule and antibody discovery platforms, with the NSCLC cohort of Indivumed’s multi-omics cancer database “IndivuType.”

In the same year, Evotec closed a partnership with the University of Oxford, gaining access to biospecimens from the biobank Quality in Organ Donation (QUOD), an initiative of the university’s Nuffield Department of Surgical Sciences (NDS) in close collaboration with the National Health Service Blood and Transplant (NHSBT) organisation in the UK. QUOD is providing blood, urine and tissue samples from heart, lung, liver and kidney from consented organ donors for researchers with anonymised integrated medical records. Evotec at present is investigating first samples from 1,000 individuals using a comprehensive multi-omics approach (genomics, transcriptomics, proteomics, metabolomics) to complement its existing patient database. The goal is to enable a better understanding of disease mechanisms across indications, i.e. cardiovascular, kidney, and liver diseases.

A particular focus of Evotec is chronic kidney disease (CKD). CKD is an impending public healthcare challenge, and the traditional diagnostic biomarkers, e.g. creatinine, have low sensitivity and specificity. Therefore, novel diagnostic and prognostic biomarkers for patients at high risk of early-stage progression are urgently needed. They may not only provide information about the etiology and mechanisms underlying CKD progression, but may also enable early diagnosis and the selection of appropriate therapies, thereby personalising therapy. Evotec closed a strategic partnership with the University Hospital of Erlangen for the molecular analysis of biospecimens from the German Chronic Kidney Disease (GCKD) cohort study initiated by the university. GCKD is the world’s largest cohort study on chronic kidney disease, enabled by scientists from eleven universities and more than 150 practicing nephrologists that monitor more than 5,000 patients with CKD. The study comprises sampling of biospecimens, clinical data and multiple interviews. The collaboration aims to better understand the various kidney disease etiologies, their respective disease mechanisms, progression, and potential complications. Together with Evotec’s existing molecular patient database, this systematic integrated exploitation of the GCKD biobank is expected to provide novel starting points for drug discovery and the identification of biomarkers, enabling precision medicine approaches for highly effective treatment options for clearly defined patient populations.

Also in kidney disease, Evotec is collaborating with Novo Nordisk to jointly identify and develop novel targets based on comprehensive medical and molecular data sets of thousands of chronic kidney disease patients, and with Chinook Therapeutics to identify, characterise and validate novel mechanisms and discover and develop precision medicines.

All collaborations leverage the EVOpanOmics and EVOpanHunter platforms with the overarching goal to develop disease-modifying therapies for the targeted treatment of patients with unmet medical needs.

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Dendritic Cells (DCs) are very efficient antigen-presenting cells and have long been considered as attractive candidates for cancer immunotherapy. They are obtained from the patient and loaded in vitro with tumour antigens and additional maturation stimuli and subsequently, infused back into the patient. However, after more than 200 clinical trials involving thousands of patients, clinical responses have been disappointing so far.

While the treatment is safe and well-tolerated and often elicits anti-tumour immunity in both patients with advanced stages of disease and those with minimal residual disease following tumour resection, only a minority of patients demonstrates objective response rates. There are several reasons why the results are disappointing, and while scientists have been able to address problems such as active immune suppression and evasion mechanisms of the tumour, some DC therapy-related aspects contributing to the limited clinical efficacy of DC therapy remain to be solved: the choice of the antigen, the method of loading, and, above all, the type of DCs used. Access to the full spectrum of DCs is limited and many subsets known to be very effective simply are not accessible as they can be derived from the patients only in very low quantities.

As a result, sentiment has switched to approaches viewed as more promising, such as checkpoint inhibitors or chimeric antigen receptor (CAR)-T cells.

Exciting advances with iPSCs

However, thanks to the recent advances made with induced pluripotent stem cells (iPSCs) interest in these vaccines has been renewed. iPSCs can be induced to produce dendritic cells and this provides an opportunity for the rational design of DC vaccines displaying additional functionality via genetic engineering technologies. As iPSCs also open up the possibility for the mass production of large numbers of high-quality iPSC-derived DCs, it is now possible to design next generation DC vaccines from engineered DCs.

