A UK Quantitative Systems Pharmacology Network

Lead Research Organisation: University of Reading
Department Name: Mathematics and Statistics

Abstract

Drug development is a time consuming and expensive process. From the time a compound is identified as having possible therapeutic benefits through to being available in the clinic, takes not only the order of a decade, but 100's of millions of pounds of investment. Successful testing of a compound in the laboratory does not imply that it will be successful in animal or human trials, and even successful animal tests can lead to failure in human trials - a result of the complexity of biology at different scales. On average only one in nine drug compounds is fully developed and approved by US and European regulatory authorities. This low attrition rate is poor for drug companies, both in terms of time and costs, and ultimately us as a society.

Understanding on the single cell scale does not easily translate to the same behaviour in human tissue, organs, whole humans and the overall population given individual differences. We wish to design drugs for large scale population use whilst accounting for the variation between individuals within a population. One technology available to us for tackling this issue is quantitative methods such as mechanistic mathematical modelling and data analysis. Current knowledge of a biological system can be used to develop mathematical models to identify key laboratory experiments, reduce reliance on animals and identify earlier which compounds are most likely to fail or succeed.

The integration of subcellular information into whole individual mechanistic mathematical models to specifically assist in the development of pharmaco-therapeutics has been termed Quantitative Systems Pharmacology (QSP). "Quantitative" because the area uses quantitated processes and data to make predictions and "Systems" because the approach is holistic across the system (single cell to organ to whole individual). This is a new area of science which will require strong interactions between theoretical modellers (mathematicians, statisticians, engineers) and life and pharmaceutical scientists to ensure its success. Individual researchers from each of these areas can be found in both UK academic institutions and leading biopharmaceutical and biotechnology sectors and need to be brought together to allow this new field to thrive and develop in the UK.

To meet this need we will establish a UK Network in QSP. The network will bring together UK pharmaceutical scientists from industry and academia, with theoretical scientists to exchange knowledge and tackle problems in QSP. The network will be arranged around three workshops (one per year), two of which will share knowledge through talks, poster sessions and group discussion on key topics in this burgeoning field. A third workshop will bring mathematical modelling expertise to bear on QSP problems highlighted by the academic and industrial network members. Satellite meetings will allow participants to further explore ideas generated from the main workshops. Our network already has strong support from biopharmaceutical and biotechnology sectors, with sites in the UK, and leading academic institutions.

The network will lead to: (i) new collaborations; (ii) project applications (grant, studentship, fellowship); (iii) scientific publications; (iv) open access mathematical models and their associated code; (v) greater awareness of QSP in the UK pharmaceutical, life and physical science communities; (vi) education and training for those based in industry (and academia) on modelling tools and techniques to support; (vii) greater public awareness of QSP in the development of new drugs and therapeutic agents; (viii) foster the development of mathematical models as surrogates for the ex-vivo and in-vivo animal systems currently used to extrapolate efficacy and toxicity responses to drugs; and (ix) develop and strengthen international links between the UK and other key international initiatives in Systems Pharmacology research.

Planned Impact

The network will impact on research in the biopharmaceutical and biotechnology (short, medium and long term) and public health arenas (medium to longer term). It is unique in terms of its multidisciplinary, academic and industrial components with no other current rivals known to exist (internationally) providing such a novel combination of scientific training and research activity. The network will bring economical and industrial benefits, impact on the strategic competitiveness of UK science, enhance public-private collaborations, allow results developed during the network to be exploited and ensure public impact is achieved through public engagement in science activities.

A mechanistic model driven approach to drug development, can take into account differences between the drivers of a myriad of diseases and is likely to be more successful than empirical approaches that have been used to date. This will add economic competitiveness to those companies involved, with expertise in each of the respective areas (pharmaceutical, biological, mathematical and engineering sciences) close to hand in the UK. The fundamental knowledge generated from innovative tools for drug development and effect at a systems level will significantly help to overcome bottlenecks and the length of time currently taken in drug design and development. The programme of network activities will generate research outcomes, concepts, innovative tools and techniques, technology and novel strategies, that will be of direct relevance to the UK biopharmaceutical and biotechnology industry.

