Some challenges in the development of new toxicity assays using in vitro methods

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1 1 Some challenges in the development of new toxicity assays using in vitro methods J Malcolm Wilkinson, CEO, Kirkstall Ltd. Quasi Vivo - saving lives through better science

2 The challenge: long drug development process DRUG DISCOVERY PRE-CLINICAL Human Cellular Assays Phase I CLINICAL TRIALS Phase II Phase III FDA review CLINIC GAP 10,000 Compounds 2D plastic culture 250 Compounds Animal Studies IND GAP 5 Compounds NDA 1 Approved drug 1.8 B$ Do not exactly represent Human physiology 6.5 years 6 years 1.5 years Time and Attrition Slide courtesy of Prof Martin Yarmush, Rutgers University & Harvard Medical School

3 The opportunity for in vitro assays DRUG DISCOVERY PRE-CLINICAL 2D plastic culture do not predict clinical response Phase I CLINICAL TRIALS Phase II Phase III FDA review CLINIC 10,000 Compounds Advanced in vitro assays which 250 will Compounds provide good IND predictions of clinical outcomes 5 Compounds NDA 1 Approved drug H 1.8 B$ Animal Studies Do not match Human physiology 6.5 years 6 years 1.5 years Time and Attrition

4 4 Advances in cell culture 2D cell culture 3D cell culture Perfusion of media through scaffolds and tissue slices Coculture and Systemic models Organ on a chip? 1960 s

5 5 Can we replace animals with advanced in vitro cellular assays? Requirements list: Systemic models eventually the whole organism Long term and repeat dose exposure Cultures that maintain homeostasis (before insult) Good disease models (the use of transgenic mice is growing rapidly but no amount of genetic manipulation will make them human) Lots of scientific evidence on the efficacy of the new tests to reassure the regulators.and complementary in silico methods can support in vitro

6 6 Contrasting perspectives on new technology ACADEMIA Driven by curiosity Time and PhD skills to fix problems If it works once publish quickly! INDUSTRY Need to be efficient Technicians to run standard assays Needs to work every day REGULATORS Risk averse Need gold standards for validation Needs to work the same in every lab PUBLIC Need safer medicines Need cost effective therapies

7 Roadmap to new method for toxicity testing General platform development and testing Focused R&D (for example cardiotoxicty) Selecting individual assay/ battery of tests Develop robust protocol Validate with CRO Regulatory approval

8 General Platform Connected chambers Systemic models 8

9 Lego kit for cell biologists! Reservoir bottle provides enough media for 3 to 7 days Individual chambers for cell culture Recirculating flow allows cells to condition media Peristaltic pump provides controlled flow in 2 or more channels Quasi Vivo - saving lives through better science Adherent cells on scaffolds /in gels or coverslip Or even tissue slices

10 New platform has clear benefits Improved cell viability Improved metabolic function Co-culture and barriers Improved barrier function

11 Route map R&D Feasibility Study Cumulative spend : 250,000 Industrialisation of Assay Cumulative spend: 1,500,000 Validation & Regulatory and Market Acceptance Cumulative spend: 5,500,000

12 12 R&D Feasibility Study (example) CVTOX- Innovate UK project number This project is investigating the creation of a co-culture representing cardiac tissue: human cardiomyocytes (HCMs), smooth muscle cells (HSMCs) and endothelial cells (HECs). Goal is long term stable culture for repeat dose testing of drug and chemical safety 7 day co-culture of HCM s (blue) HEC s (green) and SMC s (red) marked using fluorescent stains Quasi Vivo - saving lives through better science

13 Development of an in-vitro tri-culture of primary human cardiac microvascular toxicological model A collaborative project funded by UK Government

14 Route map R&D Feasibility Study Cumulative spend : 250,000 Industrialisation of Assay Cumulative spend: 1,500,000 Validation & Regulatory and Market Acceptance Cumulative spend: 5,500,000 Funding gap for SME s Need a Large Enterprise Sponsor

15 Technology Commercialisation Route Flexible R&D capability First stage of standardisation and scale up Prototype industrial test system 15

16 Conclusions / Lessons Learned Good science is needed A business case has to be made (even for academic grants!) Technology translation from academia to industry has to be managed Pioneers (risk takers) needed all the way through the process Even regulators will need to be innovative (what is the gold standard for validation if you are replacing an animal test)

17 17 Thanks for your attention! J Malcolm Wilkinson jmw@kirkstall.org Web: Phone: Quasi Vivo - saving lives through better science