Moreover, iPSCs also allow for the production of DC subsets that are not accessible as yet for therapeutic development because sufficient quantities could not be obtained. Examples are DCs facilitating anti-viral responses and a certain subset called CD141+ specialised on cross-presentation of antigens. The CD141+ subset, which is found in very low abundance in vivo, is of particular interest for cancer therapy as it induces optimal cytotoxic T lymphocyte (CTL) responses. Thanks to iPSC, these subsets now can be produced under cGMP conditions in bulk quantities.

Off-the-shelf cancer vaccines?

All in all, these advances may provide the opportunity to design off-the-shelf DC products suitable for cancer vaccines.

Evotec therefore has invested in British immune oncology company OXvax Ltd., a spin-out from the University of Oxford focused on the development of an advanced next-generation dendritic cell vaccine platform for the treatment of solid cancers. The company is pioneering the use of iPSCs as a novel source of CD141+ dendritic cells (DC) and is based on intellectual property from the Fairchild laboratory at the Sir William Dunn School of Pathology. OXvax’s technology addresses, among others, the low cross-presentation and the T-cell activation problems of past DC-based cancer treatments. The platform enables the manufacture at scale of an off-the-shelf, highly potent vaccine which addresses the major limitations that have frustrated cancer vaccine development in the past. If the approach is successful in oncology, it can also be expanded to other therapeutic areas, e.g. viral infections.

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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.

READ ABOUT OUR IPSC CAPABILITIES
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Earlier this year, Evotec hosted a complimentary webinar, ‘INDiGO-Select: profiling and selecting your optimal clinical development candidate’.

INDiGO-Select focuses on better understanding (or increasing the knowledge) of the lead molecule chemistry, its physical-chemistry properties and preclinical DMPK and safety profile, helping to minimise the risk of failure during transition into the subsequent development stages. Evotec’s Manager, Integrated Development Programmes, Sabrina Pagliarusco and Senior Scientific Project Leader, Federico Tosini, take the audience on a journey starting with the war on attrition and a deeper dive into the importance of having a well-designed approach to de-risking. A relatively small investment at the candidate selection stage allows early identification of potential developability liabilities and challenges which consequently allow for a quicker reaction, at a lower cost.

Evotec’s approach to integrated solutions in drug development – INDiGO-Select and INDiGO – are then highlighted. The INDiGO-Select package is never the same for the candidate as it depends on the data that is generated during the discovery phase. To identify any gaps and technical risks, the key areas of focus are the chemistry and pharmaceutical properties, DMPK, the PK/PD relationship and preliminary safety assessment. The next stage – INDiGO - then accelerates early drug candidates into the clinic by reducing time from nomination to regulatory submission. The advantage is that this program can be customised based on data generated during the select and be conducted at a unique site while integrated, so all actions can be performed under the same roof.

Two case studies that used the INDiGO-Select package are then highlighted. The first focuses on low bioavailability, where the client – a small Biotech – has a therapeutic target in neurodegenerative diseases. The activities performed and data presented highlight the impact that an INDiGO-Select model can have on the progress of IND-enabling activities. A second example looks at chemistry and preclinical PK variability. For this particular case study, the objective was to increase the knowledge on the candidate profile and its developability, reducing the risks of later failure in the full development phase. In this instance, the compound was characterised further and, thanks to the data generated, some potential issues were identified to be considered and monitored during the customised development phase.

Choosing the INDiGO-Select model has a number of benefits including enhanced quality of selected drug candidates, increased probability of success later in development and an overall reduction of development costs and project timelines.

Discover more about INDiGO-Select by streaming this insightful webinar from our experts now!

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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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In an unparalleled global effort, diagnostics and vaccines to identify and prevent Sars-CoV-2 infections have been made available to public health systems, with various therapeutics for acute cases of COVID-19 being currently tested in clinical trials.

