Corporate Presentation - Txcell.com

Teaching regulatory T cells to treat your disease

Corporate Presentation December 2017

FR0010127662 – TXCL

Disclaimer References herein to this presentation (the “Presentation”) shall mean and include this document, any oral presentation accompanying this document provided by TxCell (the “Company”) and any further information that may be made available in connection with the subject matter contained herein. The disclosure, distribution and publication of this Presentation may be restricted by law in certain jurisdictions and persons into whose possession any document or other information referred to herein comes should inform themselves about and comply with any such restrictions. The Company takes no responsibility for any violation of any restrictions by any person. This Presentation has been prepared by the Company and is provided for information purposes only. This document does not purport to contain comprehensive or complete information about the Company and is qualified in its entirety by the business, financial and other information that the Company is required to publish in accordance with the rules, regulations and practices applicable to companies listed on Euronext Paris, including the risk factors described in the Company’s Document de Référence (registration document) for the year ended December 31, 2016 as filed with the French financial market authority (the Autorité des marchés financiers – the “AMF”) on April 26, 2017 under number R.17-024, available on the Company’s website (www.txcell.com), in particular in Chapter 4 “Risk factors”. Information and other data appearing in such publications, and certain figures and numbers appearing in this document have been rounded. Consequently, the total amounts and percentages appearing in tables and elsewhere may not necessarily equal the sum of the individually rounded figures, amounts or percentages.

No representation, warranty or undertaking, express or implied, is made as to the accuracy, completeness or appropriateness of the information and opinions contained in this Presentation, or its use for any purpose, and no reliance should be placed on any information or opinions contained herein. The Company and its representatives accept no responsibility for and shall not, under any circumstance, be held liable for any loss or damage that may arise from the use of this document or the information or opinions contained in it. In particular, this document contains information on the Company’s markets and competitive position, and more specifically, on the size of its markets. This information has been drawn from various sources or from the Company’s own estimates which may not be accurate and thus no reliance should be placed on such information. The information and opinions contained in this document are provided as of the date of this document only and may be updated, supplemented, revised or amended, and thus such information is subject to change at any time. The Company is not under any obligation to update the information, statements or opinions contained in this Presentation. This Presentation contains certain forward-looking statements relating to the business of the Company, including the Company’s ability to develop, market, commercialize and achieve market acceptance for its products, estimates for future performance and estimates regarding anticipated operating losses, future revenues, capital requirements, and needs for additional financing. Even if the actual results or development of the Company are consistent with the forward-looking statements contained in this Presentation, those results or developments of the Company may not be indicative of future results or developments. In some cases, you can identify forward-looking statements by words such as “could,” “should,” “may,” “expects,” “anticipates,” “believes,” “intends,” “estimates,” “aims,” “targets,” or similar words. Although the management of the Company believes that these forward-looking statements are reasonably made, they are based largely on the current expectations of the Company as of the date of this Presentation and are subject to a number of known and unknown risks and uncertainties and other factors that may cause actual results, performance or achievements to be materially different from any future results, performance or achievement expressed or implied by these forward-looking statements. In particular, the expectations of the Company could be affected by, among other things, uncertainties involved in the development of the Company’s products, which may not succeed, the ability to manufacture product, the outcome of clinical trials and the delivery of regulatory authorizations necessary for clinical trials, manufacturing and marketing of the Company’s products and, in general, any factor that could affects the Company’s capacity to commercialize the products it develops, as well as any other risk and uncertainties developed or identified in any public documents described above. In light of these risks and uncertainties, there can be no assurance that the forward-looking statements made in this Presentation will in fact be realized. Notwithstanding the compliance with article 223-1 of the General Regulation of the AMF (the information disclosed must be “accurate, precise and fairly presented“), the Company is providing the information in these materials as of the date of this Presentation, and disclaims any intention or obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events, or otherwise. All persons accessing this document are deemed to agree to all the limitations and restrictions set out above. This Presentation and the information it contains are not intended to constitute, and should not be construed as an offer to sell or a solicitation of an offer to buy or subscribe to any the Company securities, in any jurisdiction. 2


Introduction

TxCell’s history 1997

Type 1 Tregs discovery by TxCell’s scientific founder

Naturally antigen-specific Type 1 Tregs 2001

TxCell Foundation

✔

Preclinical validation

✔

Clinical validation

✗

Manufacturing viability

2016 CAR-Treg Strategic shift

Engineered Tregs

✔

Preclinical validation

1st clinical PoC

?

