IMI Programme Office: Why was a project like yours needed in the first place? Which challenges were you trying to address?
Kevin Park: Drug-induced liver injury is a major public health issue because of its frequency in the clinic, and because the fear of it hinders the development of new and exciting medicines. It is a big challenge for pharmacologists, clinical pharmacologists and toxicologists in academia.
Richard Weaver: When we started back in 2011, there was a lot of heterogeneity in terms of the use of various in vitro laboratory tests [studies performed with cells outside their normal biological and physiological context] to predict the toxicity of promising new drug molecules. There was no benchmarking, no cross-industry validation.
The industry was quite divided between the many cell systems and assays available for this kind of testing. For example, there was a general consensus that the so called ‘simple cell systems’ were not fit for purpose, and yet there was evidence that many companies were using these quite successfully but there was much to be done in terms of optimising their use. The goal of our project was to see if we could improve these systems.
IMI Programme Office: Which project achievements are you most proud of?
Richard Weaver: First and foremost, because without it, we wouldn’t have achieved anything, was the industry and academia partnership that we’ve achieved over the five years, where industry could be honest with the questions they have with some the models available, and academia could join forces to really tackle some of these basic issues. Secondly, it was bringing innovative approaches to increase the performance of various in vitro systems for deployment in industry.
IMI Programme Office: And which scientific project achievements stand out the most?
Richard Weaver: An important scientific achievement was building a roadmap to look at in vitro systems that are already in use, and patient-specific factors which can impact the results… Our project used a physiological and a pharmacological approach to really take an in-depth look at how these cell systems function, even before trying to know whether or not they’re fit for purpose. That was fundamental.
In terms of the actual scientific outputs, a very good example of what our project did was looking at fialuridine, an experimental drug for hepatitis B which caused unexpected deaths of patients in a clinical trial, back in 1993. This was a very big problem for industry because the toxicity of this drug was not predicted during in vitro testing or in animal studies. Within this project, we got a mechanistic understanding and evidence of some of these in vitro tests working to predict this toxicity. This was quite an achievement.
Kevin Park: Indeed, fialuridine is a good example of what our project achieved, but in the broader context it’s also the fact that we developed definitions of the basic biological machinery in various in vitro test systems to see what purpose they’re fit for. In other words, we investigated to see which part of human processes you can capture in a test tube. Thanks to MIP-DILI, we now have a more realistic and physiologically relevant set of models for looking at some of the broad range of chemical insults that molecules can make on liver cells. This gives us a warning of this toxicity very early in the drug development process, so that chemists can focus their efforts on those molecules that can arrive safely to patients.
IMI Programme Office: Are the learnings and tests developed by your project being used in the industry?
Richard Weaver: Yes. Throughout the lifetime of the project, there’s been an uptake of these in vitro systems that we’ve been evaluating. We’ve done that effectively by having large ring trials that involve every partner in industry and academia in order to see how these models work in different laboratories. The industry now applies these learnings on a routine basis.
IMI Programme Office: Did your project contribute to the reduction of the use of animals in research, or the 3Rs?
Richard Weaver: Everything about MIP-DILI has hallmarks of the 3Rs (replacement, reduction, refinement), and has worked towards that. When you improve the value of in vitro tools in early drug discovery, as our project did, you improve the decision making process, and ensure that only the best molecules are brought forward into further trials on animals. The tools and learnings generated by our project will help pharma companies in deciding earlier on which molecules are safe enough to bring forward and which ones should be left behind.
IMI Programme Office: How did the industry benefit from this project overall? Was there a big impact and benefit?
Richard Weaver: Absolutely, for many reasons. Thanks to IMI, we worked on these issues in a precompetitive space for the first time, openly sharing questions that we all have in our respective companies. It was important for us to realise that we all have the same questions. And there was also a tremendous benefit in working with academia to tackle these questions and find solutions which can be deployed within industry.
IMI Programme Office: What about the academic community? How did it benefit from MIP-DILI?
Kevin Park: The gap analysis performed within the project revealed the need for more fundamental research in some areas, and that will be a fertile training ground for PhD students and post-doctoral fellows. And they are the future generation who will develop new medicines for different classes of diseases.
IMI Programme Office: Are patients already benefiting from this project?
Kevin Park: Indirectly, yes. Our project brought a broad benefit to the drug development process, and patients will benefit in areas where there is a need for new drugs. For example, we still need new drugs for cancer, malaria, HIV, and 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 toxicological problem related to the primary pharmacology. The tools developed within MIP-DILI will help reduce this risk, enabling pharma companies to focus their efforts on the most promising drugs, for the benefit of patients.
IMI Programme Office: And the SMEs in the project? How did they benefit?
Richard Weaver: We had five SMEs, and each of them benefitted differently. But generally, I would say that it gave them a unique opportunity to work both with 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 were also participating in our project’s joint publications, which gave them visibility and increased their reputation in the wider scientific community.
IMI Programme Office: Would any of the project achievements be possible without IMI?
Kevin Park: No. The public-private collaboration that the IMI framework has brought to this project has enabled us to achieve things in a way that none of us would have been able to achieve individually.
Richard Weaver: I completely agree. It’s only been this size and the strength of the consortium through IMI that’s allowed us to really tackle some of the big challenges that we previously tried to tackle individually without much progress. Drug-liver injury is a big issue; it’s not an easy disease to manage. It takes a full force and commitment of a consortium for making any achievement.
IMI Programme Office: What are the next steps? Is there a sustainability plan for some of the tools and databases developed within the project?
Richard Weaver: 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 our project. For now it is only available to the partners in the project, but soon it will be freely available in the public domain.
Our sustainability will also be ensured through the application and deployment of the in vitro tests which we’ve developed. We’re very enthusiastic about continuing to follow how our tests are being taken up by both industry and academia.
IMI Programme Office: What was your experience coordinating this project? Was it challenging?
Richard Weaver: I never look at challenges as a negative thing. 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. 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.