Nevertheless, a significant research gap exists in the understanding and treatment of so-called Long COVID, i.e. the delayed onset of persistent health problems following a SARS-CoV-2 infection with mostly moderate to mild symptoms. While the resulting health economic implications still need to be assessed in the long term, it is already clear that affected patients suffer significantly from reduced quality of life and individual physical and mental performance.

Lessons from the Chikungunya Virus

In a recent letter to The Lancet, a team of researchers, including a scientist from Evotec Infectious Disease Group in Lyon, France, points out that politicians and the public often picture COVID-19 as a mono-phasic infection similar to the flu. This is an understandable cognitive bias as mode of transmission, clinical presentation and the explosive shape of the epidemic curve are all very similar to the flu, in particular the Spanish flu, a pandemic that 100 years ago killed 20-50 million people world-wide. However, the authors – familiar with the biphasic nature of chikungunya virus infections – see striking similarities not between COVID-19 and the flu but between COVID-19 and chikungunya (https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00272-3/fulltext).

Chikungunya infections are spread by mosquito bites resulting in acute symptoms like fever and severe joint pain; headaches, muscle pain, swelling and rashes may be further symptoms. The infection is typically overcome within 1-2 weeks, but may cause lasting joint pain. However, it can also have serious long-term consequences and may lead to persistent mental or somatic constraints, causing both individual and economic burdens.

The researchers, therefore, call for a change in perspective when addressing COVID-19 and urge healthcare systems and politics to no longer ignore the biphasic nature of SARS-CoV-2 infections and its potential long-term disease course.

Antibody Treatments for Chikungunya Virus Infections - A Roadmap for COVID-19?

Evotec may contribute new data to allow a better understanding of fighting biphasic infections. However unlike COVID-19, there are currently no vaccines or treatments available to address chikungunya infections. To meet this medical need, the Company is developing EVT894, a first-in-class monoclonal antibody with anti-viral activity to treat and potentially prevent chikungunya virus infections, with the compound entering clinical development in late 2020.

EVT894 was derived from a patient who was infected with the chikungunya virus and shows promising data in pre-clinical testing, achieving potent neutralising activity in vitro and in vivo in both therapeutic and prophylactic disease models. It also demonstrated efficacy against all circulating chikungunya genotypes.

Future findings from the EVT894 studies may provide a blueprint for understanding - and, eventually, treating - biphasic infectious diseases such as chikungunya and COVID-19.

Further Background:

https://www.evotec.com/en/invest/news--announcements/p/evotec-starts-clinical-development-of-chikungunya-antibody-together-with-niaid-and-leading-academic-research-organisation-6020

Find out more about chikungunya:

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

The problems surrounding the economics of antibacterial drug development are well known, with the cost of simply keeping a product available for use now outstripping revenues from sales in many cases.

However, early R&D push incentives from organisations such as CARB-X and the new AMR Action Fund are keeping research going, while efforts continue to try to ensure the true value of novel antibiotics are recognised, spearheaded by the UK’s pilot of a subscription model for reimbursement of developers of new antibiotics

The challenges of running clinical trials sufficient for approval and securing adequate sales returns can affect scientific strategy, resulting in the targeting of only broad-spectrum agents most desired by clinicians. Through years of research, and discussions with members of the antibacterial research community, it became clear to me that the understandable focus on what both regulators and the market will currently support can be at odds with some of the most promising avenues in the science of antibacterial drug discovery. Narrow spectrum or even single pathogen agents may be of huge value in years to come, and from a scientific perspective, these compounds may be more readily accessible than broad-spectrum drugs.

As a medicinal chemist, my primary focus is on molecular design, and while there are many excellent reviews in the field, I felt that a perspective addressing how the many aspects of antibacterial drug discovery affect our design strategies would be a useful addition. I visualise any problems from the viewpoint of the antibiotic molecule, and consider the various challenges it must overcome to become a useful agent for clearing bacterial infections. In each case I consider how our knowledge should influence design strategies. While these principles are at the heart of our research at Evotec, I hope that sharing these ideas with the wider community will aid researchers in their work to address the growing threat of AMR.

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For more than a decade, Evotec has been closing strategic R&D collaborations in the area of induced pluripotent stem cells (iPSC), both with academic and industry partners.

