Viral-vector based immunotherapies to transform the fight against cancer and infectious diseases. January, 2019

Transcription

1 Viral-vector based immunotherapies to transform the fight against cancer and infectious diseases January, 2019

2 Disclaimer This presentation contains forward-looking statements, which are subject to numerous risks and uncertainties, which could cause actual results to differ materially from those anticipated. There can be no guarantee that (i) the results of pre-clinical work and prior clinical trials will be predictive of the results of the clinical trials currently under way, (ii) regulatory authorities will agree with the Company s further development plans for its therapies, or (iii) the Company will find development and commercialization partners for its therapies in a timely manner and on satisfactory terms and conditions, if at all. The occurrence of any of these risks could have a significant negative outcome for the Company s activities, perspectives, financial situation, results and development. For a discussion of risks and uncertainties which could cause the Company's actual results, financial condition, performance or achievements to differ from those contained in the forward-looking statements, please refer to the Risk Factors ( Facteurs de Risques ) section of the Document de Référence, available on the AMF website ( or on Transgene s website ( Forward-looking statements speak only as of the date on which they are made and Transgene undertakes no obligation to update these forwardlooking statements, even if new information becomes available in the future. 2

3 Focused on enhancing our leadership in viral vector-based immunotherapies Mature Clinical Assets Early-Stage Clinical Assets Technology Platforms TG4010 TG4001 TG6002 Pexa-Vec TG1050 First candidates in clinic in

4 World leader in viral-vector based immunotherapies Experience driven innovation Clinical pipeline Our new cutting edge technology platforms THERAPEUTIC VACCINES ONCOLYTIC VIRUSES TG 4010 TG 4001 TG 1050 PEXA-VEC TG6002 Informed decisions WORLD LEADING SCIENCE First candidates in clinic in

5 Broad pipeline of clinical-stage immunotherapies Transgene strategic trials are poised to deliver key read out in 2019 Product THERAPEUTIC VACCINES Indication Preclinical Clinical Phase Phase 1 Phase 2 Phase 3 Next Key Milestone TG4010 TG4001 Non-small cell lung cancer 1 st line Recurrent HPV-positive head and neck cancers + nivolumab (ICI) + CT + avelumab (ICI) 2H 2019: ORR (35 patients) 2H 2019: First efficacy date TG1050 Chronic hepatitis B Potential partnership + antiviral ** * * ONCOLYTIC VIRUSES Pexa-Vec Advanced HCC 1 st line (PHOCUS) Advanced HCC 1 st line + sorafenib + nivolumab (ICI) 2H 2019: Intermediary readout Mid 2019: ORR (15 patients) TG6002 Colorectal cancer ** TBC *** * Clinical collaboration / ** Rights acquired for Greater China ***Transgene has commercial rights to Pexa-Vec in Europe and additional selected countries. 5

6 Therapeutic Vaccines Pioneering virus-based immunotherapeutics

7 Lung cancer Better therapeutic options still needed for non-responders (ICIs) Most patients still diagnosed at late stages, with dismal prognosis Need to increase response rate and OS Non-small cell lung cancer First-line therapy Min. 350 K patients * 30 % of 1L patients whose tumor cells express high levels of PD-L1 ( 50 %) Pembrolizumab registered since % of 1L patients whose tumor cells express no or low levels of PD-L1 (<50 %) Pembrolizumab registered in combination with pemetrexed / carboplatin CT since 2017 (USA) and 2018 (EU) Still a major unmet need as a majority of patients do not respond to ICIs *Source: USA, EU, JP, Globocan, Company estimates 7

8 TG4010 Compelling lung cancer clinical data Improved response rate & duration of response SUCCESSFUL PHASE 2B TRIAL (RANDOMIZED, PLACEBO-CONTROLLED, 222 PATIENTS) TG4010 in combination with chemotherapy for 1 st line NSCLC TG chemotherapy 40.9 [ ] wks Non-squamous (n) ORR Median duration of response (wks) TG CT 98 40% 41 Placebo + CT 98 28% 18 Chemotherapy (n=27) 18.1 [ ] wks Placebo + chemotherapy 18.1 [ ] wks Improved response rate & duration of response Good safety profile Source: Quoix, E. et al., TG4010 immunotherapy and first-line chemotherapy for advanced non-small-cell lung cancer (TIME): results from the phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial, The Lancet Oncology, Dec. 2015, (17:212) 8

