Clinicians and drug manufacturers recognise two kinds of DILI. Dose-dependent DILI is usually detected early on in drug development and, as the name suggests, the risk of an adverse reaction increases with the dosage. However, some DILIs are so-called idiosyncratic reactions. These cannot be predicted in experimental systems, occur only in certain patients, and are not clearly dose dependent toxicities. Very often, idiosyncratic DILI problems are only picked up very late in drug development or even after regulatory approval. Estimates suggest that one in seven cases of liver failure are triggered by an adverse drug reaction in patients.
The goal of MIP-DILI was to dramatically improve the tools used to test for liver toxicity in early drug development, especially in vitro tests which measure the effect of potential drug molecules on human cell systems in a laboratory setting. By bringing together Europe’s top industrial and academic experts in the field for the first time, the project deepened our understanding of the science behind drug-induced liver injury, and then used that knowledge to overcome the many drawbacks of the laboratory tests currently used.
Looking at existing models and developing new ones
One of the main project achievements was a systematic and evidence-based evaluation of both currently available and new laboratory test systems, including cultures of liver cells in one-dimensional and three dimensional configurations. MIP-DILI really took an in-depth look into how all these cell systems function and developed definitions of basic biological machinery in various in vitro test systems to see which human processes they are capable of capturing.
The project also developed models that capture the principal types of liver injury that these in vitro systems can detect. This is important because while some cases of DILI may be triggered by something inside the liver cells, others appear to be associated with external factors, including the immune system and viral infections. These factors also need to be taken into account in laboratory tests.
Thanks to MIP-DILI, scientists working to develop new drugs now have a more realistic and physiologically relevant set of models for looking at a defined set of chemical attacks that drugs can make on liver cells. This gives them a warning of this toxicity very early in the drug development process, so that they can focus their efforts on those molecules which can arrive safely to patients.
Other important achievements
In addition to the above, the project recorded a number of other achievements, including:
- An ability to detect a major sub-type of human DILI (called cholestasis) by a new mechanism which involves bile formation and flow. This has never been achieved before and was a breakthrough in this field of research.
- A roadmap for the evaluation of DILI test systems. Developed for the evaluation of test systems within the project, this roadmap will help future projects as well.
- Development of a battery of preclinical test systems for detecting DILI, which are fit for purpose.
- Determination of what can – and what cannot – be predicted with current DILI test systems in order to inform drug development, regulators and the public.
- New understanding of the mechanisms of fialuridine toxicity (experimental drug for hepatitis B), including the first-ever evidence that some of the existing in vitro tests can successfully predict this toxicity.
- A roadmap to understand and assess potential DILI liabilities of new drugs during their development.
- A clearer identification of remaining knowledge gaps which need to be addressed in order to advance this field of research.
Considerable benefits for patients
Although DILI is rare, when it happens, it is often extremely serious or even fatal for the patient concerned. Yet drugs that pose a risk of DILI still make it to the market, and DILI is a common reason for withdrawing drugs from national prescription registries. By helping researchers to detect DILI problems during drug research, before drugs are evaluated in clinical trials and approved for use, MIP-DILI will greatly contribute to the considerable efforts being made to avoid pain and suffering on the part of patients as a consequence of these adverse drug reactions.
The project will also help patients in therapeutic areas where there is an urgent need for new drugs. One of the biggest risks in the development of a new drug is that at a late stage, after four or five years of endeavour, that drug has to be stopped because of a problem with drug safety. The tools developed within MIP-DILI will help reduce this risk, enabling pharmaceutical companies to focus their efforts on the most promising drugs.
For the benefit of academia and industry
Academic partners in the project benefited from access to reference compounds with known liver toxicity, as well as from gaining a deeper insight into industry practices and needs. Additionally, the gap analysis performed within the project revealed the need for more fundamental research in some areas, which will be a fertile training ground for future PhD students and post-doctoral fellows.
For their part, pharmaceutical companies gained a greater understanding of the complex science behind DILI, and an appreciation that the mechanisms of DILI need to be better understood before drug toxicities, especially those associated with an immune response, can ever be predicted in patients.
Thanks to IMI, the pharmaceutical companies worked on these issues in a precompetitive space for the first time, openly sharing questions that they all have in their respective companies. There was also a tremendous benefit in working with academia to tackle these questions and find solutions which can be deployed within industry. Many of the tools and learnings developed in this project are already deployed in industry, and have resulted in both cost and time savings.
The SMEs in the project gained a unique opportunity to work with both industry and academia to develop their tools and test their products. Thanks to the network created within the project, they were then able to offer those products to industry customers. SMEs also participated in the project’s joint publications, which gave them visibility and increased their reputation in the wider scientific community.
Reducing the use of animals in research
Everything about MIP-DILI has worked towards encouraging a reduction in the use of animals in preclinical research. By helping improve the value of in vitro tools in early drug discovery, MIP-DILI improved the decision making process, ensuring that only the best and most promising molecules are brought forward into further trials on animals.
All the foreground and background data generated during the lifetime of the project is stored within a database, and will continue to be sustained by one of the SMEs in the project. The project’s sustainability will also be ensured through the in vitro tests which were developed within the project and are now in use in both industry and academia.