Clinical validation

✔

expected 2020

Manufacturing viability

Meanwhile in the CAR-T effector space… 1970s Effector T cells (Teffs) discovery

2017

1st FDA approval of a CAR-T product

4

A unique positioning in the cell therapy landscape TxCell develops cellular immunotherapies based on regulatory T cells (Treg) for the treatment of autoimmune and inflammatory diseases as well as transplant rejection T cell type

T Effector Cells (Teffs)

T Regulatory Cells (Tregs)

Therapeutic strategy

Therapeutic field

Control the immune system that has turned against the patient

Engineered cells Historical FDA approvals in H2 2017 (Novartis, Kite/Gilead)

Stimulate the immune system to attack the tumor

Selected companies

Cancer

CAR-T Effector T cells engineered with a Chimeric Antigen Receptor (CAR)

TxCell’s first clinical trial expected in 2018

Autoimmunity Inflammation

CAR-Treg

Transplantation

Regulatory T cells engineered with a CAR

T-Cell immunotherapy market expected to reach 30 Bn$ by 20301 TxCell is uniquely positioned in this emerging space 1.

T-Cell Immunotherapy Market 2015-2030, Roots Analysis 2015. 5

At the crossroads of two vibrant industry segments TxCell is uniquely positioned at the crossroads of two promising technological fields

 Cellular immunotherapy now

 Therapeutic use of Tregs as a credible option

becoming a commercial reality

to induce tolerance in Autoimmunity, Inflammation & Transplantation (see deals in exhibit)

(see in exhibit)

6

A highly experienced management team

Stéphane BOISSEL Chief Executive Officer •

25 years of experience, 15 of them in the biopharma industry

•

MBA from the University of Chicago

François MEYER Head of Research • •

35 years in pharma & biotech R&D, including gene & cell therapy Graduated from the Swiss Federal Institute of Technology (ETHZ) and PhD from the Institute for Molecular Biology of Zurich

Raphael FLIPO Chief Financial Officer

•

15 years in corporate finance and auditing

•

Master in Law and graduated from EDHEC Business School

7

A considerable body of scientific and medical evidence

Natural role evidenced: • •

Cells specialized in immune tolerance induction Prevention of hypersensitivity to allergens and autoimmunity to self

Key function in inflammation and autoimmunity demonstrated:

T Regulatory Cells (Treg)

• • • •

Absence of Treg cells leads to multi-organ autoimmune syndrome Defects of Treg cells are observed in chronic inflammation and autoimmunity Decreased Treg cells specific for allergens is observed in allergic patients Treg cells increase in patients with treatment induced remission

Confirmed therapeutic potential: • • •

Tolerance and activity demonstrated in early clinical studies in Crohn’s Multiple mode of actions acting in synergy to reduce inflammation Great potential for therapeutic efficacy in humans

8

Large potential market opportunities NEUROLOGY Primary focus: Multiple Sclerosis Other possible indication: neuromyelitis optica

TRANSPLANTATION GASTROINTESTINAL Primary focus: Crohn’s disease Other possible indications: Ulcerative colitis, celiac disease, autoimmune hepatitis

Primary focus: Solid organ transplantation Other possible indication: Graft-versus-Host Disease

DERMATOLOGY Primary focus: Bullous pemphigoid Other possible indications: psoriasis, pemphigus vulgaris

RHEUMATIC Primary focus: Lupus Other possible indications: Rheumatoid arthritis, spondylarthritis, psoriatic arthritis

▪ 100+ diseases ▪ Business opportunity > 100Bn$1 with CAGR > 5%2

1. 2.

