Engineered T-Cell Therapies A New Paradigm In Oncology. Presentation Materials April 2015

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1 Engineered T-Cell Therapies A New Paradigm In Oncology Presentation Materials April 2015

2 DISCLAIMER This presentation contains forward-looking statements that are based on our management s beliefs and assumptions and on information currently available to management. Forward-looking statements include information concerning our possible or assumed future results of operations, business strategies, financing plans, competitive position, industry environment, potential growth opportunities, potential market opportunities and the effects of competition. Forward-looking statements include all statements that are not historical facts and can be identified by terms such as anticipates, believes, could, seeks, estimates, intends, may, plans, potential, predicts, projects, should, will, would or similar expressions and the negatives of those terms. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. Forward-looking statements represent our management s beliefs and assumptions only as of the date of this presentation. You should read the Company s Prospectus, including the Risk Factors set forth therein and the exhibits thereto, completely and with the understanding that our actual future results may be materially different from what we expect. Except as required by law, we assume no obligation to update these forward-looking statements publicly, or to update the reasons actual results could differ materially from those anticipated in the forward-looking statements, even if new information becomes available in the future. 2

3 IPO Nasdaq - Roadshow Proceeds: Cellectis issued 5,500,000 ADSs at a price of 41.50$, representing $228.3M; priced at a 5% discount to market close on March 24, 2015 Joint book runners: Bank of America Merrill Lynch and Jefferies, Piper Jaffray, Co-managers: Oppenheimer and The Trout Group, Deal Counsel: Jones Day (Cellectis) and Latham Watkins (Bank of America Merrill Lynch), From start to listing: 6 full months to complete the transaction, 4 day road show with close to 100 institutional investors: - 37 one-on-one investor meetings & conference calls - 17 investors in small group meetings - 36 attendees of large group luncheons From the initial offering of $115M, the deal was over-subscribed over 12X with over $1.7B of demand, Nasdaq ticker: since March the 25th 2015 [CLLS] x 45 Indica'on in shares (mm) Over 150 orders from institutional investors in the book, Ins$tu$onal Demand Build- Up (1) Incremental demand Aggregated demand from previous days x Base Deal Size 0.4x 1.6x 0 3/18 3/19 Source: BofA ML Equity Capital Markets. Note: 1-on-1 meetings include 2-on-1, 3-on-1, and conference calls. Oversubscription calculated as multiple of base deal size. (1) Overall demand based on shares indicated (2) Based on offer price of $ x 3/20 3/23 3/24 3

4 Management Team André Choulika, PhD, Founder, Chairman and CEO André is a pioneer in nuclease-based gene-editing to modify complex genomes with over 28 years of experience André developed the first approaches to nuclease-based human gene therapy, while working in the Division of Molecular Medicine at Boston Children s Hospital. Mathieu Simon, MD, Executive Vice President, COO Previous to Cellectis, Mathieu served as Group VP of Marketing and Clinical Affairs for Wyeth International in the United States, and later led several of the Wyeth Group s biggest regional subsidiaries in the Benelux countries, Italy, Greece, and the Balkans. David Sourdive, PhD, Co-Founder, Executive Vice President Corporate Development After completing his PhD, David joined one of the leading laboratories in viral immunology, at Emory University in Atlanta, Georgia Prior to co-founding Cellectis, he directed the biotechnologies laboratory of the Centre d Etudes du Bouchet for the French Ministry of Defense. Thierry Moulin, Chief Financial Officer Thierry has previous CFO experience as he was CFO of Vergnet SA, Ermewa and Toshiba TEC. Thierry has specialized in the administrative and financial management of industrial groups in France, such as AIRSEC Industries and Süd-Chemie, as well as international experience, including Japan from 1986 to Philippe Duchateau, PhD, Chief Scientific Officer Philippe joined Cellectis in 2001 to pioneer the field of genome engineering. Philippe is co-inventor of numerous patents in the field of nucleases and genome engineering and co-authors on more than 50 scientific publications. Luc Mathis, PhD, CEO Cellectis Plant Sciences Luc has been Chief Executive Officer of Cellectis Plant Sciences since 2012 and previously served as Business Development Director of Cellectis from 2006 to From 2001 to 2005, he was a research scientist at Centre National de la Recherche Scientifique. 4

