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ChondroCelect ® First cell-based medicinal product authorised under the ATMP framework Safeguarding tissues and cells for human application October 21 st , 2010 Gil Beyen, CEO. Notice.

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ChondroCelect®

First cell-based medicinal product

authorised under the ATMP framework

Safeguarding tissues and cells for human application

October 21st, 2010

Gil Beyen, CEO


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Notice

This document does not constitute or form part of any offer or invitation to sell or issue, or any solicitation of any offer to purchase or subscribe for, any shares in the Company, nor shall any part of it nor the fact of its distribution form part of or be relied on in connection with any contract or investment decision relating thereto, nor does it constitute a recommendation regarding the securities of the Company.

This document may contain forward-looking statements and estimates made by the Company, including with respect to the anticipated future performance of TiGenix and the market in which it operates. They include all matters that are not historical facts. Such statements, forecasts and estimates are based on various assumptions and assessments of known and unknown risks, uncertainties and other factors, which were deemed reasonable when made but may or may not prove to be correct. Actual events are difficult to predict and may depend upon factors that are beyond the Company's control. Therefore, actual results, the financial condition, performance or achievements of TiGenix, or industry results, may turn out to be materially different from any future results, performance or achievements expressed or implied by such statements, forecasts and estimates. Forward-looking statements, forecasts and estimates only speak as of the date of this document and no representations are made as to the accuracy or fairness of such forward-looking statements, forecasts and estimates. TiGenix disclaims any obligation to update any such forward-looking statement, forecast or estimates to reflect any change in the Company’s expectations with regard thereto, or any change in events, conditions or circumstances on which any such statement, forecast or estimate is based.


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Agenda

  • Regenerative medicine: an emerging industry

    • TiGenix

    • ChondroCelect

  • Regulatory requirements for ATMPs

    • Quality, Safety, Efficacy

    • Risk evaluation

    • Post Marketing

  • Regulatory requirements for tissues and cells to be used for industrially manufactured products

    • Directive 2004/23/EC, Directive 2006/17/EC, Directive 2006/86/EC

    • National transposition (UK and other examples)

  • Key learnings and conclusions


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Regenerative Medicine

“Regenerative medicine replaces or regenerates human cells,

tissue or organs, to restore or establish normal function”

Regenerative Medicine

Signals

Cells

Scaffolds

Cell Therapy

Tissue Engineering

Products to regenerate tissues and cure patients

4


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An emerging industry, coming of age

  • Ageing population and pressure on the healthcare budget create a strong demand for innovative cures

  • Science develops at an accelerating rate & clinical evidence starts to demonstrate benefits

  • First successes; first companies profitable

  • Big pharma & device companies moving in

  • Regulatory framework (finally) in place

“….Beyond the obvious health benefits of Regenerative Medicine, this technology is desperately needed to combat rising healthcare costs. ”

US Department of Health and Human Services


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Focus

Products

Pipeline

Locations

Regenerative medicine - Innovative local treatments for damaged and osteoarthritic joints

ChondroCelect®, autologous cell-based product for cartilage repair. First approved ATMP in Europe

ChondromimeticTM, resorbable implant for treatment of osteochondral defects. Approved in Europe (CE)

Complementary regenerative medicine products, integrating biomaterials and adult stem cells

HQ in Leuven (Belgium); Manufacturing in Leuven and Cambridge (UK)

6


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ChondroCelect®, cell-based medicinal product aimed at durable regeneration of knee cartilage

Active substance

Characterised autologous cartilage cells expanded ex vivo expressing specific marker proteins

Repair of single symptomatic cartilage defects of the femoral condyle of the knee (ICRS grade III or IV) in adults.