A direct industrial benefit of the network will be to help maintain the UK's (and Europe's) competitive market position in the face of competition from the US and the Far East. Developing innovative modelling tools and techniques in the QSP framework will also place the UK strategically at the forefront of this emerging research area. In general the network will provide innovation in terms of the development methodologies for identifying unknown mathematical relationships in a (nonlinear) pharmacological system leading to more robust tools for drug design and discovery. The network will enhance longstanding collaborations between the Universities involved and drug discovery at major pharmaceutical companies with bases in the UK. It will further facilitate new collaborations with academia and the private sector, including clinical development.
 
Description This grant has allowed QSP to establish a strong foot-hold in the UK. The award allowed a total of three main Workshops, one Spring School and one Information event to be held. A total of nine smaller Satellite Meetings focusing on topics identified through the main Workshops were also supported. Three journal publications and a Special Issue on Quantitative Systems Pharmacology in the journal Progress in Biophysics and Molecular Biology (November 2018) have so far been published as a direct result of Network activities. Further publications and a textbook on QSP modelling of oncology are pending.

Around 50-60 delegates participated in each of the main events: (i) an introductory industry-funded workshop in September 2015 held at Alderley Edge; (ii) a three day Exchange Workshop at the University of Surrey in 2016 consisting of invited and contributed talks and posters by UK and international researchers working in QSP; (iii) a five day Problem Solving Workshop focused on applying mathematical and statistical modelling techniques to problems brought by pharmacological researchers in academia and industry (University of Warwick, 2017); and (iv) a three day Exchange Workshop at the University of Reading in 2018. All workshops were advertised via the UK QSP mailing list, e-mails to all relevant physical and life/biological/pharmacology Departments within UK Universities, as well as through the British Pharmacology Society and relevant international mailing lists. Feedback forms were completed at each event with positive feedback received from all delegates.

Given the strong interest in QSP, a Spring School and Careers event was held in April 2018 at the University of Reading. The week long School was attended by 20 delegates from industry and academia with an equal number of life/pharmacological and physical scientists. Delegates came from the UK, Europe and the wider international community. Lectures and computer practicals were delivered by leading QSP researchers in the pharmacological and physical sciences from both academia and industry. Participants learnt how to build QSP models via morning lectures and afternoon computer practicals. Representatives from AstraZeneca, Certara QSP, GlaxoSmithKline, Roche, Syngenta, UCB and Unilever gave talks on QSP opportunities during the Wednesday Career's Evening. Members of the UK Organising Committee who lectured at the event are currently in the process of writing a textbook on applying QSP to Oncology.

The half day event "What is Quantitative Systems Pharmacology?" was held at the Wellcome Building in November 2018. The event was attended by a range of researchers from both academia and industry new to QSP research. The Network has also supported nine smaller Satellite Workshops (15 to 20 participants) on a range of topics related to QSP research. These have included meetings on Neuropharmacology, Model Reduction, training in Bayesian approaches to QSP, In Silico Drug Safety and Efficacy and Anti-Microbial Resistance.

As of March 2019, the UK QSP Network has around 250 people on its mailing list, is currently planning for a two day main workshop in September 2019 and further joint events with other networks and scientific organisations.
Exploitation Route The UK QSP Network is wide reaching in both its academic and industrial outlook. It is the only public QSP network in the world at present. It has over 250 academics, students and industrial researchers on its active mailing list. A number of new collaborations between academic and industry members have been formed following successful problem workshops. The PI is part of an international group of researchers in industry and academia who are members of international initiatives in the pharmacological sciences, to which the activities of the Network are always of interest. The Network is also providing training to researchers in academia and industry (nationally and internationally) through its hands on Problem Solving Workshops and Spring Schools.
Sectors Chemicals,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

URL http://www.qsp-uk.net