5 Pioneering Gene-Editing Company Corporate Background Leading Technologies And Strong IP Product Candidates And Partnerships Plant Science Subsidiary 35 M shares outstanding (as of March 31, 2015) 75 employees (as of February, 2015) Pioneering gene-editing company; >15 years in the field Discovery and development of engineered CAR T-cell therapy for oncology Founded in 1999, public since 2007, traded on NYSE Alternext Paris: ALCLS and on NASDAQ: CLLS Engineered CAR T-cells designing next generation immunotherapy products Nuclease based genome engineering TALEN, meganucleases Proprietary electroporation technologies PulseAgile 87 owned patent families 3 fully owned programs: UCART123, UCART38, UCARTCS1 Alliance with Servier on UCART targets in solid tumors Lead Product Candidate UCART19: Allogeneic CAR T-cell for CLL & ALL CTA filling planned for 2015 Initial payment of $8.07M ( 7.55M); Up to $870,2M ( 813.3M) in potential additional payments, spread over various milestones in the development and commercialization phases; royalties on sales Alliance with Pfizer on numerous targets in oncology 15 Pfizer-owned targets and 12 Cellectis-owned targets in solid and liquid tumors Upfront payment of $80M and Pfizer s 25.8M ($27.6M) equity investment (10% stake); Up to $185M per product through Pfizer targets potentially developed ($2.8B), spread over development and commercialization phases Cellectis plant sciences, located in New Brighton, MN, 16 employees (as of February, 2015) Fully owned programs in soybean, potato, canola and wheat 5

6 Cellectis Core Strengths and Strategy Competitive Strengths Ø Ø Ø Ø Gene-editing (proprietary with high precision and efficacy) Novel approach to CAR-T: off-the-shelf, allogeneic and engineered CAR T-cell based therapies Strategic alliances with Pfizer and Servier in oncology Extensive patent portfolio in gene-editing and CAR-T Our Strategy Ø Ø Ø Ø Ø Advance our allogeneic UCART19 immunotherapy product candidate into clinical trials Advance our additional UCART product candidates into clinical trials Leverage alliances to advance our research and to bring products to market Expand our product pipeline to other therapeutic indications with unmet medical needs Develop plant products through the use of our gene-editing platform 6

7 Broad CAR T-Cell Pipeline Our lead immuno-oncology product candidates Product Name Targeted Indication Discovery UCART19 CAR-T In Vitro Engineering Engineering In Animals CTA / IND Filing Alliance Acute Lymphoblastic Leukemia (ALL) Chronic Lymphocytic Leukemia (CLL) ü ü ü ü 2015 Servier UCART123 Acute Myeloid Leukemia (AML) ü ü ü ü Wholly-Owned UCART38 Multiple Myeloma (MM) ü ü Q Wholly-Owned UCARTCS1 Multiple Myeloma (MM) ü Q Wholly-Owned Alliance with Servier: Alliance with Pfizer: Cellectis proprietary candidates: up to 5 additional targets up to 15 targets in the next 4 years up to 9 additional targets in the next 4 years 7

8 CAR T-Cells - A New Paradigm in the Treatment of Cancer

9 Cellectis Next Generation Allogeneic CAR T-Cells Next step in CAR T-Cell technology enabled through gene editing Ø Ø Allogeneic cells: designed to suppress capacity for alloreactivity Proprietary gene editing technology: TALEN, Meganucleases 9

10 Cellectis platform Allogeneic CAR T 10

11 Core Technology Gene Editing

12 Sharpening the Power of T-Cell By Editing the Genome 12

13 Our product candidates are engineered cell therapies Cellectis long standing expertise: The innovation: gene editing NUCLEASES or DNA scissors! TALEN Meganucleases 15 years of gene editing experience 13

14 TALENTM NHEJ 3 criteria for genome editing technologies: I. Precision: How close a nucleotide could a sequence be targeted in the genome? II. Efficacy: What will be the percentage of viable cells following gene editing? III. Safety: How little does it cut elsewhere (off-target effect)? 14

15 GMP-Compatible Manufacturing Process

16 Cellectis Proprietary Manufacturing Process 16

17 Lead Product Candidate UCART19

18 Lead Product Candidate: UCART19 intended for ALL and CLL Cell Development Process: 1. Start from healthy, unmodified donor T-Cells 2. Insertion of single-chain CAR construct and suicide gene 3. Gene-knockout of TCR Alpha to avoid GvHD and CD52 to resist Alemtuzumab 18

19 Lead Product Candidate: UCART19 intended for ALL and CLL ü Distinct Product Features*: ü Proven efficient CAR-induced destruction of CD19+ target cells In Vitro ü Comparable/higher cytolytic capability than benchmark CAR on target cells ü TCRα & CD52 Double KO does not impact in vitro activity of the CAR ü TCR-Deficient T-Cells do not induce GvHD in vivo ü Clear Development Plan: Ø Preclinical development ongoing Ø Clinical development plan in place Ø Manufacturing process defined Ø Full GMP compatibility expected in 2015 Ø CTA Filling expected in 2015 * see Appendix for details 19