Company estimate. During the period 2016-2020. Source : Global Autoimmune Diseases Drugs Market 2016-2020, Market Research Reports, March 18, 2016. 9

Target selection A pragmatic strategy to deliver strong product & partnership potential 1/ Unmet medical need • • •

Large market with refractory sub-population, e.g. Crohn’s disease, multiple sclerosis Rare diseases, e.g. bullous pemphigoid Indications with no “game changing” pipeline, e.g. lupus nephritis

2/ Scientific relevance of Tregs •

Can a Treg work in this indication, in the targeted sup-population? • Strong inflammatory component • Relevance of the Treg mechanism of action

3/ Feasibility • • •

Adequate set of possible targets Preclinical feasibility (available model, tools & reagents) Freedom to operate / IP

Suitable targets for Treg-based therapy development Targets for large and competitive diseases  TxCell to partner-out to pharmas

Targets for rare or orphan diseases  TxCell to keep rights as long as possible 10


Technology platform

Three Treg cell populations CD4+ FoxP3+ Tregs

CD8+ FoxP3+ Tregs

Type 1 Tregs (Tr1)

19951

20072 CRTI, Inserm Nantes

19973 TxCell/Inserm

3000+ publications

Protected by 2 CRTI patents exclusively in-licensed by TxCell

Leading patent estate exclusively in-licensed and owned by TxCell

Thymus/Peripheral blood

Peripheral blood

Peripheral blood

+++

+++

+

+++

+++

+/-

(soluble factors e.g. IL-10, IL-35)

+/-

tbd

+++

Metabolism disruption

++

tbd

++

-

-

+

1st characterization

Publications / IP

Origin Differentiation status

20+ clinical trials

MECHANISM OF ACTION Contact-dependent suppression Contact-independent suppression

Cytolysis of myeloid targets

1. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of selftolerance causes various autoimmune diseases. J Immunol. 1995 Aug 1;155(3):1151-64. 2. Guillonneau, C., Hill, M., Hubert, F.X., Chiffoleau, E., Herve, C., Li, X.L., Heslan, M., Usal, C., Tesson, L., Menoret, S., et al. 2007. CD40Ig treatment results in allograft acceptance mediated by CD8CD45RC T cells, IFN-gamma, and indoleamine 2,3-dioxygenase. J Clin Invest 2007, 117:1096-1106. 3. Groux H, O'Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature. 1997 Oct 16;389(6652):737-42. 12

Construct & MoA Antigen specificity comes from a CAR (Chimeric Antigen Receptor)

Proposed mechanism of action

(Genetically-modified Tregs)

13

CAR-Treg manufacturing process First CAR-Treg manufacturing process completed in December 2017

Process lead time: ~2 weeks (before post-production QC) 14

R&D capabilities

THE TXCELL DISCOVERY ENGINE 10

APC-A

10

10

10 -10

27,4%

5

3

2

23,0%

1

10

Disease + Target antigen

ScFV sequence - Optimization - Bioinformatics - Humanization

CAR construct DNA sequence: - ScFV - Hinge - Transmembrane - Co-stimulatory - Stimulatory

Gene transfer - Lentivirus - Electroporation

48,6 %

4

0

10

2

1,0% 10

3

FITC-A

10

4

10

5

CAR-Treg profiling - CAR surface expression - CAR-dependent activation - Intracellular & extracellular Treg markers

in vivo PoC studies

Potency: - Suppressive activity - Anti-inflammatory cytokines secretion

Safety KEY OUTCOMES

Target specificity

Optimal intracellular signaling

Persistence Manufacturing process robustness

Stable CAR-Treg phenotype & potency

15

• Design & optimization of CAR constructs • Vector engineering & optimization • Cell engineering • Development of functional & analytical assays • Expertise in the biology of Treg cells

External collab.

Breakdown

35%

• Bioinformatics & modeling

• Several specifically designed clinicallyrelevant in vivo models in place (MS, RA, uveitis, IBD, organ transplantation) • Treg specific analytical tools for in vivo Treg cell tracking under implementation • Expertise in the production of murine Tregs and CAR-Tregs

Process development

• ScFV optimization through in silico modelling & bioinformatics

Preclinical

CAR

Research team & skills

• Cell therapy process development expertise • Including analytics development • Technology transfert to third parties

25% • Additional animal models from academic partners: • UBC/INSERM-Nantes : solid organ transplantation models & GvHD • LIED: skin blistering diseases

Key recent hires

40%

Overall 80% of TxCell’s staff Including 40% of PhDs

• CMOs

16

A first clinical POC with an antigen-specific approach Ovasave® Ovasave® CATS1 study

