I ntroduction and Regulatory update Workshop on Scientific and - PowerPoint PPT Presentation

I ntroduction and Regulatory update Workshop on Scientific and Regulatory Challenges of Genetically Modified Cell-based Cancer Immunotherapy Products, 15.11.2016 London Paula Salmikangas CAT Chair An agency of the European Union

Cancer Statistics for the UK Wales www.cancerresearchuk.org 1

Medicine Active substance I ndication( s) Com pany Global sales How is the oncology sector changing? $ 1 . Rituxan Rituximab, Non-Hodgkins Roche 7.5 billion  currently mAbs and protein kinase monoclonal Ab Lymphoma, chronic lymphocytic leukemia inhibitors 2 . Avastin bevacizumab Breast, colorectal, Roche 6.7 billion monclonal Ab lung, kidney, ovarian  immuno-oncology treatments – cancers particularly the PD-1/ PD-L1 inhibitors – 3 . Herceptin Trastuzumab HER2+ breast cancer Roche 6.5 billion have dominated current headlines; monoclonal Ab BMS´s Opdivo (Nivolumab) and 4 . I m bruvica Ibrutinib capsules, Mantel cell Johnson & 5.3 billion Protein kinase lymphoma, chronic Johnson/ Pharm Merck's Keytruda (Pembrolizumab) inhibitor lymphocetic leukemia acyclics — worth $33 billion by 2022? 5 . Gleevec Imatinib Chronic myeloid Novartis 4.7 billion Protein kinase leukemia, inhibitor gostrointestinal  Genetic basis of cancer better understood stromal tumors  companion diagnostics, biomarkers 6 . Revlim id Lenalidomide Multiple myeloma Celgene 4.2 billion Thalidomide analogue,  Progress also in chemotherapy, radiation immunomodulator 7 . Velcade Bortezomib Multiple myeloma, Johnson & 2.6 billion Proteasome inhibitor mantle cell lymphoma Johnson/ Takeda and surgery 8 . Alim ta Pemetrexed Non-small cell lung Eli Lilly 2.5 billion Enzyme inhibitor cancer  Cell-based immunotherapies (CAR-Ts, 9 . Erbitux Cetuximab, Colorectal, head and BMS/ Merck 1.9 billion TCR- and NK cell –based therapies) monoclonal Ab neck cancers Serono 1 0 Gardasil Human Cervical cancer Merck & Co. 1.8 billion Papillomavirus Recombinant Vaccine,  Personalised Medicine 2

Genetically modified, cell-based cancer immunotherapies to modify immune cells to attack and clear tumor cells GOAL CAR-T –cells, TCRs, NKs / TANKs, TRUCKS,… . APPROACH MEANS cell modification using viral vectors, gene editing several products in clinical studies, but science STATUS evolves fast due to new technologies more and more complex products, multiple FUTURE modifications, off the shelf/ allogeneic products safety switches, inductors, in vivo GE? 3

Cell-based cancer immunotherapies (GTMPs!) Apheresis Vector/GT/ GE material production Cell preparation Vector/GT/ GE Gene transfer material testing Cell expansion Formulation, storage Quality, Safety and Efficacy are interlinked! 4

Advanced Therapy Medicinal Products (ATMPs) Gene Therapy Somatic Cell Therapy Tissue Engineering Medicinal Products Medicinal Products Products Genetically modified cells medical device + ATMP  combined ATMP 5

The EU legal / regulatory framework PhVig legislation Tissues/ Cells Other starting Dir. 2010/84/EU 2004/ 23/ EC materials Reg. 1235/2010 Blood 2002/ 98/ EC Medical Devices 93/42/EC, 90/385/EC Clinical Trials Medicinal Medicinal 2001/20/EC GMP Products Products 2003/94/EC Paediatrics Community Code Centralised procedure Dir. 2001/83/EC Reg. 726/2004 Orphans 1901/2006 141/2000 ‘Annex I ’ Variations 2003/ 63/ EC 1084(5)/2003 2009/ 120/ EC Advanced Therapy Falsified Med. 1234/2008 1394/ 2007 Dir. 2011/62/EU 6 A new class of medicinal products with a dedicated regulation