20 UCART19 Activities In Vivo in Mice In Presence of Lymphodepleting mab Day -1 Day 0 Day +1 Raji Raji UCART19 alemtuzumab Raji alemtuzumab Raji UCART19 18 h 3 days 13 days 6/6 tumor progression 5/7 CR 2/7 PR 6/6 tumor progression 6/6 CR (research data) In collaboration with Dr. Martin Pule, University College London 20

21 Going further with Gene-Editing

22 New Possibilities with Cellectis Gene-Edited CAR T-Cells Enhancing the potential of T-cells through gene editing: Design Intended Results 1 Allogeneic, non alloreactive Off-the-shelf product 2 Resistance to chemotherapy Compatible with SoC Use in combination therapies 3 Resistance to lymphodepleting agents Enhanced engraftment 4 Resistance to tumor inhibition Enhanced efficacy 5 Suppression of cross T-cell reaction Better suited for specific tumors Three Examples*: 1. Engineering Glucocorticoid Resistant T-Cells 2. Engineering Fludarabine Resistant T-Cells 3. PD-1 Gene Knockout Ø The future of T-cell therapies is in genome engineering * see Appendix for details 22

23 Validating Strategic Alliances in Oncology

24 Alliance with Pfizer In June 2014, Cellectis entered into an alliance with Pfizer ü Scope: development of CAR-T cell therapies in oncology 15 Pfizer targets 12 Cellectis targets ü Exclusivity: For 4 years, Cellectis will not enter into another preclinical CAR T alliance in oncology No exclusivity on each product once IND filed ü Responsibilities: Both companies work together on preclinical research for 15 Pfizer targets and 4 Cellectis targets (the other 8 Cellectis targets are developed outside the alliance) Each company is responsible and has all worldwide rights for clinical development and commercialization of any product directed at its own targets Pfizer has right of first refusal on the products directed at the 4 Cellectis targets developed in the alliance. ü Financials: Upfront payment of $80M and Pfizer s 25.8M ($27.6M) equity investment Up to $185M for each product targeting a Pfizer target potentially developed, spread over various milestones in the development and commercialization phases ($2.8B in aggregate) In addition, Cellectis will receive royalties on the sales of products. 24

25 Alliance with Servier In February 2014, Cellectis entered into an alliance with Servier ü Scope: development of UCART19 in B-cell malignancies 5 other candidates in solid tumors ü Responsibilities: Cellectis will be responsible for the R&D of certain candidates through the end of clinical phase I. Servier may exercise its exclusive worldwide option for each candidate developed under the agreement. Upon exercising each option, Servier will be responsible for taking over clinical development, registration and commercialization of each product. ü Financials: Initial payment of $8.07M ( 7.55M) Up to $870,2M ( 813.3M) in potential additional payments for the six candidates potentially developed, spread over various milestones in the development and commercialization phases. In addition, Cellectis will receive royalties on the sales of products. 25

26 Conclusion

27 The take home message Our differentiated approach I. Nuclease-based genome engineering TALEN, Meganuclease II. Multi-chain Chimeric Antigen Receptor* the next CAR III. Manufacturing of off-the-shelf frozen pharmaceutical products A broad development of pipeline addressing up to 33 targets in oncology 12 targets for Cellectis 6 targets for Servier 15 targets for Pfizer CTA filing for UCART19 expected in 2015 * see Appendix for details 27

28 Appendix

29 Multi Chain CAR T-Cell Characteristics: Ø Same antitumor activity as single-chain CAR with lower surface expression mc CAR-CD19 31% 76% sc CAR-CD19 Based on the high affinity IgE receptor percentage of cell lysis 60% 50% 40% 30% 20% 10% 0% w/o w/o CAR mc mc CAR-CD19 4 g first sc sc CAR CAR-CD19 II mccar architecture is designed to provide added flexibility for: ü additional activation/co-stimulatory domains ü multiple ligands targeting ü engineering with mab and bispecific Ab 29

30 Cellectis proprietary technology for TALEN electroporation Electroporation system Proprietary large volume electroporation chamber Proprietary cgmp Electroporation buffer Proprietary PulseAgile electroporation waveform A series of high voltage, short duration pulses followed by lower voltage, longer duration pulses V ü High transfection efficacy ü High cell viability time 30