First-generation of ‘naturally’ antigen-specific Tregs (ASTrIA)

Percentage of patients receiving 106 cells in Response or Remission on CDAI (Crohn’s Disease Activity Index) 100 (n=8)

•

20 patient-study in 4th line, refractory Crohn’s disease

•

Good tolerability of Ovasave® (autologous ovalbumin-specific Tregs)

80

•

High response and remission rate with dose related efficacy at 5 to 8 weeks after single injection

60

•

Biomarkers for identification of patient responses

•

Physicians’ assessments lead to repeated injections for up to 1 year

75%

75%

38%

40

25% 20 0

•

Week 5

Phase I/II retreatments document feasibility and tolerability of multiple injection

Week 8

Response Delta CDAI ≥ 100 Remission ≤150 CDAI points

Full study results published in Gastroenterology and featured in Nature Reviews of Gastroenterology (2012)

•

Strong set of data - First clinical proof-of-concept

•

Improvement of ASTrIA manufacturing process completed in 2017

CDAI* change from baseline – Dose 106 (n=8) 50

Moyenne ± ESM

•

0 -50 -100 -150 -200 0

2

4

6

8

10

12

Weeks

17


CAR-Treg transplantation program ENTX#SOT

18

The unmet medical need in transplant rejection Key transplantation figures •

>60,000 solid organ transplant procedures performed per year (US, EU)1

•

Significant risk of organ rejection

•

•

Only 50% graft survival at 10 years for kidney2

•

High mortality rates associated with lung transplants (40-55% at 5 years)3

>160,000 patients on waiting lists (US & Europe)4

Specific unmet needs in solid organ transplantation (SOT) •

Acute and chronic rejection

•

Serious complications related to the immunosuppression itself and/or directly to immunosuppressive drugs themselves: infections, de novo malignancies, metabolic disorders, etc.

1. Sources : US Department of Health & Human Services. ‘More than 30,000 transplants performed annually for first time in United States’ January 9, 2016. European Commission, Journalist workshop on organ donation and transplantation, November 26, 2014. 2. Gondos A , Döhler B, Brenner H, Opelz G. Transplantation. 2013 Jan 27;95(2):267-74 3. Hartert M, Senbaklavaci O, Gohrbandt B, Fischer BM, Buhl R, Vahl CF. Dtsch Arztebl Int 2014; 111(7): 107–16. 4. Sources : UNOS, European Commission 19

TxCell’s CAR-Treg approach in transplantation • Aiming to induce immune tolerance specifically to the graft

Graft HLA-A2(+)

• As an alternative to nonspecific immunosuppression, regulatory T cells could provide a way to re-educate the

recipient’s immune system to tolerate the graft1

• Upcoming milestones • Deliver additional sets of preclinical proof-of-concept data

CAR-Treg cells designed to recognize specifically the HLA-A2+ graft

• Transfer manufacturing process to CMO • File regulatory dossier to start first-in-man study in Q4 2018

Donor HLA-A2(+)

Recipient HLA-A2(–)

TxCell aims at being the 1st company in the world to start a clinical trial with a CAR-Treg, in 2018, pending appropriate funding 1. Ferreira LMR, Tang Q. Am. J. Transplantation 2017 Apr; 17(4), 851-853. 20

First in vivo POC with CAR-Tregs in transplantation model •

The first preclinical POC with HLA-A2-CAR-Tregs in transplantation was published in March 2016 by the University of British Columbia (UBC)1, TxCell’s academic partner •

Human CAR-engineered Treg cells specific for the molecule HLA-A2 are significantly more effective than polyclonal (non-specific) Tregs in reducing GvHD-related inflammation GvHD model

Survival curve

Immunodeficient mice

Human white blood cells

CAR-Treg

INFLAMMATION

GvHD: Graft-versus-host disease Inflammation caused to the recipient/host by the donor/graft’s immune cells

Control Treg No Treg PBMC: peripheral blood mononuclear cells PBS: phosphate buffered saline

•

Additional preclinical POCs with human HLA-A2-CAR-Tregs in skin transplantation have been published in April 2017 by the Hannover Medical School (Germany)2 and Kings’ College London, Guy’s Hospital3

1. 2.

