74th Edition – December 2017

European Lead Factory’s compound library hits 500 000 mark

The European Lead Factory’s Joint European Compound Library now contains 500 095 compounds, taking it over the 500 000 goal set at the start of the project. Of these, 326 350 are ‘in-kind’ contributions to the project by the 7 large pharmaceutical companies in the project. The rest of the compounds were synthesised by the chemistry partners in the project: Edelris, Mercachem, Sygnature, Syncom and Taros. What’s more, these companies expect to deliver a further 20 000 compounds before the end of the project.

Analyses of the collection have highlighted the quality and diversity of the collection, which has been used to run over 150 screens for public and private partners. The results of these screens have delivered promising results in a wide range of areas, including Parkinson’s disease, diabetes, antimicrobial resistance, and cancer.

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iPie database releases ECOdrug database

IMI’s iPie project has released ECOdrug, a new database that connects drugs to their protein targets across different species. The team hopes the tool, which is freely accessible at www.ecodrug.org, will help industrial, academic and regulatory scientists to assess and manage the risks associated with pharmaceuticals in the environment. Medicines are designed to interact with specific targets (e.g. proteins) in the human body. Very often, these targets have equivalents in other species, especially those that are closely related to humans.

The ECOdrug database draws on data from multiple sources and has information on over 600 species, including other primates, rodents, birds, fish, microscopic animals, fungi, and plants. The user-friendly interface has two tabs – one for drug-related information and one for drug targets. A search of a drug name brings up a table showing the targets of the drug and how well they are conserved across different species. Similarly, a search by drug target uncovers links to all drugs that target that protein, and the interface shows an evolutionary tree showing the numbers of species in different groups that have an equivalent to the drug target.

Looking to the future, the project plans to improve ECOdrug further by integrating it with other platforms. The tool is described in detail in a paper in the journal Nucleic Acids Research. The authors conclude: ‘Through integration with the systems outlined above, the addition of new features and regular updating we aim to ensure ECOdrug is maintained as a valuable and contemporary research tool for the communities in drug discovery, comparative and evolutionary biology and (eco)toxicology.’

First batches of ULTRA-DD patient-based assay data released - ahead of publication

The ULTRA-DD project has made good on its promise to make its data open source with the publication online of datasets from experiments on autoimmune diseases such as lupus and myositis. Through the experiments, the ULTRA-DD team has identified potential new targets that could inspire the development of new treatments for these diseases. The project hopes that if other researchers probe and use the data, they may uncover further insights that will add to our knowledge of autoimmune diseases and accelerate the development of medicines for these patients, many of whom do not respond well to existing treatments. Currently, additional follow-up studies are ongoing to verify and validate the results.

The data published by ULTRA-DD comes from experiments using technically advanced tests developed by the project partners. In this case, the ULTRA-DD team studied so-called ‘B cells’ – immune cells which are known to play a central role in lupus and myositis. The project’s Scientific Director, Michael Sundström of the Karolinska Institutet says: ‘These are the first of a series of related datasets to be released, and we believe that our approach of pre-publication access to such data is truly unique.

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CHEM21 makes big contributions to green manufacturing for the pharmaceutical industry

The processes and chemicals used in drug production are often toxic, expensive and produce a lot of waste – posing a threat to the environment and the sustainability of the industry. In response, IMI’s CHEM21 project has developed new manufacturing processes for the pharmaceuticals industry to reduce the use of expensive and toxic materials. It has also developed new, more environmentally friendly methods that save time and costs, while reducing waste. Nick Turner, director of the UK’s Centre of Excellence for Biocatalysis, Biotransformations and Biocatalytic Manufacture (CoEBio3), says the project was diverse and complicated but has resulted in huge successes. ‘Our flagship outcome is the development of a new, more efficient and cheaper way of producing flucytosine,’ he says. ‘This medicine is used to treat a common and often deadly fungal form of meningitis in HIV/AIDS sufferers. Producing it at low cost will make it more accessible to those in Africa, helping in the prevention of 500 000 deaths per annum.’