31 Example 1: Engineering Glucocorticoid Resistant T-Cells Human T-cells 2 Gy irradiated NSG mice 5 days 10 days 2 weeks Mice sacrificed GR TALEN TM electroporation T-cell injection Analysis of GR gene cleavage effciency CTL GR TALEN TM ND D ND D 76% indels Engraftment analysis daily dexamethasone treatment GR GAPDH Purification of human T- cells from spleen Analysis of GR expression by Western blot: TALEN Dex Only GR-negative cells survive in vivo to dexamethasone treatment Ø In vivo, GR TALEN TM -treated T-cells resist to glucocorticoid treatment 31

32 Example 2: Engineering Fludarabine Resistant T-Cells Ø Resistance to standard of care Ø Inactivation of deoxycytidine kinase enables CD19 CAR T-cell to resist to Fludarabine or Clofarabine wt alleles mutated alleles wt TALEN TM dck 2 Normalized cell viability (%) 120 Cmax CAR T cell CAR T cell KO D/T [Fludarabine] µm 120 Cmax Clofarabine (1 µm) days post EP days 18 days Normalized cell viability (%) CAR T cell CAR T cell KO D/T [Clofarabine] µm 32

33 Example 3: PD-1 Gene Knockout Ø T-Cell insensitive to PDL-1 checkpoint inhibition signals 33

34 Cellectis CAR T-cells induce CD19+ cell destruction in vitro NT CAR T-cells transduced with vector encoding Cellectis CD19 CAR CD19 SupT1 cells CD19 SupT1 cells CD3 CD3 Efficient CAR-induced destruction of CD19+ target cells (research data) CD19 SupT1- CD19 cells CD19 SupT1- CD19 cells CD3 CD3 34

35 Cellectis CAR T-Cells: In Vitro Cytolytic Capability % cell lysis SUPT1 CD19 negative cells NT supe Benchmark CAR MP13622 supe Ctx CAR final version MP :1 15:1 8:1 3:1 Effector:Target Target cell lysis by Cr 51 release Benchmarked against FMC63-41bb-zeta CAR (used by UPENN) UCART19 CAR exhibits comparable/ higher cytolytic capability than benchmark CAR on target cells % cell lysis SUPT1-CD19 CD19 expressing cells NT supe Benchmark CAR MP13622 supe Ctx CAR final version MP13624 % cell lysis RAJI (CD19 positive Burkitt s lymphoma cells) NT supe Benchmark CAR MP13622 supe Ctx CAR final version MP :1 15:1 8:1 3:1 Effector:Target :1 15:1 8:1 3:1 Effector:Target 35

36 TCRα & CD52 Double KO Does Not Impact In Vitro Activity of the CAR Stim.: αcd19-car: - K562 (CD19-) Daudi (CD19+) Daudi (CD19+) PMA/Iono TCRα+ CD52+ TCRα KO CD52 KO CD107A NT CAR TCRα+ CD52+ NT CAR TCRα KO CD52 KO FSC In vitro antitumor reactivity is comparable in wt or CD52/TCR KO cells (research data) 36

37 No Functional T-Cell Receptor for GvHD no stimulation + TCR stimulation wt cells TCR- cells TCR-deficient cells not activated via TCR Activation marker: CD25 wt cells TCR- cells Activation marker: CD69 (research data) 37

38 TCR-Deficient T-Cells Do Not Induce GvHD In Vivo NOG mice irradiated (2.5 Gy) 1 day before T-cell injection (i.v., 30x10 6 cells) Ø Ø 5 G2, fresh non modified T-cells Time post tumour induction (days) Time post injection (days) G1 NaCl 0.9% IV Q1DX1 G2 T cells purified from frozen PBMCs (activated and plated during 3 days) IV Q1DX1 G3 T cells purified from frozen PBMCs (activated and plated during 15 days) IV Q1DX1 GvHD development, G4 associated T cells EP TpT (plated with during body 15 days) weight IV Q1DX1 loss, in all mice injected with non modified T-cells G5 T cells TCR?-/- (plated during 15 days) IV Q1DX1 Mean body weight G3, non modified T-cells, cultured 15 days With TCR-deficient T-cells: no clinical symptoms of GvHD observed G4, mock transfected T-cells G5, TCRα -/- T-cells G1, No T-cells 60 (research data) 38

39 Anti-Tumor Potency UCART19 / Benchmark CAR Tumor model: 1x10 6 Daudi-Luc cells injected in NOG mice mice treated with 4x10 6 CAR T cells Day 0 Day 1 Day 2 Day 3 Day Gy 1.44 Gy Daudi Daudi Non modified Benchm. CAR 1.44 Gy Daudi CAR 1.44 Gy Daudi UCART Gy Daudi UCART Gy Daudi Benchm. CAR Day 4 Before T-cells treatment Day 7 Day 21 (research data) 5/5 Tumor progression 5/5 3/3 5/5 5/5 5/5 Tumor cells elimination 39