9 TG4010 Compelling lung cancer clinical data Well positioned for further development in NSCLC SUCCESSFUL PHASE 2B TRIAL (RANDOMIZED, PLACEBO-CONTROLLED, 222 PATIENTS) TG4010 in combination with chemotherapy for 1 st line NSCLC Progression-free survival (months) Patients with non sq. tumors (n=196) Overall survival (months) Patients with non sq. tumors (n=196) Significant improvements in PFS and OS in patients in patients with non sq. tumors TG chemotherapy Placebo + chemotherapy 35% 19% TG chemotherapy Placebo + chemotherapy 36% 20% Clinical efficacy in both PD-L1 negative and PD-L1 positive patients Source: Quoix, E. et al., TG4010 immunotherapy and first-line chemotherapy for advanced non-small-cell lung cancer (TIME): results from the phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial, The Lancet Oncology, Dec. 2015, (17:212) 9

10 TG4010 1L To increase ORR with triple combination regimen in patients with non sq. NSCLC expressing low levels of PD-L1 (<50%) Study Proof-of-concept Phase 2 trial Collaborative agreement with BMS (supply of nivolumab) First patient treated in January 2018 Recruitment to be completed in 2Q 2019 Primary endpoint evaluation expected in 2H 2019 (ORR on 35 patients) Endpoints Primary endpoint: objective response rate (ORR) Secondary endpoints: duration of response, disease control rate, progression-free survival (PFS), overall survival (OS), and safety Protocol Up to 39 patients (35 evaluable patients) Multi-center, single-arm, open label study First-line treatment, stage IIIB-IV or delayed relapse, non sq. NSCLC with low or undetectable PD-L1 expression (<50%) Study regimen TG PFU weekly for 6 weeks then every 3 weeks by SC route Nivolumab 360 mg every 3 weeks by IV route Pemetrexed-carboplatin (or cisplatin) every 3 weeks for 4 cycles followed by pemetrexed maintenance Participating countries USA Belgium Denmark France 10

11 TG4001 HPV-positive Head & Neck Cancers (HNSCC) Phase 1b/2 in combination with avelumab (Bavencio ) MVA encoding for HPV16 E6 & E7 and IL-2 In collaboration with Principal Investigator Pr Christophe Le Tourneau, Institut Curie Protocol Up to 50 patients (France) Multi-center, single-arm, open label trial Metastatic or refractory/recurrent HPV-16+ head & neck cancer, after failure of standard therapy Endpoints (Phase 2 part) Primary endpoint: Objective response rate (ORR) Secondary endpoints: progression-free survival (PFS), overall survival (OS), duration of response and safety First patient treated in September 2017 Following positive safety evaluation, Phase 2 part ongoing and additional sites being activated Phase 1 results in 4Q 2018 (n=9 patients) Next clinical readout expected in 2H

12 TG1050 Positive Phase 1 results (safety and immunogenicity) Adeno encoding for 3 HBV antigens Phase 1 results presented at AASLD 2018 (n=48 patients) Principal investigator Prof Fabien Zoulim, Hospices civils, Lyon (France) Participating countries: Canada, France, Germany Protocol Up to 48 patients Randomized safety and dose-finding study Patients currently being treated with SoC antiviral therapy Rights for Greater China acquired by Tasly Pharmaceuticals (July 2018) Primary endpoint met: good safety profile confirmed TG1050 triggers T cell-based immune responses, specific of all 3 encoded HBV antigens Intermediate dose (10 10 vp) consistently immunogenic ( 70% of patients) New preclinical data support further investigation in combination with antivirals and immunomodulators 12

13 TG1050 Key findings of the positive Phase 1 trial Safety: Clinical trial primary end-point reached. Subcutaneous SD & MD injections of TG1050 in NUC-suppressed CHB patients is well tolerated over the 3 DLs. No negative impact on disease control, especially in the sensitive part of patients with no pre-immunity against the adenoviral vector, reinforces the robust safety profile of TG1050. Immunogenicity: TG1050 induces HBV-specific cellular immunity (IFN-g cells) in NUC-suppressed CHB patients without or with low anti-ad5 pre-immunity. 0 Induced responses are specific of single or multiple antigens expressed by TG1050 (Core/Pol & Env). Detection of Env-specific responses is encouraging in a highly tolerogenic context for this antigen. Responses are detected following single and multiple injections: Intermediate dose vp is consistently immunogenic (~70% of patients). HBsAg evolution: HBsAg decline reaches 0.4 log over time in 2 patients of vp group. Number of patients with low anti-ad5 preimmunity per dose group responding to at least 1, 2 or 3 antigens Heatmap of ELISpot responses. Patients with low anti-ad5 pre-immunity are listed as lines and test conditions as columns Individual evolution of ELISpot responses over time in patients with low anti-ad5 pre-immunity Detectable responses in both SD & MD cohorts at & vp doses ; Env-specific responses detected despite TG1050 encoding for only small domains of Env/HBsAg as well as the very high tolerance against HBsAg characterizing CHB carriers.