MacDonald KG, Hoeppli RE, Huang Q, Gillies J, Luciani DS, Orban PC, Broady R, Levings MK. J Clin Invest. 2016, 126(4):1413-1424. Noyan F, Zimmermann K, Hardtke-Wolenski M, Knoefel A, Schulde E, Geffers R, Hust M, Huehn J, Galla M, Morgan M, Jokuszies A, Manns MP, Jaeckel E. American Journal of Transplantation 2017 Apr;17(4):931-943. Boardman DA, Philippeos C, Fruhwirth GO, Ibrahim MA, Hannen RF, Cooper D, Marelli-Berg FM, Watt FM, Lechler RI, Maher J, Smyth LA, Lombardi G. Am J Transplant. 2017 Apr;17(4):931-943.

3.

21

New in vivo POC with a humanized clinical candidate •

Proprietary second-generation HLA-A2 CAR-Tregs •

•

Humanized scFv expected to minimize potential for immunogenic clearance of CAR-Tregs

Achieved positive results in preclinical transplantation model •

Same GvHD model as original POC with murine construct

•

Second-generation humanized candidate showed similar efficacy as first-generation murine candidate in preventing GvHD  Humanized candidate showed significant effect on mice survival vs. control (p=0.0182)

•

•

HLA-A2 specificity & Treg features •

Humanized candidate was shown to have higher target specificity compared to murine candidate

•

Humanization had no impact on Treg phenotype nor on Treg functions (e.g. suppressive effect, cytokine release)

Results presented at ESOT 2017 by academic partner Prof. Megan Levings from UBC1

Major step achieved towards clinical testing 1.

Levings M. Alloantigen-specific regulatory T-cells generated with a chimeric antigen receptor. Oral presentation at the 18 th Congress of the European Society for Organ Transplantation (ESOT), September 24-27, 2017, Barcelona, Spain. 22


CAR-Treg programs for autoimmunity and inflammation

23

A strong rationale in autoimmunity and inflammation •

Tregs are naturally involved in the prevention of autoimmunity

•

Defect of Treg cells have been identified as one of the cause of deregulated immunity in autoimmune diseases (Skin inflammatory diseases, SLE, Multiple Sclerosis, etc.) •

Initial targets:

•

Bullous pemphigoid

•

Multiple sclerosis

•

Lupus Nephritis

Current status ✓ Ongoing in vitro and in vivo studies by TxCell showing promising preliminary results in relevant models of autoimmune diseases, such as multiple sclerosis ✓ Confirm TxCell’s CAR-Treg platform strategy ✓ Presentations and/or publications expected in the next few months

24

CAR-Treg academic collaborations

Ospedale San Raffaele (OSR) Milan, Italy

Multiple Sclerosis & Transplantation

Bullous Pemphigoid

Lupus Nephritis

Lübeck Institute of Experimental Dermatology (LIED) Lübeck, Germany

Center for Research in Transplantation and Immunology (CRTI) Nantes, France

European expert in cell and gene therapy. Contributed to the development of Strimvelis

Leading institution in translational research on skin blistering diseases

Center of excellence in the field of transplantation and immunology

•

•

Bullous pemphigoid is a rare, potentially fatal autoimmune disease characterized by tense inflammatory skin blisters

•

Expansion of TxCell’s research efforts to explore the therapeutic potential of engineered CD8+ Treg cells (exclusively in-licensed in Dec. 2016)

•

Pharmacology and toxicology studies conducted in bullous pemphigoid

•

•

Development and commercialization rights retained by TxCell

Multiple sclerosis is an autoimmune disease of the Central Nervous System affecting approximately 2.3 million people worldwide2. Permanent consequences can be highly debilitating.

•

Pharmacology and toxicology studies conducted in multiple sclerosis

•

Development and commercialization rights exclusively optioned-out to TxCell

• •

1. 2.

