Living immunotherapies Corporate Presentation MAY 2018
All of the information herein has been prepared by the Company solely for use in this presentation. The information contained in this presentation has not been independently verified. No representation, warranty or undertaking, express or implied, is made as to, and no reliance should be placed on, the fairness, accuracy, completeness or correctness of the information or the opinions contained herein. The information contained in this presentation should be considered in the context of the circumstances prevailing at that time and has not been, and will not be, updated to reflect material developments which may occur after the date of the presentation. The Company may alter, modify or otherwise change in any manner the content of this presentation, without obligation to notify any person of such revision or changes. This presentation may contain certain forward-looking statements and forecasts which relate to events and depend on circumstances that will occur in the future and which, by their nature, will have an impact on the Company s business, financial condition and results of operations. The terms anticipates, assumes, believes, can, could, estimates, expects, forecasts, intends, may, might, plans, should, projects, will, would or, in each case, their negative, or other variations or comparable terminology are used to identify forward-looking statements. There are a number of factors that could cause actual results and developments to differ materially from those expressed or implied in a forward-looking statement or affect the extent to which a particular projection is realised. Factors that could cause these differences include, but are not limited to, implementation of the Company s strategy and its ability to further grow, risks associated with the development and/or approval of the Company s products candidates, ongoing clinical trials and expected trial results, technology changes and new products in the Company s potential market and industry, the ability to develop new products and enhance existing products, the impact of competition, changes in general economy and industry conditions and legislative, regulatory and political factors. While we always intend to express our best judgment when we make statements about what we believe will occur in the future, and although we base these statements on assumptions that we believe to be reasonable when made, these forward-looking statements are not a guarantee of our performance, and you should not place undue reliance on such statements. Forwardlooking statements are subject to many risks, uncertainties and other variable circumstances. Such risks and uncertainties may cause the statements to be inaccurate and readers are cautioned not to place undue reliance on such statements. Many of these risks are outside of our control and could cause our actual results to differ materially from those we thought would occur. The forward-looking statements included in this presentation are made only as of the date hereof. We do not undertake, and specifically decline, any obligation to update any such statements or to publicly announce the results of any revisions to any of such statements to reflect future events or developments. 2
Medigene at a glance 1 A global leader in T cell immunology 2 Growing clinical pipeline in multiple indications 3 High-throughput assays for antigen and TCR discovery 4 DC vaccines as first validation of cellular therapies 5 High-profile partnerships to drive near and long term value 6 Strong and experienced management team 3
Progress of immunotherapy pipeline PROJECT INDICATION (TARGET) PRECLINICAL PHASE I PHASE II DC vaccine Acute myeloid leukemia (WT-1 / PRAME ) TCR 1 (MDG1011) AML, MDS,MM (PRAME) TCR-IIT * Multiple myeloma (MAGE-A1) Start 2018e TCR 2 Undisclosed TABs T cell leukemias + new applications * Investigator-initiated trial (IIT) of a publicly funded collaboration between MDC, Charité and Medigene. Additional IITs utilizing Medigene s DC vaccine technology are ongoing at LMU Munich (Phase I/II in AML) and Oslo University Hospital (Phase II in prostate cancer) 4
Personalized cancer treatment with TCR-Ts 4 Patient 1 Thawing and reinfusion into patient Leukapheresis & T cell isolation TCR-T cell product 3 2 GMP: expansion, freezing and quality tests GMP: activation of T cells and transfer of TCR from TCR pipeline 6