The scope ranges from broad, long-term alliances to targeted research-driven collaborations. These partnerships support Evotec’s growing iPSC activities, strengthen the capabilities, and thus comprise a strong foundation for success within Evotec’s iPSC Lighthouse.

A brief overview of key references for iPSC partnerships is provided below.

Industry partnerships

In 2006, Evotec and CHDI Foundation, Inc. (“CHDI”) closed a strategic collaboration to advance drugs for the treatment of Huntington´s disease. The partnership builds on Evotec’s integrated neuroscience platform and its iPSC platform, among others, and was extended in 2018.

In 2016, Evotec and Celgene (now Bristol Myers Squibb) signed a broad R&D collaboration to develop disease-modifying treatments for neurodegenerative disorders based on Evotec's unique iPSC platform. The platform allows for systematic drug screening in patient-derived disease models. The partnership was expanded to include additional cell lines in 2018 and new cell types in 2019. Following the acquisition of Celgene by Bristol Myers Squibb, the agreement with Evotec was again expanded to further broaden the number of cell lines in 2020.

In 2020, Evotec formed an alliance with Sartorius and Curexsys to advance an iPSC-based exosome approach. The collaboration combines Evotec’s iPSC platform with Curexsys’ proprietary exosome isolation technology, while Sartorius will support Curexsys in setting up a GMP-compliant and scalable manufacturing platform.

Scientific collaborations

The first iPSC partnership was a collaboration with the Harvard Stem Cell Institute ('HSCI') in 2013 to identify compounds which prevent or halt the loss of motor neurons, a key symptom of amyotrophic lateral sclerosis ('ALS').

In 2017, Evotec entered into a research collaboration with the Center for Regenerative Therapies TU Dresden ("CRTD") to discover novel small molecule candidates for retinal diseases. Gola of the collaboration is to combine CRTD's expertise in stem cell-based retinal disease modelling with Evotec´s iPSC technology platform to generate promising drug candidates for potential clinical development.

In 2018, Evotec and Centogene signed an agreement for a global drug discovery collaboration to develop novel small molecules in rare hereditary metabolic diseases, which are generated by a joint high-throughput platform.

The collaboration was expanded into Gaucher´s disease in 2020, leveraging Evotec’s iPSC platform and broad drug discovery and development capabilities and Centogene´s proprietary rare disease platform, including iPSC lines, to generate novel treatment approaches for this orphan drug indication.

In 2021, Evotec and the Medical Center Hamburg-Eppendorf (“UKE”) signed a partnership for the development of a novel, innovative first-in-class cell therapy based on Engineered Heart Tissue for the treatment of heart failure. The goal is to produce human, clinical-grade heart muscle cells (cardiomyocytes) for implantation.

Evotec is continuously looking to expand its iPSC portfolio through industry and academic partnerships both within existing disease areas but also to expand into new disease areas. Reach out to us for questions around collaborations and partnerships.

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Ezio Bettini, Ph.D., Manager Plate Based Assay, Discovery Electrophysiology. In vitro Pharmacology, Aptuit (Verona) Srl, an Evotec Company
Paolo Manfredi, M.D., Chief Scientific Officer, Relmada Therapeutics
Stephen M. Stahl, M.D., Ph.D, Adjunct Professor of Psychiatry, University of California San Diego, Chairman, Neuroscience Education Institute

COVID-19 Long Term Neuropsychiatry Effects

Since the COVID-19 pandemic began, it has become increasingly clear that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cannot be simply defined as a respiratory virus only targeting the respiratory system and lungs. On the contrary, Sars-Cov-2 virus, showed an ability to infect multiple cell types, mainly due to the widespread tissue distribution of its main receptor target ACE2, and an ability to trigger a dysregulated immune response, so causing a variety of symptoms, ranging from mild to severe and affecting multiple tissues and organs (Gupta et al, 2020). Reports of acute neuropsychiatry and neurological symptoms in COVID-19 patients have been numerous during the pandemic and were recently clustered in three distinct groups: anosmia and hypogeusia; dizziness, headache, and limb weakness; photophobia, mental state change, hallucination, vision and speech problem, seizure, stroke, and balance disturbance (Mirfazeli et al, 2020). The discovery that Sars-Cov-2 virus, or a relevant virus protein such as spike 1 protein (S1), can reach the brain, has provided the biological substrate for reported neuropsychiatric and neurological symptoms in COVID-19 (Meinhardt et al 2020, Rhea et al 2020).