Lupus Nephritis is one of the most serious complications of Lupus, a chronic systemic autoimmune disease affecting over 5 million people worldwide1

Pharmacology and toxicology studies conducted in Lupus Nephritis Development and commercialization rights exclusively optioned-out to TxCell

Source: Lupus Foundation of America Multiple Sclerosis Research Foundation (arsep foundation). 25


Financials & Outlook

Key financials P&L *

Cash flow * In million of euros

06/30/2017 1.3 (3.9) (1.8) (0.6) (5.0) (5.3)

Revenue Other income Research and development expenses General and administrative expenses Expenses related to share-based payments Current operating profit / (loss) Net profit / (loss) *

In million of euros Net cash flows from operating activities Net cash flows from investing activities Net cash flows from financing activities Net cash flows as of June 30, 2017 Cash position as of December 31, 2016 Cash position as of June 30, 2017 *

06/30/2017 (5.1) (0.3) 10.6 5.2 3.5 8.7

IFRS data

IFRS data

H1 2017 current operating expenses (excl. expenses related to-share based payments)

Research and development expenses

32%

Cash position In million of euros

Amount

Cash position as of December 31, 2016

3.5

Cash position as of March 31, 2017 (incl. ABSA €11.1 M gross)

11.3

Cash position as of June 30, 2017

8.7

Cash position as of Sept 30, 2017

7.0

General and administrative expenses

68%

Cash burn guidance 2017 On the basis of the Company's development plan

Cash burn estimation Around €13M

27

Main shareholders and liquidity Main shareholders Auriga Partners 33,3%

Free float 8,9%

Auriga Partners 28,2%

Free float 29,3%

As of Jun. 30 2015

(incl. Seventure Partners : 4.2%)

As of Dec. 31, 2016

Seventure Partners

Bpifrance

15,2%

42,6%

Seventure Partners 6,5%

Free float 48,8%

As of Oct. 20, 2017

Bpifrance 36,0%

Bpifrance 31,6%

To the best knowledge of TxCell as of October 20, 2017

Number of shares as of October 20, 2017: 21,279,996

Fully diluted capital

Liquidity

As of October 20, 2017

Number of shares

Basic shares outstanding (non diluted capital)

21,279,996

TxCell share: average volume before and after the capital increase of February 24, 2017 (as of October 20, 2017) 200 000

Incentive plans (management and staff)

1,722,674

180 000

Convertible notes with attached warrants (OCABSA, Yorkville)*

1,139,870

160 000

Listed warrants (shareholders)

4,157,859

140 000

Fully diluted capital **

Auriga Partners 19,6%

28,300,399

181k

120 000 100 000

* Including outstanding warrants and theoretical number of shares to be issued by conversion of outstanding convertible Notes, based on 93% of the lowest daily VWAP over the ten days preceding October 20, 2017 (i.e. €1.56).

** Based on the full exercise of issued and outstanding instruments giving access to the Company’s capital, excluding the PACEO equity line on which TxCell has committed not to drawdown, and excluding 150 unexercised warrants giving access to notes with share subscription warrants attached (OCABSA), which TxCell plans to use primarily in the event that the listed cash warrants from the Feb. 2017 capital increase are not fully exercised at maturity (Feb. 26, 2018).

80 000

76k

60 000 40 000 20 000 0 Before transaction (3 mo.)

Post transaction (October 20, 2017)

28

Financing options secured for 2018 • Listed cash warrants issued as part of February 2017 capital increase could finance the Company until 1st CAR-Treg IND approval (by end 2018) • 75% coverage: 4 equity warrants give the right to subscribe to 3 new shares

• Strike price: €2.60 per new share upon exercise of the warrants • 12-month maturity: Can be exercised at any time until February 26, 2018 • In the event of a full exercise of warrants: additional €10.8m net product

• As an alternative, optional OCABSA financing program has been renegotiated to reduce cost of capital for TxCell and dilution for shareholders • €15 million in gross proceeds guaranteed in monthly installments now at TxCell’s sole option • Temporary solution as TxCell actively works towards securing a longer-term financing with

acceptable terms (e.g. strategic partnership and/or fund raising if market cap increases)

Cash runway extended even if listed cash warrants are not fully exercised by Feb. 26, 2018 29

Where do we go from here? • Over the next few months, TxCell expects to:  Communicate additional preclinical validation data sets to the scientific community  Focus on 4 to 5 preclinical programs with the highest potential and likelihood of reaching clinical development in the near term  As a result, certain discovery programs and/or academic collaborations may be terminated  Initiate transfer of CAR-Treg manufacturing process to cell therapy CMO to prepare for first clinical trial with HLA-A2 CAR-Treg program in solid organ transplantation  Continue dialogue with industry players (pharma and biotech companies) with the aim of entering into strategic partnerships  Identify the best long-term financing options going forward

