VCLS presentation from Cécile Rousseau at the Phacilitate Cell & Gene Therapy Europe 2017

1. WHAT ARE THE NEED-TO-KNOW CHARACTERISTICS OF PRECLINICAL
R&D SPECIFIC TO THE CELL, GENE AND IMMUNOTHERAPY FIELD?
A NONCLINICAL PERSPECTIVE
Phacilitate Cell & Gene Therapy Europe 2017, Berlin - Workshop

2. 2
Agenda
Regulatory environment for Advanced Therapy Medicinal Products (ATMPs)
EMA: "A medicine for human use that is based on genes, cells or tissue engineering” with
the following classification:
- Gene therapy medicinal product (GTMP)
- Somatic cell therapy medicinal product (CTMP)
- Tissue engineered product (TEP)
- Combined ATMP (cATMP): any of the above combined to a medical device
ATMP Nonclinical (NC) evaluation compared to Drugs/Biologics NC evaluation: same
objectives but different strategies
NC considerations and approach
Take-home messages: Integrated approach CMC / NC / Clinical

3. 3
ATMP Nonclinical (NC) evaluation compared to Drugs/Biologics NC evaluation: same objectives but
different strategies (1/2)
Proof-of-concept / Pharmacology
- What are they? Definition, characterization (CMC, potency assay, markers)
- How do they work? Activity, Mode of Action
- What is the best way to test them? Relevant in vitro and/or in vivo model(s)
Toxicokinetic and pharmacokinetic studies: ADME usually not applicable
- Single / Repeat Dose toxicity studies: define the dose-response relationship in vitro / in vivo
for the intended effect and for the potential safety concerns
- Where do they go? Biodistribution, Migration
- How long and How do they stay? Persistence, Duration of Exposure
o Cells-based medicinal products: Engraftment, proliferation, differentiation
o Gene medicinal product : Insertion, Transitory effect
- How / When are they eliminated? Clearance, Shedding
Regulatory Environment | ATMP NC evaluation| Nonclinical considerations and approach | Take-home messages | Contact

4. 4
ATMP Nonclinical (NC) evaluation compared to Drugs/Biologics NC evaluation: same objectives but
different strategies (2/2)
Safety: safety pharmacology, toxicity
- Are they safe? Toxicity, insertional mutagenesis, germline transmission
- What can they turn into? Tumorigenicity, Carcinogenicity
Additional consideration for GTMP: Environmental Risk Assessment (GMOs)
Regulatory Environment | ATMP NC evaluation| Nonclinical considerations and approach | Take-home messages | Contact
From Baldo et al., Current Gene Therapy, 2013:13

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Nonclinical considerations and approach (1/3)
Starting point for NC study design
- Previous experience in animal models and/or in human with the same product
- Previous experience in human with a similar product (e.g. EPAR)
- Availability of
o Relevant in vitro models
o Relevant animal models
Proof-of-concept
- Model of the disease in vitro and/or in vivo
- Relevant animal models
o Immunocompromised / immunosuppressed / knock-out
o Transgenic
o Humanized
o Disease model
o Animal homolog
3 R’s
Regulatory Environment | ATMP NC evaluation | Nonclinical considerations and approach | Take-home messages | Contact
Be aware of your
model(s) limit(s)
Need justification
with supportive
literature / data

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Nonclinical considerations and approach (2/3)
Combined approach CMC / NC / Clinical
- Product characterization
- Identification of biological activity markers
- Identification of clinical intended use: route of administration, frequency
NC Development Plan
- Risk based approach
- In vitro and/or in vivo model(s) validation: to ensure translation to clinical
- Importance of positive and negative controls
Regulatory Environment | ATMP NC evaluation | Nonclinical considerations and approach | Take-home messages | Contact

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Nonclinical considerations and approach (3/3)
NC study designs adapted to the product features for pharmacology,
pharmacokinetics and toxicology
- Designs need to be adapted to the product features
- No strictly speaking ADME, instead:
o Viability
o Distribution / Migration
o Proliferation / Differentiation
o Persistence / Clearance
- Importance of working from final product
o Manufacturing process related variations
o Immunogenicity
o Impurity (ies)
Regulatory Environment | ATMP NC evaluation | Nonclinical considerations and approach | Take-home messages | Contact

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Take-home messages
Nobody knows better your product than you do: don’t assume agency knows why
your product is as you say, make sure to characterize fully the product to be used for
NC and Clinical studies
Describe specific properties / features of the product that can be used to answer to
NC questions
Justify study design, test model (in vitro and/or in vivo), absence of specific studies etc.
Be innovative with reasons: use your imagination to leverage your product intrinsic
properties and use them to develop characterization methods and don’t forget to
validate models / study design / analytical methods with the Agency through
Scientific Advice
Use integrated approach CMC / NC / Clinical is key for any pharmaceutical product
but is even more critical for ATMPs
Regulatory Environment | ATMP NC evaluation | Nonclinical considerations and approach | Take-home messages | Contact

9. 9
Integrated approach of ATMP development
From Salako et al., Regulatory Rapporteur, 2017:14(6)
Regulatory Environment | ATMP NC evaluation | Nonclinical considerations and approach | Take-home messages | Contact

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Find full presentation and other useful content on how to use regulatory
strategy to accelerate your healthcare product development on
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