Moreover, there has been growing concern that COVID-19 survivors might be at increased risk of long term sequelae, extending far beyond acute infection, even among those who experience mild illness (CDC: 2021 Apr 8): long COVID is the name used for referring to the range of symptoms that can last weeks or months after first being infected with the virus that causes COVID-19 or can appear weeks after infection. Anxiety and depression are amongst the major symptoms manifested in people experiencing long COVID. A recent report, published in Lancet Psychiatry, estimated the risks of major neurological and psychiatric conditions in the 6 months after COVID-19 diagnosis, by analysing health records of more than 230,000 patients, mostly from the United States (Taquet et al, 2021). It was discovered that a stunning more than 33% of COVID-19 survivors had been diagnosed with neurological or psychiatric illnesses within six months, with nearly 13% receiving their first neuropsychiatric diagnosis. These disorders were significantly more common in COVID-19 patients than in comparison groups of people who recovered from flu or other respiratory infections over the same time period. Anxiety, at 17%, and mood disorders, at 13%, were the most common, and did not appear to be related to how mild or severe the patient’s COVID-19 infection had been (Taquet et al, 2021).

Possible Mechanism of COVID-19 Long Term Neuropsychiatry effects

A recent article published in the JAMA Psychiatry journal reviewed possible mechanisms leading to COVID-19 long term neuropsychiatry effects (Boldrini et al 2021). Neuro-inflammatory mediators are hypothesized to play a relevant role in the sequela of events which can finally culminate in long term COVID neuropsychiatric symptoms. Among neuro-inflammatory mediators, a major role could be played by quinolinic acid (QA), a breakdown metabolite of the amino acid tryptophan and an endogenous inflammatory mediator with neurotoxic potential. QA mediates its neurotoxic effects by activating N-methyl-D-aspartate receptor (NMDAR). QA is normally present in nanomolar concentrations in the brain. However, increased levels of QA can be produced by activated macrophages and microglia in pathological conditions. Accumulation of endogenous QA has been implicated in the aetiology of neurological diseases and psychiatric disorders, including depression. An increase in plasma QA levels has been reported in COVID-19 patients (Collier et al, 2021; Thomas et al, 2020).

Innovative Approach for a Sustainable Treatment

In a collaborative study with Relmada Therapeutics, we studied esmethadone and its ability to antagonise quinolinic acid effects in recombinant CHO cells expressing different isoforms of human NMDAR (Bettini et al: manuscript in preparation). Esmethadone is a very safe and well tolerated NMDAR channel blocker, which showed rapid and robust efficacy in Phase 3 trials for the treatment for major depressive disorder (MDD) (Fava et al: manuscript submitted). In our studies, Esmethadone showed potential for reducing increases in calcium influx induced by QA alone or in combination with sub-saturating concentrations of L-glutamate. Because of the hypothesized mechanism of action, the strong signal for efficacy for patients with MDD, and a very favorable safety, tolerability, and pharmacokinetic profile, esmethadone has the potential to be tested in controlled trials for prevention and treatment of complications secondary to COVID-19.