14 Entering the field of individualized immunotherapies using our unique proven MVA based platform

15 myvac TM Individualized immunotherapy platform Targets patients neoantigens Immunotherapy Safety Efficacy MVA-based therapeutic vaccine Therapeutic class with established track-record Proven anti-tumor activity The advantages of personalised treatment without the drawbacks of autologous approaches Individualized One cancer, One patient, One vaccine Flexible Versatile platform and AI integration Clinical First trials will start in

16 myvac TM Transgene s vaccine expertise provides the insights needed to leverage multiple cutting edge technologies Artificial Intelligence Gene editing Genome sequencing 16

17 myvac TM Targeting unique patient specific set of mutations Because of deficient repair mechanisms and rapid proliferation, tumor cells accumulate DNA mutations Some mutations lead to the generation of non-self proteins (therefore immunogenic) These neoantigens are more immunogenic than classical tumor associated antigens Transgene s myvac vaccines against neoantigens are expected to induce broader and stronger T cell responses 17

18 myvac network combines bioengineering & digital transformation Identify patients eligible for individualized immunotherapies Secure and exploit genomic data Select the most relevant neo-antigens Manufacture myvac product in controlled time and cost Realize clinical proof of concept 100 Percent survival 50 Vaccin Placebo Time (days) World renown US and UK clinical centers 18

19 Clinical protocols being finalized with 2 international KOLs Dr Christian Ottensmeier presenting at SITC 2018 HPV negative head and neck cancers After surgery and adjuvant therapy Ovarian cancer After surgery and adjuvant chemotherapy Trials are expected to start in 2019 (Europe & USA) 19

20 Oncolytic Viruses Pioneered by Transgene A new and highly promising therapeutic class in the fight against cancer. Transgene leading the development of multifunctional OVs for the enhanced modulation of the TME via a single therapeutic.

21 Pexa-Vec Lead oncolytic virus Transgene owns development and commercialization rights in Europe Licensor: SillaJen (KOSDAQ: ) HCC 1L Global Phase 3 trial Combination Phase 2 trial conducted by Transgene Global clinical development plan Other solid tumors Exploratory Phase 2 trials conducted by Transgene Exploratory Phase 1 trials led by SillaJen (RCC 2L, CRC 2L/3L) 21

22 Pexa-Vec Large unmet medical need in HCC Dismal prognosis Better therapeutic options needed 25,000 eligible patients in Europe* First-line therapy Sorafenib - modest activity ORR: 2% ; median OS: 10.7 months Lenvatinib recently approved with non-inferiority results (USA, EU, Japan) Nivolumab could become a new therapeutic option: Promising activity in Phase 3 (still ongoing) Second-line therapy Regorafenib ORR: 10%; median OS: 10.6 months Nivolumab approved by FDA (2017) ORR: 18%; median OS: 15.6 months Pembrolizumab approved by FDA (2018) ORR: 17%, median OS: 12.9 months * Source: Globocan, Company estimates 22

23 Pexa-Vec Key Phase 2 clinical trial results Clinical activity demonstrated in multiple trials Trials with >300 patients treated with Pexa-Vec in variety of tumor types, including liver, colorectal and kidney Proof of concept for MOA: active immunotherapy 30-patient dose-finding Phase 2 trial in HCC (80% of patients first-line) OS results - high dose versus low dose Median OS: 14.1 (high dose) vs. 6.7 months (low dose) Hazard Ratio = 0.39 p = Nature Medicine, Volume 19, Issue 2, February