Read the interview with project coordinators
Achievements & News
Many medicines are harmful to the liver, and drug-induced liver injury (DILI) ranks as one of the leading cause of liver failure and transplantation in western countries. However, predicting which drugs will prove toxic to the liver is extremely difficult, and often problems are not detected until a drug is already on the market. IMI’s MIP-DILI project deepened the understanding of the science behind drug-induced liver injury, and improved laboratory tests which are used to predict DILI in the early stages of drug development. ###This is already helping pharmaceutical companies to make better decisions on which drug molecule to take forward into further research, saving time and resources, and helping ensure that only the safest and most promising drugs reach patients. In an interview with the IMI Programme Office, Richard Weaver of Servier and academic coordinator, Kevin Park of the University of Liverpool, describe the project’s most important achievements, and explain how they are already benefitting industry, academia, and patients, while at the same time reducing the use of animals in research. ‘We went into this with a vision that we’re going to make a difference, and that energy drove us to see the project through in five years,’ said Weaver. ‘There were no ifs and buts on the way. That philosophy took us through some big hurdles and challenges, but it’s the satisfaction coming out on the other side of it that matters: we went in as a team, we came out as a team and we made significant accomplishments in a very challenging field.’ Read the full interview
Drug-induced liver injury (DILI) still ranks as the leading cause of liver failure and transplantation in western countries. However, predicting which drugs will damage the liver is extremely difficult and often problems are not detected until a drug is already on the market.### In pre-clinical experiments, pharmaceutical companies initially test the toxicity of drugs on various single-cell models – such as HepG2 and HepaRG cell lines and primary human hepatocytes – using basic cell health tests. But how reliable are those commonly-used tests? In the first study of its kind, recently published in the Archives of Toxicology, scientists from IMI’s MIP-DILI project selected 13 compounds, some of which are known for their potential to cause liver damage, and tested them in multiple labs across the EU. The outcome? Primary human hepatocytes are no better than cell lines in being able to predict the likely risk of DILI. Furthermore, none of the single-cell models can distinguish faithfully between DILI and non-DILI compounds in early drug discovery when using the simplest of tests. ‘This was a substantial piece of work offering clearer insight into the usability of simple cell culture tests for the pharmaceutical industry,’ said Richard Weaver of Servier. The rich data set generated from this study forms the basis from which more complex in vitro models (such as 3D micro tissues) will be developed within MIP-DILI. The ultimate aim of MIP-DILI is to enhance the tools used by the pharmaceutical industry by improving the understanding of DILI’s mechanisms.
ParticipantsShow participants on map
- Abbvie Deutschland GMBH & Co Kg, Wiesbaden, Germany
- Astrazeneca AB, Södertälje, Sweden
- Bristol-Myers Squibb Company Corp, Princeton, NJ, United States
- Eli Lilly And Company LTD, Basingstoke, United Kingdom
- Glaxosmithkline Research And Development LTD., Brentford, Middlesex, United Kingdom
- H. Lundbeck As, Valby, Denmark
- Institut De Recherches Internationales Servier Iris, Suresnes, France
- Janssen Pharmaceutica Nv, Beerse, Belgium
- Merck Kommanditgesellschaft Auf Aktien, Darmstadt, Germany
- Orion Oyj, Espoo, Finland
- Sanofi-Aventis Recherche & Developpement, Chilly Mazarin, France
- UCB Biopharma, Brussels, Belgium
Universities, research organisations, public bodies, non-profit groups
- Albert-Ludwigs-Universitaet Freiburg, Freiburg, Germany
- Deutsches Krebsforschungszentrum Heidelberg, Heidelberg, Germany
- Karolinska Institutet, Stockholm, Sweden
- Klinikum Rechts Der Isar Der Technischen Universitat Munchen, Muenchen, Germany
- Lhasa Limited, Leeds, United Kingdom
- Stichting Vu, Amsterdam, Netherlands
- The University Of Liverpool, Liverpool, United Kingdom
- Universite De Rennes I, Rennes, France
- Universiteit Leiden, Leiden, Netherlands
- Universiteit Utrecht, Utrecht, Netherlands
Small and medium-sized enterprises (SMEs)
- Interface Europe, Bruxelles, Belgium
- Kaly-Cell, Plobsheim, France
- Solvo Biotechnology Zrt, Szeged, Hungary
- Takara Bio Europe AB, Göteborg, Sweden
- Institut National De La Sante Et De La Recherche Medicale, Paris, France
|Name||EU funding in €|
|Albert-Ludwigs-Universitaet Freiburg||412 663|
|Cxr Biosciences Limited (left the project)||471 939|
|Deutsches Krebsforschungszentrum Heidelberg||956 615|
|Interface Europe||725 580|
|Kaly-Cell||1 302 043|
|Karolinska Institutet||1 548 817|
|Klinikum Rechts Der Isar Der Technischen Universitat Munchen||837 312|
|Lhasa Limited||552 494|
|Solvo Biotechnology Zrt||477 128|
|Stichting Vu||1 149 061|
|Takara Bio Europe AB||926 749|
|The University Of Liverpool||2 863 103|
|Universitatsklinikum Bonn (left the project)||602 463|
|Universite De Rennes I||886 114|
|Universiteit Leiden||1 087 035|
|Universiteit Utrecht||536 422|
|Total Cost||15 335 538|