30

Key highlights • CAR-Treg transformation achieved • Pioneering technology at the crossroads of two vibrant environments: Tregs & CAR-T • Addressing significant unmet medical needs • Large markets: >100 Bn$ in annual sales and >5% CAGR • Major short-term and mid-term catalysts • A real status of publicly-listed company following the 2017 financing

Strategic refocusing

2016

Multiple preclinical POCs

2017

First-ever first-in-man CAR-Treg study

2018

2019

Clinical POC

2020

31


TxCell

Thank you

www.txcell.com @TxCellSA


Back-up slides

Hot CAR-T environment • Historical FDA approvals of Novartis’s Kymriah® (Aug. 30, 2017) and Kite’s Yescarta® (Oct. 18, 2017) • Kymriah® (tisagenlecleucel, CTL019) • Treatment of children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL) • One expert on FDA panel called Kymriah® “the most exciting thing I've seen in my lifetime”

Picture: Novartis

• Price set at $475,000 per one-time treatment, response-based

• Yescarta® (‘Axi-Cel’, axicabtagene ciloleucel, KTE-C19) • Relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (NHL) • Price set at $373,000 per one-time treatment

• Gilead acquired Kite Pharma for $11.9Bn • Gilead purchase price: 180$ per share (29% premium) • Kite share price +300% since Jan 1st, 2017 34

Hot Treg environment Date

Buyer Golden Meditech

Target

Type of deal

Financial terms

Technology

Indication

Phase

Company creation:

Initial investment: 10M$ + 10M$ in warrants

Umbilical cordderived Treg cellular therapy

Autoimmune diseases

Clinical

IL-2 receptor agonist

Autoimmune diseases

Preclinical

Nanoparticles

Type 1 diabetes

Preclinical

Low-dose IL-2

Lupus, autoimmune diseases

Phase II

IL-2 receptor agonist

Autoimmune diseases

Phase I

Undisclosed

Nanoparticles

Immune tolerance

Preclinical

Overall: up to 12M$

CRISPR-Cas9 gene edited Tregs

Autoimmune diseases

Preclinical

Sept 2016

Upfront: 300M$ Jan 2017

Acquisition

Apr 2017

Exclusive ww license

May 2017

Exclusive license option

Milestones: up to 475M$

Undisclosed

Upfront: 8M€ Milestones: up to 200M€ Upfront: 150M$

Jul 2017

Co-development

Aug 2017

R&D collaboration

Sept 2017

Exclusive ww license Research coll.

Milestones: up to 250M$

35

Target antigen selection 1/ Antigen distribution • Local or Systemic: • Local: tissue-specific antigen (not necessarily linked to the pathology) • Systemic: disease-specific antigen OR antigen present in secondary lymphoid tissues

2/ Specificity • Antigen expression should be specific of the targeted tissue

3/ No cross-reactivity of CAR ligand binding domain • Target Structure: avoid strong similarities with other proteins • Target absence of homology with Infectious pathogens: avoid side effects due to Treg activation

4/ Cross-linking availability • Cross-linking is necessary to really activate CAR-Tregs • Various options: • Surface antigen CAR-Treg • Macromolecule • Polymer CAR

Macromolecule or polymer with repeated epitope

Surface antigen

CAR-Treg CAR

36

Key collaborations with leading scientists worldwide Dr. Ignacio ANEGON

Dr. Carole GUILLONEAU

Dr. Megan LEVINGS

CRNS scientist and co-director of the CRTI team number 2, Nantes FRANCE

INSERM scientist and co-director of the CRTI team number 2, Nantes FRANCE

Dr. Ralf LUDWIG Head of the LIED Model Systems of Inflammatory Skin Diseases, Institute of Experimental Dermatology, Lübeck GERMANY

Pr. Chiara BONINI

Head, Immunity in Health and Disease, Child & Family Research Institute, University of British Columbia, Vancouver CANADA