Centralized Marketing Authorisation obligatory for ATMPs Scientific advice (national and/or EMA), certification MAA Post Clinical trials Development Preclinical Review Marketing PhI PhII PhIII GMP GMO Pre MAA PSUR application CT application Meetings cycle (national authorities) (Rapp & Co-Rapp) Quality & Manufacturing CE marking/ Safety Evaluation of structural Efficacy Component(s) by Risk Managem ent Plan Notified Body 7

EMA Committees for ATMPs CAT CHMP Chair: P.Salm ikangas Chair: T.Salm onsson 5 „double m em bers“ - 18 quality experts - 12 non-clinical experts - 21 clinical experts (including 4 members representing physicians) - 1 inspector - 4 patient representatives - 8 other (scientists, heads of departments etc.) Total 6 8 experts 8

Marketing authorization applications / CAT 2009-2016 (September) 2009 2010 2011 2012 2013 2014 2015 2016 Total Approved Submitted 3 1 2 3 2 2 1 1 15 8 GTMP 2 1 2 1 1 6 2 SCTMP 1 1 1 TEP 1 2 2 1 1 7 3 Variations 0 0 1 1 9 4 3 4 22 Approved: ChondroCelect for cartilage repair, 2009 *(withdrawn 06/2016) MACI for cartilage repair, 2012 *(closure of EU manufacturing site 09/2014) Glybera for treatment of LPL deficiency, 2013 Provenge for treatment of advanced prostate cancer, 2013 *(withdrawn 05/2015) Holoclar for treatment of limbal stem cell deficiency, 2015 Imlygic for treatment of advanced melanoma, 2015 Strimvelis for treament of ADA-SCID, 2016 Zalmoxis for treatment of high-risk haematological malignancies (adjunctive to HSCT)  2 ATMPs under evaluation, several new ones expected 2017 9

Classifications 2009-2016 Other CAT procedures (October 2016) - 2 1 1 scientific advice procedures for ATMPs - 4 7 PIPs - 1 8 ATMP applications for PRIME, 6 granted - Over 3 0 0 ATMPs have been studied in clinical trials during 2011-2015 (~ 200 CTs during 2004-2010) 10

Cells as pharmaceuticals? Aspirin Signalling Morphology Functionality Apoptosis Gene expression Integrity of organels Energy Motility Metabolic activity Respiration Quality of proteins Viability Differentation Proliferation Eucaryotic cell 11

Cancer immunotherapy products Toxicity Efficacy Quality

Way of building the evidence – applicable for innovative products?  Conditional MA  Adaptive Pathways Clinical  PRIME studies  Registries Non-clinical PD, PK, tox  Real World Data Characterisation  HTA and reimbursement Manufacturing developm ent 13

Applicants type and products submitted (September) 1 SME Orphan 22 2 2 22 2 5 Other Non-Orphan Academic* N= 48 N= 44 3 1 Strong presence of ATMPs in Biological 1 3 applications and products granted (up Chemical to September 6 out of 10 granted) 15 ATMP Immunological Herbal 12 N= 44 Jordi Llinares Regulatory and scientific management department

Risk-based approach - Propectively planned strategy to justify the need for data in the MAA, proportionate requirements based on risks - Does not provide a rigid classification system of different risks of a product as whole (e.g. high-risk product vs. low-risk product) - Is intended to provide flexibility to regulation of ATMPs - Should help developers to overcome challenges due to the specific nature of the ATMPs - How to do the risk/risk factor profiling?  GL on risk-based approach ( EMA/CAT/CPWP/686637/2011)  Q/A document on RBA under preparation  scientific advice 15

Available EU guidance for genetically modified cells Guideline on cell-based Reflection paper medicinal products (2008) Guideline on the on stem-cell based Risk-based MPs approach (2013) Quality, preclinical and Scientific Requirements for the clinical aspects of gene Follow-up of patients Environmental Risk Assessment therapy m edicinal administered with gene therapy of Gene Therapy Medicinal products ( 2 0 1 7 ?) medicinal products Products Guideline on Potency testing of cell-based Development and Manufacture of MPs containing immunotherapy MPs for treatment Lentiviral Vectors genetically of cancer (2007) modified cells Non-clinical studies required before first clinical use of gene Non-Clinical testing for Inadvertent Germline therapy medicinal products transmission of Gene Transfer Vectors http:/ / w w w .em a.europa.eu/ htm s/ hum an/ hum anguidelines/ biologicals.htm 16 16

Thank nk y you ou f for or you our a atte ttent ntion! on! 17