24 Pexa-Vec Triggers antitumor immunity after single IV administration Prior to planned surgery of locally advanced, poor prognosis or metastatic cancers Pexa-Vec shown to Selectively target tumor tissue after single IV administration Stimulate the adaptive and innate anti-tumor immune response Induce expression of PD-L1 and PD-1 pathways Single IV Pexa-Vec Surgery Post-surgery d1 d2 d3 d5 d14 ± 4d 1m 3m Peripheral blood samples collected n = 8 ; 3 with metastatic melanoma and 5 with colorectal cancer metastases to the liver (CRLM) One complete and one partial tumor pathological response at the time of surgery on four evaluable CRLM patients Presence of Pexa-Vec in tumor tissue Normal tissue Tumor-specific adaptive T cell responses (T cell Elispot) Patient : Mel. CRLM TAA : MART1 CEA Preinfusion PBMCs exhibited robust activation by 24 hrs post-infusion Expression of CD69 (an early activation marker) was enhanced on effector cell populations, notably NK & T cells Expression of PD-L1 was increased CD69 PD-L1 CRLM tissue showing expression of Pexa-Vec, signs of inflammation and fibrosis, necrotic cells 1 month postinfusion Data support ongoing development of Transgene s Vaccinia virus-based oncolytics Source: Samson, A. et al, Single intravenous preoperative administration of the oncolytic vaccinia virus Pexa-Vec to prime anti-tumor immunity, ASCO 2018, June

25 Pexa-Vec Clinical development plan in HCC - 1 st line Pivotal Phase 3 and combination Phase 2 Position Pexa-Vec with current and future standard of care Advanced HCC 1 st line Phase 3 Pexa-Vec + sorafenib Conducted by Advanced HCC 1 st line Phase 1/2 Pexa-Vec + Opdivo (nivolumab) Conducted by Multi-center Phase 3 trial in Europe, USA, Asia Randomized, two-arm trial Ongoing global recruitment First patient included in China in Sept First data (efficacy vs SoC) expected in 2019 Multi-center Phase 1/2 trial in France, Italy, USA Open-label, single-arm trial Safety review committee expected before year-end 2018 Interim analysis (15 patients) expected mid-2019 (primary endpoint ORR) 25

26 Next Generation of Oncolytic Viruses Transgene s novel Oncolytic Viruses are based on its optimal Vaccinia virus backbone armed with either chemo or immuno payloads

27 Oncolytic viruses Three complementary ways to act on the tumor Oncolysis Specific replication in tumor cells, and direct lysis of infected cells Immune response Induction of immunogenic cell death, engagement of both innate and adaptive anti-tumor immunity Many routes to reach the tumor (i.e. IV, IT) Immuno-modulating payloads delivery Targeted delivery of anti-tumor modalities, synergistic with other MOAs (e.g. targeted CT, or immune modulation of TME) 27

28 Vaccinia virus (VV) The optimal oncolytic backbone Excellent Oncolytic activity of the Copenhagen vaccinia strain Good immunological balance (Th1 vs Th2, anti-tumor vs antiviral responses, etc.) Large genome capacity (up to 25 kb), to accommodate multiple transgenes Tumor selective replication in numerous cancer cell types, and good safety profile Pure cytoplasmic replication (no risk for genome integration or mutagenesis) Well-established processes for GMP manufacturing 28

29 CAL33 HepG2 HCT116 Hela SK-Mel1 PANC1 A549 Hs746T SKOV3 UMUC3 LoVo SW780 OE21 U87MG MIA PaCa2 OE19 U118MG KATO3 SNU5 OVCAR3 Magnitude of replication % surviving cells VV COP TK-RR- Targets a large spectrum of human tumors Replication 20 tumor cell lines, MOI 10-3, 48 hrs post-infection 10 5 Oncolytic activity 10 cell lines, MOI variable, day 5 post-infection

30 TG6002 Our VV oncolytic backbone enhanced by tumor targeted chemotherapy

31 TG6002 Advanced OV already in the clinic Viral oncolysis + local production of chemotherapy Multiple Advantages: TG Excellent oncolytic properties 2. Highly tumor selective 3. IV delivery 4. Targeted chemotherapy with FCU1 gene - allowing the production of 5-FU in the tumor FCU1 gene Unique and proprietary High 5-FC to 5-FU conversion rate No FCU1 related safety issue Preclinical results confirm potency Greater China rights acquired by Tasly Biopharmaceuticals as part of a $48 million (July 2018) 31

32 TG6002 Significant anti-tumor activity in multiple human cell lines Example: Evaluation of systemic injection of TG6002 in the colorectal cell line (LoVo) P < 0,05 P < 0,005 TG FC Mice: n=12 Similar results with other cell lines: pancreas (MiaPaca2); glioblastoma (U-87MG), esophaegal (OE19), stomach (HS746T), hepatocarcinoma (Hep G2) 32

