Discovery of drugs and drug resistance. Model organisms. Plants and livestock. Cell-based disease modelling. Therapeutics

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1 Genome editing for the engineering of cell lines and animal models Major applications are in: Discovery of drugs and drug resistance Model organisms Plants and livestock Cell-based disease modelling Therapeutics 1

2 Genome editing based products a growing, R&D space Gene therapy products are commonly based on viral/bacterial vectors, genetically modified cells, plasmids (in US) and more recently genome editing/edited products Genome editing based products (GE) currently developed are only few compared to categories of gene therapy products AAV 5% Gene Therapy Medicinal Products in development Lenti 8% HSV 2% POX 9% Other 4% Bacteria/ yeast 4% Plasmids 31% Over 700 scientific papers published in 2017 on CRISPR-CAS GE based products Retro 21% Adeno 16% Source: FDA.gov, 2017 Genome editing systems are becoming increasingly used tools for drug discovery and development and even gene therapy

3 Potential genome editing applications Repair/Restore Fix broken gene(s) or modulate genes/ phenotypes to restore or preserve a healthy status Typically desired to be permanent Delivery problem in vivo Examples: Well-validated Mendelian Disorder Duchenne s MD Retinitis pigmentosa Inborn errors of metabolism KO control elements: Sickle cell anemia, Thalassemia Redirect/Rewire Program cells to carry out activities different from the normal state Usually ex vivo Can be transient or permanent Examples: CAR T lymphocytes Modulate immune reaction of infused cells Modify NK, TIL or Treg function

4 Genome editing EU Clinical Trial Overview No current Clinical Trial using CRISPR-Cas based products (EudraCT + Clinicaltrial.gov) Several pre-clinical programmes ongoing mainly in US, by Academic sponsors and SMEs (Adis) Several ongoing clinical trials are evaluating ZFNs to target monogenic and infectious diseases (i.e. HIV)

5 EMA expert meeting on genome editing 18 October The European Medicines Agency (EMA) convened an expert meeting with the aim to discuss scientific and regulatory opportunities and challenges of medicinal product development using genome editing technologies. Session 1: Genome editing and technologies: state of the art and future outlook Session 2: Application of genome editing by Academia Session 3: Case studies using genome editing technologies: CRISPR- Cas9, TALENs and Zinc finger nucleases 5

6 Scientific challenges of genome editing

7 Scientific challenges - Off-Target considerations Several methods available to detect and consequently measure off-targets no gold standard yet in several cases methods are still in a developmental stage In-silico methods to be validated and established (organoids, animal models) Relevance and impact of off-targets Off-target could be without effect if it affects genes expressed in tissues not involved Variant of Unknown Significance (VUS) cannot be interpreted Need to consider tissue specificity INTERPRETATION OF OFF-TARGETS REMAINS A CHALLENGE 7

8 Regulatory challenges of genome editing Is the current GTMP definition adequate for all possible situations of use of GE? Ex vivo - in vivo potential and requirements Current CAT position: All genome editing technology medicines should undergo the same regulatory scrutiny by CAT as ATMPs EU ATMP risk-based approach applicable / transferable to genome editing? Can the current regulatory framework be applied for patient specific mutations? Product specific vs. algorithm Challenges for evidence generation using current CT framework

9 Other considerations: Unknown long term effects of on/off- target genome editing and the delivery systems Implication on immunogenicity à testing requirements Gene editing products and GMO regulation: definition of the GMO, contained use vs. deliberate release Quality requirements on gene editing (starting) materials Promote state of the art GMP facilities Relevant and necessary nonclinical requirements

10 Genome Editing next steps: Dissemination of the expert meeting outcome envisaged 2018 Revision of the CAT/CHMP guideline on genitically modified cells (ex vivo) Reflections on other guidance (in vivo genome editing) Harmonise ERA/GMO requirements (ongoing)

11 Conclusions A promising pipeline and a lively research and business space Only limited CT developments worldwide so far Challenges in developing these products: not new to innovative products Continue to listen to developers Support development by fostering early regulatory dialogue Cooperation to facilitate marketing authorisation and access to patients, at EU and international level What we see What EMA can do CT using CRISP-Cas

12 Thank you! European Medicines Agency 30 Churchill Place Canary Wharf London E14 5EU United Kingdom Telephone +44 (0) Facsimile +44 (0) Send a question via our website Follow us