Oct 2, 2017 - R.17-024, available on the Company's website (www.txcell.com), in particular in ... Even if the actual res
Teaching regulatory T cells to treat your disease
Corporate Presentation October 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
Teaching regulatory T cells to treat your disease
Introduction
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
Therapeutic strategy
Therapeutic field
Selected companies
Engineered cells Historical FDA approval in Aug. 2017 (Novartis)
T Effector Cells (Teffs)
T Regulatory Cells (Tregs)
Stimulate the immune system to attack the tumor
Control the immune system that has turned against the patient
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. 4
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)
5
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
6
Key dates in the history of Teffs and Tregs First clinical trial with non-modified Teffs (Rosenberg, 1998)
Teffs Discovery of Teffs antigen specificity in the 1970’s
1970
First clinical trial with genetically modified Teffs
1990
2000
Discovery of Tregs (Sakagushi, 1995)
Discovery of Type 1 Tregs by TxCell’s scientific founder (Groux, Nature 1997)
2010
First clinical data with non-modified Tregs (Trzonkowski,2009)
First FDA approval of a CAR-T product in cancer
2016
Preclinical POC with CAR-Tregs (Eshhar, 2014)
First clinical data with TxCell’s Treg drugcandidate Ovasave in Crohn’s disease (Desreumaux, 2012)
Increasing number of publications on Tregs since the end of the 1990s1
Preclinical POC with human CAR-Tregs (Levings, 2016)
1998 2000 2002 2004 2006 2008 2010 2012 2014
Tregs
First proof of efficacy of CAR-Ts in clinical trials
Tregs: a recent discovery rapidly gaining momentum in the scientific community 1. Source : « Treg cells » research on PubMed, Medline extraction. 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
Teaching regulatory T cells to treat your disease
Technology platform
CAR-Treg transformation successfully achieved Contrary to conventional approaches based on non-specific polyclonal Tregs, TxCell is exclusively developing antigen-specific Tregs. Decision to shift the initial focus on ‘naturally’ antigen-specific Treg to a new generation of Treg products in which the antigen specificity is introduced via a CAR
✓ Developing a CAR-Treg is technically doable and works in clinically relevant models
✓ CAR-Tregs have a broader therapeutic potential and their production will be more scalable
✓ CAR-Tregs are more appealing than non-modified cellular products for pharmas and investors 12
CAR-Treg platform Antigen specificity comes from a CAR (Chimeric Antigen Receptor)
Proposed mechanism of action
(Genetically-modified Tregs)
13
From blood sample to medicinal product
Production outsourced to 2 CMOs: Starting material
1
Injection of drug product to patient
6
2
Fill & store
• Lentiviral vector
5
Isolation of Treg cells
Lentigen Technology, Inc. appointed for HLA-A2 CAR manufacturing
• Cellular therapy product
4
Expansion of CAR-Treg cells
3
CAR transduction
Cell therapy CMO to be appointed by end 2017
Developing a viable manufacturing process is a key objective for TxCell CAR-Treg process expected to be completed by end 2017 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
Teaching regulatory T cells to treat your disease
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 •
CAR-Treg cells designed to recognize specifically the HLA-A2+ graft
2017: Deliver additional sets of preclinical
proof-of-concept data •
2017: Develop CAR-Treg manufacturing process and transfer manufacturing process to CMO
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
Teaching regulatory T cells to treat your disease
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
Teaching regulatory T cells to treat your disease
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
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 : 4.4%)
As of Dec. 31, 2016
Seventure Partners
Bpifrance
15,2%
42,6%
Seventure Partners 6,5%
Free float 47,1%
As of Sep. 12, 2017
Bpifrance 36,0%
Bpifrance 32,7%
To the best knowledge of TxCell as of September 12, 2017
Number of shares as of September 12, 2017: 20,563,568
Fully diluted capital
Liquidity
As of September 12, 2017
Number of shares
Basic shares outstanding (non diluted capital)
20 563 568
TxCell share: average volume before and after the capital increase of February 24, 2017 (as of September 12, 2017) 114k
120 000
Incentive plans (management and staff)
1 730 299
Convertible notes with attached warrants (Yorkville) *
1 730 114
Listed warrants (shareholders)
4 157 859
Fully diluted capital **
Auriga Partners 20,2%
100 000
80 000
76k
28 181 840
* Including outstanding warrants and theoretical number of shares to be issued by conversion of outstanding convertible Notes (i.e excluding unexercised warrants giving access to convertible Notes with share subscription warrants attached), based on 93% of the lowest daily VWAP over the ten days preceding September 12, 2017 (i.e. 1,54€). ** Based on the full exercise of issued and outstanding instruments giving access to the Company’s capital (i.e. excluding PACEO equity line and unexercised warrants giving access to Notes with share subscription warrants attached).
60 000
40 000
20 000
0 Before transaction (3 mo.)
Post transaction (September 12, 2017)
28
Capital increase completed in February 2017 • Capital increase successfully completed with support from existing shareholders and international investors • Offer subscribed at 100% • Issue of 5,549,300 new shares with warrants attached • Gross proceeds: €11.1 million
• Warrants attached to new shares • Warrants are listed on a separate line: FR0013231792 • 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 gross product (4,161,975 new shares) • Would finance TxCell up until IND approval to start first-in-man CAR-Treg study, in 2018 29
Where do we go from there? • 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 Depending on availability of resources, initiate transfer to a cell CMO of CAR-Treg manufacturing process Objective: launch first clinical trial within 12 months of tech transfer initiation 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 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
Teaching regulatory T cells to treat your disease
TxCell
Thank you
www.txcell.com
@TxCellSA
Teaching regulatory T cells to treat your disease
Back-up slides
Hot CAR-T environment • Historical FDA approval of Novartis’s CAR-T product
Aug. 30, 2017
• Kymriah® (tisagenlecleucel, CTL019) • Approved by the FDA for the 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
• Gilead to acquire Kite Pharma for $11.9Bn
Aug. 28, 2017
• ‘Axi-Cel’ (axicabtagene ciloleucel, KTE-C19) • Relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (NHL) • BLA under FDA review; PDUFA date Nov. 29, 2017
• Gilead purchase price: 180$ per share (29% premium) • Kite share price +300% since Jan 1st, 2017
34
Hot Treg environment
5 Treg deals signed in less than 12 months Date
Buyer
Target
Type of deal
Financial terms Upfront: 300M$
Jan 2017
Acquisition
Apr 2017
Exclusive ww license
May 2017
Exclusive license option
Jul 2017
Codevelopment
Aug 2017
R&D collaboration
Milestones: up to 475M$
Undisclosed
Technology
Indication
Phase
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
Nanoparticles
Immune tolerance
Preclinical
Upfront: 8M€ Milestones: up to 200M€ Upfront: 150M$ Milestones: up to 250M$
Undisclosed
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
38
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