Derek Leishman, Senior Research Fellow at Eli Lilly.

What is Eli-Lilly´s main field of specialization?
Lilly is a large pharmaceutical company focused on human medicinal products.  We are active in most therapeutic areas.

How has your company been involved in the project?
Lilly has been directly involved in the organ work packages, especially cardiovascular, liver and GI.  We have been EFPIA leads in the cardiovascular area and EFPIA co-chair of the TransQST project.

What are your main achievements in TransQST? And the main challenges that your team has faced across the project? 
There are three particularly significant achievements for us in TransQST.  The first was in helping develop a model of dog haemodynamics able to determine the likely mechanism of action for any observed effect in telemetry-enabled cardiovascular safety pharmacology studies.  We conducted additional rodent studies to help bridge between technologies available for cardiovascular assessment in rodents to those routinely used in large animal telemetry cardiovascular studies.  The second was in being able to pivot to examining the potential cardiovascular risk of drugs being re-purposed to treat COVID-19.  This was an excellent opportunity to use the models developed within TransQST to address a pressing human medical need.  We were able to partner with a contract research organization to get the necessary input data, we also facilitated a collaborative effort with an EFPIA company not involved in TransQST to bring together a comprehensive package of information for the risk assessment. The third was in the area of liver toxicogenomics. A Lilly tool was the genesis of much of the toxicogenomic mapping work conducted in TransQST.  We have continued to support this toxicogenomics work and conducted important studies to help understand the adaptive and regenerative processes involved in liver biology.  The biggest challenge was time, sourcing suitable data and generating additional studies in the midst of a pandemic was a challenge and we were unable to test the newest models with several proprietary molecules where we have data available.

In the development and testing of which tool/models has your institution been involved in and what is their impact?
As described above we’ve been involved in the development of the cardiovascular models, both haemodynamic and cardiac. Primarily in a leadership capacity, but also through knowledge, experience and data generation. Lilly were also involved in developing new models for liver injury processes. Lilly was the originator of the toxicogenetics modelling tool which spawned the tool used extensively in the liver and kidney work packages. Lilly has conducted significant liver studies on surgical interventions to provide non-pharmaceutical information regarding regenerative and adaptive processes in the liver. We provided additional ongoing toxicogenetics and pathology support to the liver and kidney work packages.

What do you believe is the main contribution of TransQST in the field?
The experience of QST modelling in the cardiovascular and hepatic area demonstrates that this is a long-term initiative. The first cardiac models were developed in 1960, haemodynamic models in 1970 and the DILIsym liver model can trace its roots back nearly two decades. At 6.5 years in duration TransQST could only be along for part of the journey. I believe significant contributions have arisen from the project. Notably toxicogenomics mapping in the liver and kidney can help elucidate the mechanistic root of toxicities in an area where diverse mechanisms are possible. In the cardiac space where a principal mechanism of toxicity is well characterized the models have extended the ability to put that mechanistic effect into context and better define risk. The cardiac models have also now branched into effects on contractile function. This opens a whole new area of functional modeling and starts to connect the cardiac model to the haemodynamic endpoints. The haemodynamic endpoints and the TransQST haemodynamic model are important now as global regulatory authorities start to produce guidance around haemodynamic testing for chronic use medications. Thus, even if the timescale of TransQST has been short in overall journey for QST models there has been significant contributions to the field.