33 TG6002 In Phase 1/2a GI cancer clinical study Viral oncolysis + local production of chemotherapy administered IV Gastro-intestinal adenocarcinoma with liver metastasis (colon cancer) (Tumors known to be 5-FU sensitive) Protocol Multi-center Phase 1/2a trial Phase 1 part (dose escalation): up to 24 patients Phase 2a part (efficacy): 35 patients Trial will include biodistribution analysis Principal investigator Prof Philippe Cassier, centre Léon Bérard (Lyon, France) Regimen TG6002 IV: D1, D8, D mg/kg/day Oral 5-FC prior to TG6002 Additional cycles until disease progression INDs granted in Belgium, Spain, France First patients recruited in Q Expected Ph 1 Readout: H

34 Our new generation oncolytic products The Invir.IO TM Platform: Immuno-armed Vaccinia Virus (VV)

35 Multiple options for immune modulation of the tumor micro-environment via immuno-armed oncolytic VVs Chemokines Favoring tumor infiltration Undisclosed sdabs Unlocking local immunosuppression Better release of tumor Ags, and of related immunostimulatory molecules hcd Local expansion, and activation of APC and effectors cells Cytokines TNFR-Ls TCEs Agonistic sdabs Degradation of immunosuppressive metabolites and cells in the TME Undisclosed enzyme ICIs Anti-CTLA-4 35

36 OV encoding for anti-ctla-4 mab Improving on validated MoA of ipilimumab Preclinical PoC Building a potent multifunctional OV Transgene s OVs deliver functional mab in the TME (1) BioInvent s full length human recombinant anti-ctla-4 Abs promote depletion of intratumoral Treg cells (2) Improved efficacy compared to combination of separate Ab and OV (1) Longer duration of expression Expected improved tolerability owing to lower systemic antibody exposure in peripheral nontumor compartments Indications: multiple solid cancers In late stage preclinical development (1) Kleinpeter P. et al., Vectorization in an oncolytic vaccinia virus of an antibody, a Fab and a scfv against programmed cell death -1 (PD-1) allows their intratumoral delivery and an improved tumor-growth inhibition, OncoImmunology, Oct (5:10) (2) Vargas F. et al., Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies, Cancer Cell, April 2018 (33: 1-15) 36

37 Transgene to deliver multiple valueenhancing clinical data readouts and preclinical milestones in 2019

38 Significant anticipated value-creating news flow Portfolio to deliver news flow in the near-term 1H H 2019 Pexa-Vec + nivo 1L HCC Safety review committee TG4010 1L NSCLC Recruitment completed TG4010 1L NSCLC ORR on 35 patients Pexa-Vec + nivo 1L HCC Interim analysis (ORR) on 15 patients TG6002 Phase 1 clinical readout TG4001 SCCHN First efficacy readout Pexa-Vec Phase 3 1L HCC Futility analysis Pexa-Vec Phase 3 1L HCC Interim analysis 1 st product in clinic 1 st product in clinic Clinical results Clin. trial milestone Next generation platforms 38

39 Company funded to deliver multiple value generating milestones Key figures 26.6 million Cash and cash equivalents as of September 30, 2018 Key shareholders As of December 31, million 25 million Operating revenues as of September 30, 2018 (incl. the sale of the TG1050 rights in China for 35.6 million) Expected cash burn for % Free float 43 % Financial visibility to end September 2019 (excl. the potential monetization of the Tasly Biopharmaceuticals shares - $48 million) Market capitalization: ~ $200 million as of December 31, million shares outstanding million options and restricted stocks Listed on Euronext Paris ISIN: FR Ticker: TNG 39

40 Transgene A world leader in viral-vector based immunotherapies Strong late stage clinical pipeline of therapeutic vaccines multiple value adding milestones expected in 2019 Novel myvac individualised immunotherapy platform results from Transgene s significant clinical vaccine expertise First clinical trials to start in 2019 Well positioned to be a best-in-class in oncolytic viruses via the further development of TG6002 and our Invir.io platform Both are based on our proprietary large capacity VV COP TK-RR- backbone First Invir.io product to enter the clinic in 2019 Adequate financial resources to fund business 40

41 Contact Jean-Philippe Transgene 400 Boulevard Gonthier d Andernach - Parc d Innovation - CS Illkirch Graffenstaden Cedex France Tél.: + 33 (0)