PRAME is the target of Medigene s 1 st lead TCR PRAME (Preferentially Expressed Antigen of Melanoma) is a well described cancer-testis (CT) antigen Literature reports (in addition to in-house data) that PRAME expression is high in tumors but very scarce or absent in normal tissues Medigene s clinical trials indicate that using a PRAME DC vaccine is safe and well tolerated, confirming other vaccine trials targeting PRAME PRAME mrna is expressed in 9 out of 10 common nonhematological cancers (NCI): bladder, breast, colorectal, kidney, liver, lung (NSCLC & SCLC), prostate, thyroid and uterus 7
PRAME broadly expressed across tumors types Tumor expression patterns: Scale is given as RSEM. RSEM quantifies gene and isoform abundances from single-end or paired-end RNA-Seq data. 8
PRAME shows high safety profile Analysis by immunohistochemistry Normal tissue expression: only testis among 30 tissues at RNA and no expression in 43healthy tissues at protein levels Source: Indivumed GmbH, Germany 9
Phase I/II clinical trial of MDG1011 in myeloid and lymphoid malignancies Target: PRAME (Preferentially Expressed Antigen in Melanoma) PRAME is a well characterized tumor antigen overexpressed in multiple hematological and solid tumor indications The drug, MDG1011: T cells expressing a HLA-A*02:01-restricted T cell receptor (TCR) specific for PRAME Trial outline: Combined Phase I/II safety, feasibility and early efficacy clinical trial Disease indications for Phase I, all in advanced stages: acute myeloid leukemia (AML) myelodysplastic syndrome (MDS) multiple myeloma (MM) 2 of the 3 indications will be carried over into Phase II https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-000440-18/de 10
MDG1011 clinical trial design Phase I Phase II Approx. 12 patients in up to 4 dose cohorts 3+3 dose escalation design, up to 4 cohorts Each indication needs to be represented in a cohort Dose ranges from 100,000 to 10,000,000 transduced T cells per kg body weight Progression between dose cohorts will be decided by an independent Data and Safety Monitoring Board (DSMB). Multi-center study at three sites (University of Regensburg, Würzburg and Erlangen, Germany) 40 treated + 40 control patients 2 of 3 indications to be carried into Phase II after a positive DSMB assessment and PEI/ethics committee vote 40 HLA-A*02:01 and PRAME positive patients to be treated with MDG1011 (20 per indication) Another 40 patients, PRAME positive but HLA-A*02:01 negative, serve as control groups (20 control patients per indication) https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-000440-18/de 11
MDG1011 clinical trial endpoints Phase I: Primary endpoint: Safety (incidence, severity of adverse events (AEs) at 3 months, maximum tolerated dose (MTD) based on dose limiting toxicities up to 28 days) Feasibility (percent of patients receiving the planned dose) at 3 months Secondary endpoints: Safety (incidence, severity of AEs at 6 and 12 months) Overall response rate (ORR), duration of response (DoR), time to progression (TTP), progression-free survival (PFS), overall survival (OS), quality of life (QoL) and the correlation of PRAME expression with the antitumor response, measured at 3, 6 and 12 months Phase II: Co-primary endpoints: Safety (incidence, severity of AEs) at 3 months Efficacy (ORR) at 3 months Secondary endpoints: Safety (incidence, severity of AEs) at 6 and 12 months ORR at 6 and 12 months, DoR, TTP, PFS, OS, QoL and the correlation of PRAME expression with the antitumor response at 3, 6 and 12 months 12
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Medigene s approach to DCs vaccines GM-CSF + IL-4 monocytes New generation maturation cocktail with TLR 7/8 agonist mdc IL-12 high IL-10 low 2 days 1 day New New generation 3-day polarized mature 3d-mDCs Optimized interleukin (IL) secretion pattern for innate and adaptive immunity Optimal phenotype and function Fast production in 3 days Use of defined antigens (i.e. C/T, neo-antigens) Capacity to activate complex CD4+ and CD8+ T cell responses Use of frozen cells with long shelf-life 14