Indication

Biopsy

Implantation

Controlled manufacturing

process & quality control


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Regenerative solutions to bridge the gap

Regeneration

Symptom relief

Replacement

Joint revision

Joint replacement

GAP

Microfracture

Debridement

Severity of symptoms

HA-injections

Pain killers

Nutraceuticals

Adapt lifestyle

Time: duration of symptoms


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ChondroCelect: developed as medicinal product

  • Goal: develop a cell-based product in line with the following standards:

    • High quality, standardised and characterised product

    • Evidence based

       Benefit for the patients

      • GXP (GMP, GLP, GCP) requirements ensuring standard quality, safety and efficacy and positive benefit/risk evaluation

         Benefit for society

      • Regulatory submission/approval = no grey ‘legal/ethical’ zone

      • Confirms long-term commitment of company (strong R&D basis)

      • Regulatory precedent in field of regenerative medicine


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Regulatory path Europe

No regulation or fragmented Transition period

regulation

ATMP regulation

(central route mandatory)

SCTMP(1)

Cell and tissue directive

2002 2005 2007 2009 2012

Start of Positive

pivotal trial trial

Classified results

as SCTMP

MAA

submitted

at EMEA

October 5, 2009:

First approved ATMP

(1) Somatic Cell Therapy Medicinal Product


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ATMP regulatory framework and challenges

  • Regulatory framework

    • ATMP Regulation 1394/2007

      • Regulation: in force in all EU MS immediately without national transpositions (harmonised)

    • Tissues and Cells Directives (2004/23/EC, 2006/17/EC, 2006/86/EC)

      • Directives: need transposition in national legislation (partly dis-harmonised)

         Interface between two regulatory frameworks


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ATMP development challenges

  • Limited benchmarks for ATMP products

    • New scientific field, first product

    • Regulatory framework constructed as a variation on the ‘classical’ pharmaceutical theme

  • Scientific review process ‘in progress’

    • CAT, SAGs and WP’s gearing up

    • Detailed guidelines emerging


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Development challenges (1)

  • CMC requirements

    • Consistent manufacturing according to GMP

    • Stringent product release criteria

  • Challenges for a cell-based (autologous) product

    • Complex composition (living cells)

    • Individual starting materials and products

    • Biological variability (cell growth, characteristics and differentiation pattern)

    • Lack of established / validated methods and markers

CMC: Chemistry, Manufacturing and Controls


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Quality control

Biopsy harvest

Ensuring quality manufacturing

Surgeon training

Standardization

Digestion process

Manufacturing process

Expansion process

Cell yield

Cell growth

Identity

Quality attributes

Viability

Viability

Purity

Potency

Sterility


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Development challenges (2)

  • Non-clinical expectations

    • Safety

    • Proof of concept in (large) animal model

  • Challenges

    • Finding the relevant preclinical model

      • Rejection of the xenograft / relevance of homologous model

      • Different biology of the joint (and cells)

      • Adapted surgery

      • Difficulties in rehabilitation

    • What is a relevant and feasible long-term outcome?


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Example: Goat model as proof of principle

Repair tissue after 10 weeks in goat model – Toluidine blue staining


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Development challenges (3)

  • Clinical requirements

    • Randomised Controlled Trials

    • Clinically meaningful efficacy

    • Safety

  • Challenges

    • Selection of the comparator and blinding of the trial

    • Number of patients to enrol and trial compliance

    • Standardisation of surgery and rehabilitation

    • Validated clinical and structural outcome measures

    • Duration of follow-up (long term durability and clinical benefit)

    • Safety: product vs. procedure


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Superior structural tissue regenerate at 12 months

Clinical benefit over microfracture at 36 months

Continuous clinical improvement

Responder status favors ChondroCelect

Failure profile favors ChondroCelect

No unexpected safety issues and no difference in safety profile

(Safety data: > 500 patients)

Demonstrated clinical benefit

Prospective Randomized Controlled Trial of

ChondroCelect versus Microfracture in the

Repair of Symptomatic Cartilage Defects of the Knee

The American Journal of Sports Medicine , Volume 36, No 2, Februry 2008

The American Journal of Sports Medicine , Volume 37 - Supplement 1, November 2009

