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.  

What’s next?

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