MIP-DILI

Mechanism-Based Integrated Systems for the Prediction of Drug-Induced Liver Injury
Ongoing | IMI1 |
Mechanism-Based Integrated Systems for the Prediction of Drug-Induced Liver Inju

FACTS & FIGURES

Start Date
End Date
Call
IMI1 - Call 3
Grant agreement number
115336

Contributions
IMI Funding
15 335 538
EFPIA in kind
12 648 466
Other
4 319 043
Total Cost32 303 047

Summary

Many medicines are harmful to the liver, and drug-induced liver injury (DILI) now ranks as 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. For the first time, the IMI project MIP-DILI brings together Europe’s top industrial and academic experts in the field. Together, they will develop new tests that will help researchers detect potential liver toxicity issues much earlier in development, saving many patients from the trauma of liver failure.

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, most DILIs are so-called idiosyncratic reactions. These cannot be predicted in experimental systems, occur only in certain patients, and are not dose dependent. Very often, idiosyncratic DILI problems are only picked up very late in drug development or even after regulatory approval. Over 1 000 approved drugs have been associated with idiosyncratic DILI; in most cases, around 1 in 10 000 patients are affected, although for some drugs the incidence of DILI is higher, at around 1 patient in 100. Estimates suggest that one in seven cases of liver failure are triggered by an adverse drug reaction, and DILI is now the leading cause of liver transplantation in many countries.

A new look at liver toxicity
The goal of MIP-DILI is to dramatically improve the tools used to test for liver toxicity during drug development. The team aims to deepen our understanding of the science behind drug-induced liver injury, and use that knowledge to overcome the many drawbacks of the tests currently used.

A major focus will be on 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. The more complex models integrate different types of liver cells to form three-dimensional units that accurately mimic human liver physiology. The project will also develop models that take into account the natural differences between patients. This is important because factors such as certain genes, the liver’s immune response, and viral infections have all been associated with an increased risk of DILI.

The project will seek to address the current lack of human liver cells available to researchers by using induced pluripotent stem cells (iPSCs, i.e. cells that have been altered so that they can turn into any kind of cell found in the body) generated from patients who are particularly sensitive to DILI.

Another strand of the project will develop computer models to unravel the complex, often inter-related mechanisms behind DILI. Finally, the team will assess how accurate the results of laboratory tests are at predicting actual outcomes in patients.

A leap forward for liver safety
Until now, the quest to develop better tests for DILI risk in potential drugs has been hampered by a lack of collaboration between industry and academia. By bringing together experts from these sectors in a single, coordinated effort, MIP-DILI promises to both advance our understanding of drug-induced liver injury and deliver tests to detect it early on in drug development.

Academic partners in the project will benefit from access to reference compounds, with known liver toxicity, that are held by pharmaceutical companies. For their part, pharmaceutical companies will gain a greater understanding of the complex science behind DILI.

The stakes are high; all too often, DILI and other toxicity problems are only identified extremely late in drug development, when vast amounts of time and money have been spent on a potential drug. According to a report from the Society for Medicines Research, just a 10% improvement in predicting failure before the start of clinical trials could cut the costs of drug development by upwards of €75 million.

Safer treatments for patients
Although DILI is rare, when it happens, it is often extremely serious or even fatal for the patient concerned. Yet too many drugs that pose a risk of DILI still make it to the market, and DILI is a common reason for withdrawing drugs from the market. By helping researchers to detect DILI problems during drug research, before drugs are evaluated in clinical trials and approved for use, MIP-DILI will prevent considerable pain and suffering on the part of patients.
 

Achievements & News

MIP-DILI sheds light on limitations of liver toxicity tests
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. (September 2016)

Participants Show participants on map

EFPIA companies
  • AbbVie Deutschland GmbH & Co. KG, Wiesbaden, Germany
  • AstraZeneca AB, Södertälje, Sweden
  • Bristol-Myers Squibb Company , Princeton, NJ, United States
  • Eli Lilly and Company Ltd, Basingstoke, United Kingdom
  • Glaxosmithkline Research And Development LTD, Brentford, Middlesex, United Kingdom
  • H. Lundbeck A/S, Valby, Denmark
  • Institut De Recherches Internationales Servier, Suresnes, France
  • Janssen Pharmaceutica NV, Beerse, Belgium
  • Merck KGaA, Darmstadt, Germany
  • Orion Corporation, Espoo, Finland
  • Sanofi-Aventis Research and Development, Chilly Mazarin, France
  • UCB Biopharma SPRL, Brussels, Belgium
Universities, research organisations, public bodies, non-profit groups
  • Albert-Ludwigs-Universitaet Freiburg, Freiburg, Germany
  • Deutsches Krebsforschungszentrum, Heidelberg, Germany
  • Karolinska Institutet, Stockholm, Sweden
  • Klinikum rechts der Isar - Technische Universitaet Muenchen, Muenchen, Germany
  • Lhasa Limited, Leeds, United Kingdom
  • Stichting VU, Amsterdam, Netherlands
  • Universiteit Leiden, Leiden, Netherlands
  • Universiteit Utrecht, Utrecht, Netherlands
  • University of Liverpool, Liverpool, United Kingdom
  • Université de Rennes 1, Rennes, France
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
Third parties
  • Institut National De La Sante Et De La Recherche Medicale, Paris, France

CONTACT

Project coordinator
Dominic P. Williams
AstraZeneca AB
+00 44 7884 735519
Dominic.P.Williams[at]astrazeneca.com
Managing entity
Kevin Park
The University of Liverpool
b.k.park[at]liverpool.ac.uk