Welcome! 10 th anniversary event. Wednesday, January 31 st 2018 Mont-Saint-Guibert

Transcription

1 Welcome! 10 th anniversary event Wednesday, January 31 st 2018 Mont-Saint-Guibert

2 Welcome Serge Goblet Board Member

3 Introduction Michel Lussier MS BME, MBA Chairman of the Board

4 Agenda & Speakers 5:30 7:00pm Presentations Welcome, by Serge Goblet, Member of the Board of Directors, Celyad Introduction and agenda, by Michel Lussier MS BME, MBA, Chairman of the Board of Directors, Celyad Cancer and Celyad s technology, by Sophie Agaugue, PhD, R&D Manager, Celyad 2017 Progress and Learnings, by Christian Homsy, MD, MBA, CEO, Celyad AML and Celyad s potential, by Xavier Poire, MD, Service Hématologique Adulte, Institut Roi Albert II, Clinique universitaire de St-Luc CYAD-01 rationale in colorectal cancer, by Alain Hendlisz, MD, PhD, Head of the Gastro-Enterology Unit, Medical Oncology Clinic, Jules Bordet Institute Celyad s Clinical Development Plan, by Frédéric Lehmann, MD, PhD, VP of Clinical Development &Medical Affairs, Celyad Celyad s R&D strategy, by Peggy Sotiropoulou, PhD,R&D Manager, Celyad Celyad s SNOWY project, by Valérie Steenwinckel, PhD, Industrialization Director, Celyad 2017 Progress and learnings, by Christian Homsy, MD, MBA, CEO, Celyad Willy Borsus, Minister-President of Wallonia Closing, by Christian Homsy, MD, MBA, CEO, Celyad Q&A 7:00 9:00pm Cocktail & Networking 4

5 Forward looking statements Forward-looking statements In addition to historical facts or statements of current condition, this presentation contains forward-looking statements, including statements about the potential safety and feasibility of CYAD-01 cell therapy, including current and planned preclinical and clinical trials for Celyad s product candidates; the clinical and commercial potential of these product candidates and the adequacy of Celyad s financial resources; Celyad s intellectual property portfolio, including plans related thereto; Celyad s expectations regarding its strategic collaborations and license agreements with third parties, including Novartis, Celdara Medical, and Dartmouth College, and the potential impact of such collaborations on Celyad s future financial condition; and Celyad s expected cash burn, which reflect Celyad s current expectations and projections about future events, and involve certain known and unknown risks, uncertainties and assumptions that could cause actual results or events to differ materially from those expressed or implied by the forward-looking statements. These forward-looking statements are further qualified by important factors and risks, which could cause actual results to differ materially from those in the forward-looking statements, including risks associated with conducting clinical trials; the risk that safety, bioactivity, feasibility and/or efficacy demonstrated in earlier clinical trials or preclinical studies may not be replicated in subsequent trials or studies; risks associated with the timely submission and approval of anticipated regulatory filings; the successful initiation and completion of clinical trials, including its clinical trials for CYAD-01; risks associated with the satisfaction of regulatory and other requirements; risks associated with the actions of regulatory bodies and other governmental authorities; risks associated with obtaining, maintaining and protecting intellectual property, Celyad s ability to enforce its patents against infringers and defend its patent portfolio against challenges from third parties; risks associated with competition from others developing products for similar uses; risks associated with Celyad s ability to manage operating expenses; and risks associated with Celyad s ability to obtain additional funding to support its business activities and establish and maintain strategic business alliances and business initiatives. A further list and description of these risks, uncertainties and other risks can be found in Celyad s U.S. Securities and Exchange Commission (SEC) filings and reports, including in its Annual Report on Form 20-F filed with the SEC on April 4, 2017 and subsequent filings and reports by Celyad. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements. These forward-looking statements speak only as of the date of publication of this document. Celyad expressly disclaims any obligation to update any such forward-looking statements in this document to reflect any change in its expectations with regard thereto or any change in events, conditions or circumstances on which any such statement is based, unless required by law or regulation. We kindly remind you that this presentation will be video recorded. The video will be posted on Celyad s website shortly after the event. 5

