1. Catapult is a Technology Strategy Board programme Clinical development of cell based therapies in the UK Natalie Mount PhD Chief Clinical Officer Cell Therapy Catapult Nov 2013 natalie.mount@ct.catapult.org.uk

2. UK Catapults 2 Catapults are core funded by the Technology Strategy Board as ‘not for profit’ companies to bridge the gap between business, academia, research and government Working from the science base to create new manufacturing industries for the UK £200m+ assigned for 7 Catapults; Cell Therapy Catapult formally started in Jan 2013 and has been the only life science Catapult operating to date Catapults use their critical mass of expertise to accelerate projects

3. Cell Therapy Catapult 3 Significant unmet medical needs Early stage in market with large potential for growth World class science base supported by government and charity research funders Development and production of cell therapies is complex Majority of therapies from academic researchers

4. Mind the (translational funding) gap 4 Catapult Little evidence yet that new cell therapies can be developed, licensed and adopted successfully Limited investment from commercial sector Cell Therapy Catapult partners on clinical development projects with academia, SMEs and large pharma

5. 5 Key barriers to commercialisationPertinent issues for cell therapies Regulatory affairsUnderstanding and navigating a path Pre-clinical scienceConducting the right studies to support the clinical program Clinical development Studying the best population; measuring the best endpoints Manufacturing and GMP readiness Move from bench/small scale GMP process to large scale manufacture; integrating manufacturing changes with clinical data Supply chain management New models of delivery required; plan and test what is workable Investment readinessValue proposition to inform potential investors Cell therapy products need to address the industry barriers to commercialisation

6. Addressing Barriers 6 Economics Health Economics Manufacture & Supply vs Service Business Plans Business COGS & Scale up GMP Characterisation & Analytical Comparability Delivery Manufacturing and Supply Chain Regulatory Landscape Pre Clinical Packages Clinical trial design NHS partnering Clinical And Regulatory Clinical Operations & Regulatory Affairs Process Development Business Development

7. Global cell therapy industry Established medical practice: e.g. haematopoietic stem cell transplantation Commercial products: Rapidly growing global market Global turnover of >$2bn in 2012; predicted to rise to $4-5bn in 2014; driven by diversity of small products (Apligraf, Dermagraft, Provenge made >$100m each in 2012) Therapies licensed as ATMPs in the EU: ChondroCelect, Glybera, MACI, Provenge Therapies in development: Rapidly growing ~ 250 products in clinical development 7

8. 8 Overview of autologous process From Smith, Regen Med (2012); 7 (5), 721-732

9. Overview of allogeneic process 9 From Smith, Regen Med (2012); 7 (5), 721-732

10. 10 Marketing Authorisation European centralised licence (MAA) (CAT) EMA Licensed ProductClinical Trials Clinical Trial Authorisation National (MHRA) EU Tissues and Cells Directive or Blood Directive Transplants or Transfusions ATMP regulation EC 1394/2007 STARTING MATERIAL Human Blood, Tissues or Cells No Yes ATMP Pre Clinical Post Marketing 30 Years Traceability Efficacy PhV follow-up Manufacturing Authorisation (MIA) Manufacturing Authorisation Investigational Medicinal Products (MIA(IMP)) GMP Requirement (Eudralex Volume 4) Substantial manipulation and/or non homologous use GLP Regulation of cell therapies

11. 11 Marketing Authorisation European centralised licence (MAA) (CAT) EMA Licensed ProductClinical Trials Clinical Trial Authorisation National (MHRA in UK) EU Tissues and Cells Directive or Blood Directive Transplants or Transfusions ATMP regulation EC 1394/2007 STARTING MATERIAL Human Blood, Tissues or Cells No Yes ATMP Pre Clinical Post Marketing 30 Years Traceability Efficacy PhV follow-up Manufacturing Authorisation (MIA) Manufacturing Authorisation Investigational Medicinal Products (MIA(IMP)) GMP Requirement (Eudralex Volume 4) Substantial manipulation and/or non homologous use GLP EU Regulatory Framework Orphan designation Paediatric plan Unlicensed product supply Accelerated approval paths

12. Databases of UK preclinical (<2 yrs from clinic) and clinical stage cell therapies (April 2013) 12 CategoryNumberComparision Preclinical (<2 yrs from clinic) 37 More allogeneic therapies in preclinical stage Larger variety of cell types in preclinical stages Larger range of indications for preclinical projects Few commercially sponsored projects in both pre clinical and clinical stages Clinical (UK trial ongoing)34 Total71 http://ct.catapult.org.uk/

13. Bone marrow derived cells still predominate but T-cells are a rising class amongst greater diversity 13

14. Field is growing into a broad range of disease indications 14

15. What’s special about cell therapy clinical trials? Trial design aspects: Usually administer cautiously to patients in first instance (not healthy volunteers) Sometimes already have some non-trial patient experience (eg compassionate use) Choosing patient population- risk:benefit assessment (early vs late stage disease, adults vs paediatrics) Informed consent 15

16. Trial design aspects: Dose choice / escalation may be limited Seamless safety and efficacy components in initial ‘transitional type’ studies can be efficient; efficacy needs to be demonstrated in adequately powered studies Randomised, blinded, controlled clinical trials are the gold standard, but may not be suitable for some therapies: Historical control groups Parallel observational groups Blinded assessors Randomised, non blinded 16 What’s special about cell therapy clinical trials?

17. Trial conduct aspects: Need clinician champions Usually need long term patient follow-up (cell survival, persistence, engraftment) Protocol deviations and amendments; ways to minimise these (dosing windows etc..) Safety oversight and reporting 17 What’s special about cell therapy clinical trials?

18. Trial conduct aspects: Central importance of a very close relationship with the manufacturing team: Logistics, logistics, logistics… (site selection, patient selection, visit scheduling etc…) Clinical staff training in cell handling and administration Understanding route of therapy through the hospital Cell donation, procurement, testing, traceability, GMP, QP release Integrate clinical and manufacturing plans 18 What’s special about cell therapy clinical trials?

19. Summary examples of cell therapy trial design considerations (Lunn et al., 2011) 19

20. Blood Bone and cartilage Cardiovascular Dermatology/wound healing Diabetes Gastroenterology Immunology Liver Metabolic Neurological Other Ophthalmology Respiratory Oncology hESC iPS MSC Immune Cell Other Somatic Building the Portfolio 20 Manufacturability

21. Share of expertise Support for in house projects Phase 2 clinical trials Scale up, Assays, Freezing and distribution of cells Manufacturing partner, Regulatory, Clinical trial design and delivery Large Cap Company Immune tolerance Clinical development path, business models 21 Regenerative tissue (cells on scaffold) Videregen; UCL, NHSBT, Royal Free Some project examples..

22. Success for the Cell Therapy Catapult means.. Leadership in building an emerging industry, addressing barriers to commercial investment Increased numbers of cell therapies in UK trials and clinical use Investible propositions creating successful UK companies Demonstrating that the UK is the place to do this work Being a leader in building a £10bn industry 22

23. Catapult is a Technology Strategy Board programme Industry Cell Therapy Catapult Investment Researchers NHS