Additionally, the project has developed new, more efficient screening methods to find more enzymes that can be used as biocatalysts for chemical reactions. The discovery of new ones could make drug manufacturing processes more efficient and safer as they can eliminate production steps and could be substitutes for expensive or toxic substances currently used by the industry. Turner concludes: ‘The development and launch of pharmaceuticals is a long process, so it is to be expected that many more benefits will become realised in the next 5-10 years.’

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EbolaMoDRAD makes progress in developing a fast, local test for deadly Ebola

When it comes to Ebola, diagnosing infected patients quickly and accurately is key to controlling the spread of the virus. However, this can currently only be done in relatively sophisticated laboratory settings, which may be many miles from affected areas. To tackle this problem, IMI’s EbolaMoDRAD project is developing and validating new diagnostic tests for Ebola that can be carried out wherever patients are located, quickly and safely, without the need for highly technical laboratory equipment or training. The project researchers have investigated various techniques for detecting the Ebola virus infection in blood samples, including testing for the presence of the virus itself and measuring molecules that reflect the immune response to viral infection.

The most promising method is known as isothermal amplification, which detects the genetic material inside the virus. Unlike other gene detection methods that require samples to be taken through multiple cycles of heating and cooling over several hours, isothermal amplification is carried out at a constant temperature of around 60⁰C and takes less than an hour. The team is now validating the test with samples collected from infected patients in West Africa, ensuring that it is accurate, sensitive and reliable enough to be used in the field. As well as detecting Ebola, the isothermal amplification technique can also be adapted to diagnose other similar viruses, such as the Marburg virus. ‘If there is an outbreak of a new disease we can add that to the test and we can detect several viruses with just one assay,’ says project coordinator Ali Mirazimi of Sweden’s Public Health Agency. ‘It is challenging but if we are ready for the next outbreak we can make a difference.’

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PREDECT’s new tumour models could lead to more effective treatments

Laboratory tests are not sufficiently predictive of cancer drugs’ activity in humans. The rate of failure to take drugs from laboratory to registration for clinical use has been estimated to be as high as 90 %. In clinical trials, patients are thus exposed to drugs that don’t work and the cost to industry is enormous and unsustainable. Real human cancers are complex: genetic changes within tumours over time cause cells in one cancer to differ from each other. To this complexity is added the cancer’s interaction with normal cells. IMI’s PREDECT project tackled the problem of complexity by creating laboratory models of the disease that better represent the complex characteristics of different cancers. More appropriate laboratory models for preclinical studies should increase the ability to predict drug efficacy. This will expand the number of treatments available for different types of cancer, potentially providing patients with a higher chance of survival.

‘We chose to focus on complex and sometimes difficult models of cancer,’ explains project coordinator John Hickman of the Servier research institute in France. ‘As an academic-industrial consortium we believed that although our models may not be rapid, nevertheless they better represent the complexity of cancer. These models provide a high content of information more relevant to human cancer. With the high rate of failure of current high-throughput and rapid models to predict clinical activity, we considered something had to change in the way industry looks for drugs.’

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DRIVE-AB recommendations to stimulate the development of new antibiotics

New antibiotics will have to be used sparingly to preserve their efficacy. IMI’s DRIVE-AB focuses on ways to stimulate their development. A combination of incentives is required, the researchers note. In particular, they highlight the need to ‘delink’ the revenue generated by new drugs from the quantities sold. To do so, they propose a combination of push and pull mechanisms. Priority grants could, for example, be used to get the innovation process moving. A system of rewards for market entry could be set up to encourage its completion. This type of approach would contrast with the business model traditionally applied to drugs, where income depends on the volume of sales.

DRIVE-AB ends in December 2017, and the partners are preparing to publish their final report along with detailed recommendations. ‘We have aimed to encourage a balance between innovation and responsible use,’ says Nicole Mahoney of Merck Sharp & Dohme (MSD), one of the project partners. Policymakers and other stakeholders could find ample inspiration in DRIVE-AB’s conclusions. As a first step, the project’s findings might, for instance, feed into pilot studies at national levels, says Mahoney. ‘We may well see individual countries trialling some of these ideas and setting up reward mechanisms that work within their local context,’ she concludes.

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