6 Cancer and Celyad s technology Sophie Agaugue, PhD R&D Manager 6

7 What is cancer? Normal cells grow, divide and die in an orderly fashion Cancer cells do not die, they just grow and divide in an uncontrolled way Genetic, environmental factors 2 types of cancer: solid and liquid 02/02/2018 7

8 A tumor is a micro-environment by itself Metastases Primary tumor 02/02/2018 8

9 How does the immune system fight against cancer? 02/02/2018 9

10 But this is not enough: tumor microenvironment impedes activation of the immune system Immune Suppression Immune Activation 02/02/

11 How to make our own immune cells fight cancer? The explosion of immunotherapy Antibody approach: Breaks the tumor inhibitory effect on immune system Cellular approach: Accelerates the immune effect against the tumor Tumor antigen 02/02/

12 T-cells need to be armed to fight Cancer CAR-T cells = tumor specific gene modified T-cells Issues: low frequency of tumor specific T-cells in patients No good tumor specific antigen to select T-cells 02/02/

13 How to «arm» a T-cell: standard CAR-T construct Chimeric Antigen Receptor (CAR) T-cell scfv (single chain variable fragment) Chimeric Antigen receptor Signalling domain 02/02/

14 CD19 CAR-T: an extraordinary technology that has now come to the market 02/02/

15 CYAD-01: a unique construct only developed at Celyad in clinical development CYAD-01 a unique CAR-T combining properties of NK and T cells + 02/02/

16 A Single NK Cell Receptor Binding 8 Different Ligands expressed in the majority of tumors Celyad s unpublished data Cancer type Expression of at least one NKG2D ligand Bladder carcinoma 96% (mets 100%) TNBC 100% Colorectal cancer 100% Ovarian carcinoma 84% Pancreatic cancer 90% Lung cancer (NSCLC) 100% Dulphy et al unpublished data AML 100% 02/02/

17 CYAD-01 cells destroy diverse types of tumors and prolong survival of mice PANCREATIC CANCER OVARIAN CARCINOMA Barber et al. 2009, J Immunol LYMPHOMA Zhang et al. 2007, Cancer Res 02/02/ Demoulin et al. Future Oncology 2017

18 Beyond direct killing, inducing multifaceted attack on the tumor Lonez et al., BMJ Open, /02/

19 2017 Progress and learnings Christian Homsy, MD, MBA CEO 19

20 THINK Study (THerapeutic Immunotherapy w/ NKG2D-based therapy) o 3 dose levels (3x10 8,1x10 9 and 3x10 9 ) THINK Trial Washout period 1st CYAD-01 (D1) 2nd CYAD-01 (D2) 3rd CYAD-01 (D3) Tumor assessment First patients in January 2017 First experience in oncology 3 administrations Primary Endpoint: Safety &Tolerability Secondary Endpoint: Efficacy as Monotherapy (w/o preconditioning) Hematological & solid tumors D-35 D-21 D1 D15 D29 D43 D57 Apheresis End safety 13 weeks w/o any other non-investigational cancer therapy Seven advanced refractory tumor indications Global development: EU and USA 20

21 THINK study: Status Report THINK Trial Total: 15 patients (10 at pre-defined dose) Safety - All adverse events are unrelated to CYAD-01 - No critical toxicity events related to date > THINK confirms the safety profile of CYAD-01 21

22 THINK study: Status Report THINK Trial Total: 15 patients (10 at pre-defined dose) Feasibility - Further improvement of manufacturing process achieved - First dose of dose-level 3 produced & administered > Celyad s manufacturing process optimized 22

23 THINK study: Status Report THINK Trial Total: 15 patients (10 at pre-defined dose) Clinical activity - Hematological arm: CYAD-01 active in 3/3 AML patients (w/o pre-conditioning): - 1 MLFS World Premiere - All blast reduction during treatment - All hematological improvements - Solid arm: CYAD-01 resulted in 2 out of 4 Stable Diseases for CRC patients and 1 ovarian cancer - 6 patients out of 10 treated at the per-protocol dose reached Stable Disease (SD) till Complete Response (CR) > THINK validates the activity of NKG2D 23