Head of Unit, Experimental Hematology San Raffaele Hopital, Milan ITALY

Dr. Attilio BONDANZA

Dr. Olivier DANOS

Assistant Professor and Immunotherapy Group Leader, Institute San Rafaelle, Milan ITALY

CSO, Regenxbio, Maryland UNITED STATES

Dr. Bernard MALISSEN

Research Director, Immunology Center of Luminy, Marseille, FRANCE

Pr. Zelig ESHHAR Prof. of Immunology, Chair of Immunology Research Weizmann Institute of Science, Rehovot ISRAEL 37

Exclusive worldwide license on broad CAR-Treg patent REDIRECTED, GENETICALLY-ENGINEERED T REGULATORY CELLS AND THEIR USE IN SUPPRESSION OF AUTOIMMUNE AND INFLAMMATORY DISEASE (EP2126054)

Patent family Europe Patent granted by EPO in June 2016

United States Patent under review by USPTO

Inventors : Zelig Eshhar, Eran Elinav Applicant : Yeda Research and Development Co. Ltd., Rehovot, Israel (technology transfer arm of the Weizmann Institute of Science)

Exclusive worldwide license granted to TxCell in June 2016

TxCell’s exclusive access to broad umbrella CAR-Treg patent enhances first mover advantage • Licence covers claims that include all redirected regulatory T cells (Tregs) comprising a Chimeric Antigen Receptor

(CAR) and actively equipped with specificity towards a selected antigen • CAR-Tregs have great potential for the treatment of autoimmune and inflammatory disorders in the likes of the ongoing groundbreaking results obtained with CAR-T cells in hematological cancers • Patent further strengthens TxCell’s position as a leading company in the Treg therapeutic field • Patent reinforces and enables TxCell’s ambitious business development strategy

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Ovasave®: CDAI assessment at weeks 5 and 8 CATS1 study Response rate (% patients)

Remission rate (% patients)

100%

100%

80%

75%

80%

75%

60%

40%

60% 40%

40% 33%

38%

40%

33%

25% 17%

20%

17%

0%

0%

20%

15% 10%

0%

0% 0% 0%

0%

Week 5

Week 8 All (n=20)

106 (n=8)

Week 5 107 (n=3)

Response: Delta CDAI ≥ 100

All (n=20)

0% 0% 0%

108 (n=3)

Week 8 109 (n=6)

Remission: ≤ 150 CDAI points

CDAI Week -2

CDAI Week 0

CDAI Week 5

Delta CDAI W0 vs W5

CDAI Week 8

Delta CDAI W0 vs W8

377 ± 81.8

363.7 ± 80.5

281.5 ± 116.1

-82.2 ± 95.4

292.0 ± 108.1

-63.0 ± 87.9

p=0.003 106 (n=8)

400.9 ± 101.2

395.1 ± 91.7

251.8 ± 157.9

-143.4 ± 105.0 p=0.039

p=0.006 244.6 ± 130.1

-131.6 ± 65.4 p=0.031

Source:, Gastroenterology 2012;1207-1217

39

Ovasave®: Consistent results across multiple measures CATS1 study

Reduction in Crohn’s disease activity

Moyenne ± ESM

CDAI* change from baseline – Dose 106 (n=8) 50 0 -50 -100 -150 -200

Weeks

0

2

4

6

8

10

12

10

12

Improvement in patient quality of life

Average ± ESM

IBDQ* change from baseline – Dose 106 (n=7) 80 40 0 -40 -80

Weeks

0

2

4

6

8

CRP* change from baseline – Dose 106 (n=8) 20

Decrease in inflammation

Average ± ESM

10

0 -10 Weeks

-20

0

2

4

6

8

10

12

OVA* proliferation change from baseline – Dose 106 (n=8)

Proliferative response of cells to antigen biomarker of response

Average ± ESM

0.0 0.0 0.0 Weeks

-0.1 Source: Company, Gastroenterology 2012;1207-1217

0

2

4

6

8

10

12

*Notes: CDAI: Crohn's disease activity index, indice d'activité de la maladie de Crohn; IBDQ: inflammatory bowel disease questionnaire, questionnaire pour les maladies intestinales inflammatoires; CRP: C reactive protein/protéine C réactive, OVA: ovalbumin (antigen)/ovalbumine (antigène)

40