References

Boldrini M, Canoll PD, Klein RS. How COVID-19 affects the brain. JAMA Psychiatry. 2021 Mar 26. https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2778090

CDC: 2021 Apr 8: https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects.html

Collier ME, Zhang S, Scrutton NS, Giorgini F. Inflammation control and improvement of cognitive function in COVID-19 infections: is there a role for kynurenine 3-monooxygenase inhibition? Drug Discov Today. 2021 Feb 18:S1359-6446(21)00075-1. https://www.sciencedirect.com/science/article/pii/S1359644621000751

Gupta A, Madhavan MV, Sehgal K et al. Extrapulmonary manifestations of COVID-19. Nat Med 26, 1017–1032 (2020). https://doi.org/10.1038/s41591-020-0968-3

Meinhardt J, Radke J, Dittmayer C et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci 24, 168–175 (2021). https://doi.org/10.1038/s41593-020-00758-5

Mirfazeli FS, Sarabi-Jamab A, Jahanbakhshi A et al. Neuropsychiatric manifestations of COVID-19 can be clustered in three distinct symptom categories. Sci Rep 10, 20957 (2020). https://doi.org/10.1038/s41598-020-78050-6.

Rhea EM, Logsdon AF, Hansen KM et al. The S1 protein of SARS-CoV-2 crosses the blood–brain barrier in mice. Nat Neurosci 24, 368–378 (2021). https://doi.org/10.1038/s41593-020-00771-8

Taquet M, Luciano S, Geddes JR, Harrison PJ. Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA. Lancet Psychiatry 8(2):130-140 (2021). https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(20)30462-4/fulltext

Thomas T, Stefanoni D, Reisz JA, Nemkov T, Bertolone L, Francis RO, Hudson KE, Zimring JC, Hansen KC, Hod EA, Spitalnik SL, D'Alessandro A. COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status. JCI Insight.5(14):e140327 (2020). https://insight.jci.org/articles/view/140327

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Each year, more than 400 000 people die of malaria – a preventable and treatable life-threatening parasitic disease. Almost half the world’s population (about 3.2 billion people) are at risk of malaria with 229 million new malaria infections reported in 2019 and an estimated two thirds of deaths being among children under the age of 5.

The last 2 decades have seen a period of unprecedented progress in malaria control with the mortality rate dropping by up to 60% between 2000 and 2015 and a further 11 countries being officially certified as malaria free. The last 5 years however have seen a progress plateau, with senior health leaders calling for a renewed response to the treatment and prevention of malaria. The creation of new financing mechanisms, such as the Global Fund to Fight AIDS, Tuberculosis and Malaria and the EU Malaria Fund, together with robust political commitments has led to large scale deployment of malaria testing and access to artemisinin-based combination therapies (ACT’s), the recommended first line treatment for uncomplicated P.falciparum malaria.

However, malaria control is facing one of its greatest threats, an increasing trend of drug resistant parasites. ACT’s are used in most malaria endemic countries and remain a highly efficacious treatment, but with resistance confirmed in two of the four human malaria parasite species in areas of Southeast Asia and evidence of mutations linked to partial resistance in Africa, further spread of resistance could jeopardize important gains in the fight against malaria.

Working together for a malaria free world

In 2018, Evotec joined the fight to eliminate malaria and resistant pathogens with its acquisition of Sanofi’s infectious diseases R&D site in Lyon, France, with approximately 115 employees, a highly skilled and experienced infectious diseases team and an R&D portfolio in antibacterials, antivirals and global heath including tuberculosis and malaria.

Capabilities span from early drug discovery to clinical trials with proven experience of WHO recommendations, the specificities of antimalarial drugs, and target candidate/product profiles (TCP–TPP) as well as an extensive knowledge of the Plasmodium in vitro/in vivo models at all stages of the parasite life cycle.

Evotec’s highly experienced malaria team has access to a vast network of labs and organisations recognised for their expertise in antimalarial assays/models as well as internal PK/PD experts able to translate discovery data into appropriately designed antimalarial clinical trials.

Complementing this experience is an established leading-edge integrated anti-infective drug discovery platform, enabling the discovery and development of innovative new therapies to prevent and treat global life-threatening infections.

 

With the SARS-CoV2 pandemic representing a formidable challenge to malaria responses and the impact of this still being largely unknown, this World Malaria Day Evotec joins with other organisations to celebrate the achievements of countries that are approaching - and achieving malaria elimination #researchneverstops

Resources : World malaria report 2020, Final report of the E-2020 initiative

 

Contact info@evotec.com to speak with our malaria experts

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