24 Going forward THINK Trial in 2018 Complete dose escalation Plan expansion phase with second cycle of treatment potentially improving response durability Hematological Solid 3 new studies 3 new studies 24

25 Acute Myeloid Leukemia (AML) Xavier Poiré, MD Unité de greffe médullaire Service d Hématologie Adulte Institut Roi Albert II Cliniques Universitaires St-Luc (Bruxelles) 25

26 Acute Myeloid Leukemia Where are we and where are we going to? Xavier Poiré, MD Unité de greffe médullaire Service d Hématologie Adulte Institut Roi Albert II Cliniques Universitaires St-Luc Bruxelles 31/01/2018

27 Normal hematopoiesis X. Poiré, 31/01/

28 Cellular division and leukemogenesis X. Poiré, 31/01/

29 X. Poiré, 31/01/ How does chemo/radiotherapy work? CHEMO/RT

30 X. Poiré, 31/01/ Induction and consolidation therapies INDUCTION CONSOLIDATION Normal hematopoiesis 60-70% SURVIVAL GOOD LEUKEMIA Leukemic cells 10-20% SURVIVAL 4-6 weeks BAD LEUKEMIA

31 X. Poiré, 31/01/ Allogeneic stem cell transplantation NORMAL STEM CELLS BAD LEUKEMIA IMMUNE CELLS

32 Allogeneic stem cell transplantation 4-6 weeks Conditionnement Greffe Prévention GvHD Relapse? Globules blancs Immunosuppression 50% SURVIVAL Chimio Radiothérapie Fièvre Mucite Diarrhée Transfusion Aplasie X. Poiré, 31/01/ DLI

33 X. Poiré, 31/01/ Immunotherapy CAR-T cells IMMUNE CELLS

34 CAR-T cells does it work? X. Poiré, 31/01/

35 AML and MDS What are the challenges? X. Poiré, 31/01/

36 NKG2D CAR-T cells X. Poiré, 31/01/

37 X. Poiré, 31/01/ NKG2D CAR-T cells Does it work in AML/MDS? +8/del(7)(q22q36), FLT3/NPM1 wild-type DNMT3A mutation Normal cytogenetics 46,XY,i(7)(p10)[2]/46,XY[18] DNMT3A/IDH2 mutations 46,XY,i(7)(p10)[3]/46,XY[17] Negative NGS pannel

38 Advanced ColoRectal Cancer: the path towards Immunotherapies Alain HENDLISZ MD, PhD Head of the Gastro-Enterology Unit, Medical Oncology Clinic Jules Bordet Institute

39 + Advanced ColoRectal Cancer: the path towards Immunotherapies Alain Hendlisz Institut Jules Bordet, Université Libre de Bruxelles Novembre 2017

40 Colorectal Cancer: Belgian Overview CRC incidence in men and women Total: women men Incidence CRC is 3 rd most common cancer in men & 2 nd most common cancer in women * Belgian Cancer Registry, Cancer Incidence in Belgium 2011, available at Belgian Registry 2012

41 Colorectal Cancer: stages & survival CRC Stage at Diagnosis 5% CRC STAGE TREATMENT 5-YEAR SURVIVAL RATE (%) 20% 39% Stage I Surgery 74 Stage II Surgery Chemotherapy % Stage III Surgery Chemotherapy Localized Regional Distant Unknown Stage IV Cryo- or radiofrequency ablation Chemotherapy Targeted therapy 6 Schmoll Ann Oncol 2012 ASCO

