1

Major applications are in: •  Discovery of drugs and drug resistance

•  Model organisms

•  Plants and livestock

•  Cell-based disease modelling

•  Therapeutics

Genome editing for the engineering of cell lines and animal models

Genome editing based products

a growing, R&D space Gene Therapy

Medicinal Products in development

Genome editing systems are becoming increasingly used tools for drug discovery and development and even gene therapy

Bacteria/yeast4%

Plasmids31%

Adeno16%Retro

21%

Lenti8%

AAV5%

POX9%

HSV2%

Other4%

Source: FDA.gov, 2017

•  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

•  Over 700 scientific papers published in

2017 on CRISPR-CAS GE based products

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

Potential genome editing applications

Genome editing EU Clinical Trial Overview

No current Clinical Trial using CRISPR-Cas based products (EudraCT + Clinicaltrial.gov)

Several ongoing clinical trials are evaluating ZFNs to target monogenic and infectious diseases (i.e. HIV)

Several pre-clinical programmes ongoing mainly in US, by Academic sponsors and SMEs (Adis)

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

Scientific challenges of genome editing

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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

•  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

Regulatory challenges of genome editing

•  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

Other considerations:

•  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)

Genome Editing – next steps:

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

What we see

• 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 EMA can do

CT using CRISP-Cas

Thank you !

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