Ongoing DC Phase II part of clinical trial in AML Target: WT-1 with or without PRAME WT-1 = Wilms tumor 1 PRAME = preferentially expressed antigen in melanoma Clinical product: Dendritic cells of AML patients presenting WT and PRAME antigens Clinical trial outline: AML patients in complete remission after chemotherapy, not eligible for allo-transplantation. Goal is to assess prevention of relapse Phase I/II: open-label, prospective, non-randomized trial Completed recruitment of 20 AML patients: 6 phase I + 14 phase II Continuous vaccination for 2 years or until progression/death Primary study objectives: feasibility and safety Secondary study objectives: overall survival (OS), progression free survival (PFS), control of minimal residual disease (MRD), time to progression (TTP), induction of immune responses Single center trial at Oslo University Hospital ClinicalTrials.gov Identifier: NCT02405338 15
Recent DC vaccine data from AACR 2018 IIT study presented by Oslo University Hospital: Clinical data for DC vaccine in 20 prostate cancer patients Seventy-five percent of the patients remain without biochemical relapse with a mean observation time of 47.5 (range 29-82) months 5 of 20 patients received DCs generated with Medigene s proprietary maturation cocktail The 5 patients given the new type of DCs have not experienced PSA relapse Adjuvant dendritic cell vaccines in high-risk prostate cancer patients following radical surgery can reduce the incidence of biochemical relapse Data on the successful production of AML DC vaccine: 20 patients with a median age of 59 years (range 24-73 years) were recruited Successful production runs of dendritic cells for vaccination were achieved for all 20 AML patients Aliquots prepared to deliver 5-10 million cells per vaccine dose An additional apheresis for a second production run in order to generate sufficient vaccine doses was needed for only 4 out of the 20 patients Feasible and robust production protocol for high numbers of mature, clinical grade DCs from heavily pretreated, post-remission AML patients 16
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TCRs vs CARs HER2 CD19 Minor histocompatibility antigens Cancer-germline antigens Differentiation antigens Viral antigens Mesothelin CD38 Universal antigens Mutations CARs target only surface proteins: App. 30% of human proteome Limited to cell surface antigens, only tens of options Recognition is Major Histocompatibility Complex (MHC)-independent Higher risks of side effects TCRs target also intracellular proteins: App. 70% of human proteome Recognize intracellular targets, with many thousands of options (more addressable targets) Recognition is MHC-dependent (adds specificity) Lower risk for side effects if TCRs are natural, nonmutated structures TCRs offer more options, more power, more sensitivity and more control 18
TCR-based immunotherapies Essential steps for TCR-based immunotherapies Antigen / epitope selection Well suited for indication(s), both liquid and solid tumors Adequate tumor expression Safe for healthy tissues T cell receptor discovery Optimal affinity TCRs High TCR surface expression TCR transfer of multi-functionality (cytokines and cytotoxicity) Recipient T cell production Pre-selected starting recipient T cells Consistent product characteristics under GMP Expansion and persistence of T cells in patients Innovative clinical trials Safe & feasible pre-treatment and cell dosing Multiple indications compared at early stage Genetic control groups for comparison to SoC 19
Bioinformatic tools for antigen selection Tool Source Content Information gained regarding HESPERIA The Cancer Genome Atlas (TCGA) Expression Atlas Human Protein Atlas Seven combined databases Patient tumor mrna expression Cancer cell line and normal tissue mrna expression Cancer tissue protein expression Healthy tissue protein and mrna expression Indications: Expression comparisons in different cancers Frequencies: Frequency of expression in patients with selected indications Variations: Variations in levels of expression of antigens in healthy and cancer tissues Epitopes: Expression of epitopes in healthy tissues, identification of mismatched epitopes for safety assessments 20
In vitro tools confirm suitability of selected antigens Tool Purpose Nanostring assay of proteins and RNAs Sensitive detection of antigens in healthy and tumor tissues Immunohistochemistry Patterns of antigen expression in tumors and healthy tissues qrt-pcr Biosensors Quantitative assessment of antigen in patient tumor samples Expression of specific pmhc ligands on healthy and tumor tissues 21