18


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Development challenges (4)

  • Risk evaluation:

    • Benefit/risk of the product is significantly influenced by the level of compliance with the defined procedures throughout the treatment, from the biopsy harvest till the correct physiotherapy

    • There is unknown long-term durability of the product efficacy (> 3 years)

  • Risk management:

    • Educational materials and controlled distribution

    • Generate data on larger patient population

      • Further document efficacy & safety:  confirmatory study

      • Document long-term function restoring

    • Pharmacovigilance


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ChondroCelect Marketing Authorisation:Quality, Safety, Efficacy and Benefit/Risk

  • Quality

    • Robust and validated manufacturing process

    • Product quality attributes and product characterisation

  • Safety

    • Adverse events ‘as expected’

    • No major safety risks identified

    • Risk management strategy in place

  • Efficacy

    • Structural superiority

    • Demonstrated clinical benefit

  • Positive benefit/risk assessment

  • Continuous control and confirmation of product profile in ‘real life’ setting


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Regulatory requirements for tissues and cells

  • ATMP Regulation, Article 3

    Where an ATMP contains human cells or tissues, the donation, procurement and testing of those tissues or cells shall be made in accordance with Directive 2004/23/EC

  • Directive 2004/23/EC

    Setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells


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Regulatory requirements for tissues and cells

Directive 2004/23

Regulation 1394/2007

and Directive 2001/83

Directive 2004/23

Regulation 1394/2007

and Directive 2001/83

Directive 2004/23

Other legislations


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Transposition of Tissues and Cells Directives in national legislation: UK

  • Human Tissue Act 2004

  • Human Tissue (Quality and Safety for Human Application) Regulations 2007 (The Regulations)

  • Directions (HTA)

    Policy statement of HTA and MHRA (19 March 2008) on the

    relationship between the Advanced Therapy Medicinal Products

    Regulation and the Quality and Safety Regulations

    • If status is unclear, ask advice (MHRA-EMA)


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Transposition of Tissues and Cells Directives in national legislation: UK

  • Licenses for every activity (procurement, testing, storage, …)

  • Licenses are not tissue-specific

  • License holder – Designated Individual

  • Third party agreements (not for storage)

  • Agreements between procurement sites and manufacturer of ATMPs, outlining both parties’ responsibilities (e.g. transport, traceability, notification SAEs/SARs, …)

  • Licensed procurement site encouraged to provide this agreement to HTA


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Transposition of Tissues and Cells Directives in national legislation: other EU countries

  • Belgium:

    • No license for procurement needed

    • 4 different establishment licenses: tissue bank, production establishment (autologous ATMPs), intermediary structures (tissue and cell products and allogeneic ATMPs, biobank)

    • Licenses are tissue-specific

    • Responsible person (DI) shall be a medical doctor

  • Germany:

    • Two different licenses: ‘donation, procurement and testing’ and ‘processing, preservation, storage and distribution’

    • Licenses are tissue-specific

    • Different CAs per Bundesland (and more), not only national, but also regional differences


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Transposition of Tissues and Cells Directives in national legislation: challenges and learnings

  • Challenges:

    • Important differences between the EU MS

    • Some countries: regional differences

    • Fairly recent framework: learning process for CAs and companies

  • Learnings:

    • Invest sufficient time in getting to know national legislation

    • Involve national CAs early on, establish communication

    • Make agreements between procurement sites and company as country specific as possible to facilitate (national law firms)


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Key learnings and conclusions legislation: challenges and learnings

  • Increased requirements

    • In interest of patients and public (safeguarding health)

    • Need for clear framework/set of rules

       ATMPs: harmonised framework

       Tissues and Cells: partly harmonised framework

  • Most companies active in Regenerative Medicine are fairly small

    • Harmonisation is desirable to lower administrative burden


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Thank you for your attention legislation: challenges and learnings


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