42 + ESMO Guidelines L1 L2 L3 L3 Van Cutsem et al. Ann Oncol. 2014

43 mcrc: Treatments over Time Saltz 1 Douillard 2 Saltz 1 Douillard 2 Goldberg 3 Hurwitz 4 Falcone 6 Saltz 5 Bokemeyer 7 Van Cutsem 8 Douillard 9 Passardi 10 Bokemeyer 12 Stintzing 14 5-FU/LV bolus FU/LV infusion 14.1 IFL 14.8 FOLFIRI 17.4 FOLFOX 19.5 IFL + bevacizumab AVF2107g 20.3 FOLFOXIRI Italian GONO Trial 22.6 XELOX/FOLFOX + bevacizumab NO FOLFOX + cetuximab OPUS (KRAS) 22.8 FOLFIRI + cetuximab CRYSTAL (KRAS) 23.5 FOLFOX + panitumumab PRIME (KRAS) 23.9 FOLFOX or FOLFIRI ITACA 20.6 FOLFOX or FOLFIRI + bevacizumab ITACA 20.6 Ciardiello 11 FOLFIRI + cetuximab CRYSTAL (RAS) 28.2 FOLFOX + cetuximab OPUS (RAS) 19.8 Schwartzberg 13 mfolfox6 + bevacizumab PEAK (RAS) 28.9 mfolfox6 + panitumumab PEAK (RAS) 41.3 FOLFIRI + bevacizumab FIRE-3 (RAS) 25.0 FOLFIRI + cetuximab FIRE-3 (RAS) 33.1 Lenz 15 FOLFOX or FOLFIRI + bevacizumab CALGB (RAS) 31.2 FOLFOX or FOLFIRI + cetuximab CALGB (RAS) SURVIE GLOBALE (MOIS) 1. Saltz. NEJM Douillard. Lancet Goldberg. J Clin Oncol Hurwitz. NEJM Saltz. J Clin Oncol Falcone J Clin Oncol Bokemeyer. Ann Oncol Van Cutsem. J Clin Oncol Douillard. J Clin Oncol Passardi. J Clin Oncol 31, Ciardiello. J Clin Oncol Bokemeyer. J Clin Oncol Schwartzberg. J Clin Oncol Stintzing. Ann Oncol Lenz. Ann Oncol. 2014

44 Cremolini et al, Lancet Oncol 2015 Metastatic ColoRectal Cancer different valid strategies Median Survival 29,8 months (95% CI ) Median Survival 25,8 months ( )

45 + Metastatic ColoRectal Cancer different strategies-same results CAIRO 1 trial Median survival 17.4 mo (95% CI ) Median survival 16.3 mo (95% CI ) HR 0.92 (95% CI ) p= Koopman, Lancet 2007

46 Therapeutic Strategies mcrc Resectable 15% Maybe Resectable 20% Non Resectable 65% Aggressive Treatment Response Conservative Treatment Control Cure 5% Palliative Treatment %

47 Metastatic ColoRectal Cancer: Defining Principles of Chemotherapy Principle nr 1 Strategy influences Treatment: Why comes before How Principle nr 2 Use all drugs available Principle nr 3 Efficacy and Toxicity with number of drugs combined Primum non nocere

48 Koopman, Lancet Metastatic ColoRectal Cancer Long-Term Results Disappointing CAIRO 1 trial Median survival 16.3 mo (95% CI ) Median survival 17.4 mo (95% CI ) HR 0.92 (95% CI ) p=0.3281

49 General Approaches for Cancer Immunotherapy IL-2 IFN IL-15 IL-21 Active immunotherapy Adoptive cell transfer immunotherapy Peptide vaccine DC vaccine Genetic vaccine CD40 OX40 CD137 CTLA-4 PD-1 T cell cloning TCR or CAR genetic engineering

50 Pembrozilumab in metastatic CRC Le DT NEJM 2015

51 Checkmate 142: Nivolumab & Ipilimumab MSI-H mcrc MSI = 5-10 % of the mcrc patients Overman et al J Clin Oncol 2018

52 Toxicity Grade Toxicity Immune Checkpoint Inhibitors Rash, pruritus Liver toxicity Diarrhea, colitis Hypophysitis Wks 14 Weber et al. J Clin Oncol 2012 & 2015

53 + CONCLUSIONS mcrc remains major Health Issue in Industrialized World Huge Progresses in Therapeuties allow Treatment Personnalization Hope in Immunotherapies but currently only for MSI-H patients Promising new immunotherapies are currently being explored

54 What is next?

55 CYAD-01 Clinical Development Frédéric Lehmann, MD, PhD VP of Clinical Development & Medical Affairs

56 CYAD-01: Clinical Development Plan Overview CYAD-01 (aka NKR-2 CAR-T) Multiple cancer indications Hematological indications Solid cancer indications THINK Study Stand alone THINK Study 1 st objective clinical response in the Phase I dose escalation (1 st dose-level) r/r AML patient has reached a MLFS with CYAD-01 without pre-conditioning lymphodepletion Reinforces confidence and the validity of NKG2D ligands as a target 56