TCR discovery process using healthy donors Antigen selection Healthy donors GM-CSF + IL-4 Monocytes Lymphocytes Cancer antigen (ivt-rna) Proprietary maturation cocktail Priming of T cells with mature DCs Enriched T cell repertoire Mature DCs Isolation of antigen specific T cell clones Sequencing and full characterization of TCRs Vector encoding selected TCR sequence (SIN-virus) 22
Using three approaches to gain optimal-affinity TCRs DCs with self-hla only DCs plus selected non-self HLA (Medigene s proprietary approach) Foreign antigen Self antigen Self antigen Foreign HLA as ivt-rna + autologous T cells + autologous T cells + autologous T cells Abundant T cell clones (self-hla + foreign ag) Rare T cell clones (self-hla + self ag) Abundant T cell clones (non-self HLA + self ag) T cell clones are sources of unique TCRs for further studies 23
Rapid and efficient TCR lead candidate identification Antigen selection Preparation Priming Expansion Selection Highest level of standardization and reproducibility Exemplified by output over 12 month timeframe: TCR leads from priming 45.000 wells automatically screened 15.000 screened clones 1.500 characterized specific T cell clones 24
TRBV Robust recipient cell process established Patient-derived recipient cell population with desired characteristics Selected TCR vector TCR-expressing T cells + Specifically-enriched cell populations allowing expansion, persistence and multi-functionality Safe vector system SIN- RV (self-inactivating retrovirus) TCR sequence matched to patient HLA, antigen and indication CD8 High transduction efficiency Strong TCR expression 25
Poly-functional T cells identified simultaneously at single-cell level Multi-color Elispot assay replaces three different technologies to define five functional parameters Deep insight of T cell function at single-cell level Enormous savings of time and cost High-throughput application Individual colored dots represent single T cells producing one or more functional molecules (cytokines and killer proteins) 26
Steady progress in science-driven innovation Cutting-edge technologies assessed to improve functional properties of T cell immunotherapies: Enhancement of T cell effector function in situ (Cancer Research 77:3577, 2017) Recombinant T cells with improved efficacy in challenging solid tumor environments (Collaboration with Rxi Pharmaceuticals) Innovative approaches to improve safety of next generation T cell therapies under evaluation and development: Specific tracking tools for T cells during GMP manufacture and in patient samples Suicide safety switch Inducible TCRs 27
TCR candidate pipeline demonstrates power of platform Project Indications Target identification/ validation Target selected Priming and TCR seq determination TCR lead candidates selected Initial TCR characterization ( Assay tree ) Clinical TCR lead selected Non-clinical development Submission of CTA Phase 1 PRAME MAGE-A1* AML, MDS, MM MM, liver, lung not disclosed n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. Own and partnered projects n.d. n.d. n.d. * Investigator-initiated trial (IIT) of a publicly funded collaboration between MDC, Charité and Medigene 28
Value creation in TCR development TCR generation module TCR leads GMP production module TCRmodified T cells Clinical development program TCRbased therapies TCR discovery collaborations b b TCR development collaborations MAGE-A1 development in MM with academic partners TCR clinical stage partnerships Medigene s PRAME TCR study MDG1011 Unique discovery capabilities, immune monitoring platform cgmp process potentially of interest to other parties Proprietary TCR therapies 29
Financial guidance 2018 FY 2017 GUIDANCE 2018 Total revenue 11.4 m 7.5-9.5 m R&D expenses 14.9 m 22-24 m EBITDA loss 12.1 m 21-23 m Cash usage 20.4 m 21-26 m Liquide assets as of 31 Dec 2017 amounted to 51.7 m. Medigene has sufficient financial resources for beyond the planning horizon of two years No milestone payments or cash inflows are included from existing or future partnerships or transactions 31
Outlook 2018 MDG1011, Medigene s first TCR trial: Treatment of first patient Treatment of first dose cohorts DC trial in AML, Oslo: Presentation of preliminary data on certain aspects of the trial Final read-out in 2019 TCR IIT, Berlin: Clinical trial authorization Study start Progress in bluebird collaboration 32
Medigene AG Lochhamer Straße 11 82152 Planegg / Martinsried Germany T +49-89 - 20 00 33-0 F +49-89 - 20 00 33-2920 investor@medigene.com www.medigene.com Listed on Frankfurt Stock Exchange (MDG1, Prime Standard, TecDAX)