57 CYAD-01: Clinical Development Plan Overview CYAD-01 (aka NKR-2 CAR-T) Multiple cancer indications Hematological indications Overall Safety Overview Solid cancer indications 57

58 CYAD-01: Clinical Development Plan Overview CYAD-01 (aka NKR-2 CAR-T) Multiple cancer indications Hematological indications THINK Study Safety: No DLT at dose-level 1 2 nd dose-level ( /dose) ongoing Clinical status 58 Data as of December 31, 2017

59 CYAD-01: Clinical Development Plan Overview CYAD-01 (aka NKR-2 CAR-T) Multiple cancer indications Two out of four metastatic colorectal cancer patients treated at per-protocol dose reported as stable disease up to 3-months follow-up*+ * Median progression free survival in these patients under standard of care is between 1.9 and 3.2 months (e.g. regorafinib or trifluridine/tipiracil). + Fifth CRC patient treated at a dose lower then per-protocol dose did not show signs of clinical activity Solid cancer indications THINK Study Safety: No DLT at dose-level 1&2 3 rd dose-level ( /dose) activated Clinical status 59

60 CYAD-01: Clinical Development Plan Overview CYAD-01 (aka NKR-2 CAR-T) Multiple cancer indications Hematological indications Solid cancer indications THINK Study Stand alone THINK Study Protocol Amendment Increase the durability of the early signs of clinical activity by increasing the number of CYAD-01 injections (>3) 60

61 CYAD-01: Clinical Development Plan Overview CYAD-01 (aka NKR-2 CAR-T) Multiple cancer indications Hematological indications Solid cancer indications THINK Study Stand alone THINK Study AML-SHRINK Study Concurrent with SoC SHRINK Study DEPLETHINK Study SIBLINK Study Preconditioning (CY-Flu) Loco-regional DEPLETHINK Study LINK Study

62 CYAD-01: Clinical Development Plan Overview CYAD-01 (aka NKR-2 CAR-T) AML-SHRINK Study Concurrent with SoC SHRINK Study Open-label dose escalation Phase I study Multiple IV administrations of CYAD-01, concurrently with standard therapy for a specific disease 1. Immediate tumor debulking by the standard of care 2. Synergism effect by combination standard treatment and CYAD-01 Increase the NKG2D ligand expression on tumor tissues Better proliferation & expansion of CYAD-01 due to the lymphopenia status Better CYAD-01 infiltration into the tumor environment Induce an antigen spreading boosting the adaptive memory immune response 62

63 CYAD-01: Clinical Development Plan Overview CYAD-01 (aka NKR-2 CAR-T) DEPLETHINK Study SIBLINK Study Preconditioning (CY-Flu) DEPLETHINK Study Open-label dose escalation Phase I study CYAD-01 + Preconditioning lymphodepletion chemotherapy Phase I refractory cancer pts 1. Evaluate the standard lymphodepletion preconditioning (CAR-T paradigm ) 2. Increase the CYAD-01 expansion and persistence 3. Improve anti-tumor activity/synergism effect 63

64 CYAD-01: Clinical Development Plan Overview CYAD-01 (aka NKR-2 CAR-T) Loco-regional LINK Study Open-label dose escalation Phase I study Multiple hepatic transarterial administrations Unresectable liver metastases from colorectal cancer pts 1. Lower systemic toxicity 2. Higher and persistent concentration of the CYAD-01 infused cells into the tumor 64

65 CYAD-01: Integrated Clinical Development with data end 2018 CYAD-01 (aka NKR-2 CAR-T) Multiple cancer indications 65

66 What lies ahead Peggy Sotiropoulou, PhD R&D Manager

67 1 st Challenge: Fratricide in vitro and in vivo Self-fratricide (suicide) Fratricide (canibalism) NKG2D NKG2D CYAD-01 NKG2DL CYAD-01 NKG2DL 02/02/

68 CYAD-02: Elimination of ligands CD314 NKG2D Self-fratricide (suicide) Fratricide (canibalism) NKG2D No in vitro fratricide CYAD-01 NKG2DL CYAD-01 NKG2DL Production of required amount of cells made possible NKG2D NKG2D NKG2D CYAD-01 NKG2DL CYAD-01 NKG2DLs CYAD-01 68

69 2 nd Challenge: Time-consuming process in the autologous setting Autologous Allogeneic Infusion CAR-T cell production CAR-T cell production CAR T CAR T CAR T CAR T CAR T CAR T Off the shelf

70 CYAD-101: Allogeneic approach of CYAD-01 Alloreactivity controlled through co-expression of an inhibitory peptide (termed a T-cell receptor inhibitory molecule TIM) to reduce TCR-signaling and thereby reduce GvHD. 02/02/

71 Solid Hematopoietic 3 rd Challenge To increase efficacy of CAR T therapy in solid tumors Hartman et al, EMBO Mol Med

72 CYAD-03 NKG2D CAR-T cells in solid and recalcitrant tumors Homing Infiltration Face immunosuppressive microenvironment Targeting tumour heterogeneity Migration towards the tumour Tumortropic factors 02/02/2018

73 What is next? Automation, towards a new paradigm Valerie Steenwinckel, PhD Industrialization Director

74 Intensely Focused on Manufacturing Improvements in Anticipation of Commercial Ready Product Evolution from drug product manufactured in academic setting (DFCI) towards a commercial-ready process that is reproducible and scalable, with attractive COGs Legacy method (LY process) failed to consistently yield drug product with target T cell numbers Of 15 patients treated at December 31, 2017, 10 were dosed at per-protocol intended dose and 5 were treated at lower doses New manufacturing process is currently being used in the clinic mab manufacturing process inhibits NKG2D expression on the T cell surface during production Enables significantly higher cell numbers than the legacy process Validated in both in vivo and ex vivo models CMC amendments to THINK protocol are in effect with applicable regulators First patient treated January 2018 Continued focus on next-generation process improvements, including automated and closed system approach 74

75 Automation Program Mission Celyad would like to develop an automated machine that will allow to bring CAR-T cell therapies to all patients in the most cost effective and efficient manner. 02/02/

76 Why it is important to automate? Ease of manufacturing Increase reproducibility Reduce time of manipulation Ease of Tech transfer to potential other sites Decrease batch failure (human error) Cost of good reduction Less operator time per batch Scalability Increased capacity of centralized manufacturing approach Footprint Parallel processing Possibility adapt to market demand De-centralized model Point of Care approach (machine in hospital) Less environmental needs/control 02/02/

77 To treat large number of patients Celyad needs to automate and close the production process Ideal features of the machine: Automated with closed system from start to end Minimal Operator interactions Ultra Low batch failure Parallel batch production Ultra-low cost of Goods of disposable Able to evolve towards point of care when market will growth...like GMP in a box 02/02/

78 Celyad has already evaluated the close system manufacturing options Evaluated and selected the core technologies that could be used to automate our CAR-T process (ex: washing, concentration, ) Tested the complete concept with a prototype (in house) Example of cartridge and machine Mature the concept to be compatible with PoC: cartridge based approach with parallel processing 02/02/

79 Conclusion Christian Homsy, MD, MBA CEO 79

80 Conclusion: Towards CAR-T leadership NKG2D platform; Leveraging Stress Ligands based CAR-T Autologous Cell Manufacturing Paradigm shift Allogeneic CAR T Cell Therapy Building on early signals Process Development Strong IP position Improving outcomes Improved yields and CoGs Patents concerning TCR knockdown in CAR T cell therapy providing broad coverage in the field Initial focus on AML and CRC Automation Execution Making Autologous Cell Therapies feasible and cost effective Allogeneic NKG2D Platform Continuing Development Plan Broaden indications beyond AML and CRC Towards Point of Care Processing Enabling large indications Development of TIM8-CYAD 01 (CYAD-101) Allogeneic TIM Platform Developing broad based Allogeneic CAR T products 80

81 Willy Borsus Minister-President of Wallonia 81

82 Closing Christian Homsy, MD, MBA CEO 82

83 Q&A 83

84 Merci! Dank u! Thank you! 84