Overview of Boehringer Ingelheim in Oncology

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1 Overview of Boehringer Ingelheim in Oncology 2017 Conversations in Oncology in Shanghai, China Victoria Zazulina, MD BI Symposium

2 Boehringer Ingelheim (BI) in Brief Family-owned global corporation Founded 1885 in Ingelheim, Germany Focus on human pharmaceuticals, animal health and biopharmaceuticals Approximately 50,000 employees worldwide Expenses for R&D: EUR 3.1 billion R&D expenditure corresponds to 19.6% of net sales 19 production facilities (Human Pharma) in 9 countries Boehringer Ingelheim Center Our headquarters in Ingelheim, Germany 143 affiliated companies worldwide Total net sales 2016: EUR 15.9 billion EUR, euros; R&D, research and development. 2 Sources: 1. Boehringer Ingelheim. Annual Report, 2016: (Accessed: 5 April 2017); 2. General Boehringer Ingelheim Boilerplate for use as of 5 April 2017.

3 BI Cancer Research Facilities Cancer Research: Tumour cell targeted Cancer Immunology: Immune cell targeted & immunomodulatory Vienna, Austria Biberach, Germany Ridgefield, USA 3

4 Cancer Cell-Directed Therapies: Focus Areas Targeting key cancer hallmarks and driver pathways 1 2 Focus on the three Cancer Hallmarks 1 Focus on four Cancer Driver Pathways 2 Blocking aberrant cancer cell signaling Inducing tumor cell death (including immunogenic cell death) Reverting oncogenic gene expression RTK/RAS signaling WNT signaling Cell death pathways MYC/Transcription 4 1. Hanahan and Weinberg. Cell 2011; 144(5): ; 2. Vogelstein et al, Science 2013; 339(6127):

5 Cancer Immunology: Focus Areas Low immunogenic Immunogenic but TIL low Immunogenic & TIL high Improve T cell priming Improve T cell infiltration Reactivate TILs in TME Cancer Vaccines Checkpoints T cell Engagers Checkpoints + Ag cargo Oncolytic Viruses + Cargo Step 1&2: Improve T cell priming and trafficking (vaccines, oncolytic virus, Tcell engagers Step 3: Release brakes of immune suppressive tumour environment (CPI, immune receptors) 5

6 IMMUNE CELLS (Cancer Immunology) CANCER CELLS (Cancer Research) BI Oncology Drug Discovery Growth signalling ErbB family blocker, PDGFR/FGFR/VEGFR inhibitor, VEGF/Ang2 or IGF neutralizing Apoptosis regulation CD37 antibody, SMAC mimetic and several NBEs and NCEs in preclinical development Epigenetic and transcriptional regulation Several NCEs in preclinical development Reactivation/infiltration PD-1 inhibitor in combination with monoclonal antibodies Redirection CD37 antibody, CD33 antibody, several NBEs in preclinical development Priming Cancer vaccines (mrna-based ICV), SMAC mimetic, Vira-T oncolytic virus Tumour cell Ang2, angiopoietin-2; ErbB, epidermal growth factor receptor tyrosine kinase family receptor; FGFR, fibroblast growth factor receptor; IGF, insulin-like growth factor; mrna-based ICV, messenger ribonucleic acid-based immunotherapeutic cancer vaccine; NBE, new biological entity; NCE, new chemical entity; PDGFR, platelet derived growth factor receptor; PD-1, programmed cell death protein 1; SMAC, second mitochondria-derived activator of caspase; VEGFR, vascular endothelial growth factor receptor. 6

7 BI Oncology Pipeline Overview Target Compound Phase I Phase II Phase III Approved EGFR (ErbB1), HER2 (ErbB2), ErbB3, ErbB4 Afatinib* NCE po UC HNSCC NSCLC 1L EGFR M+* SqNSCLC VEGFR; FGFR; PDGFR Nintedanib NCE po Mesothelioma NSCLC 2L VEGF BI Bevacizumab biosimilar candidate nsnsclc mcrc IGF ligands Xentuzumab NBE iv NSCLC BC (I/II) CRPC (I/II) CD33 BI NBE iv AML MDS CD37 BI NBE iv NHL CLL CLL DLBCL (I/II) VEGF/Ang-2 BI KEY 6 antigens: NY-ESO-1; MAGE C1; MAGE C2; TPBG; Survivin; MUC1 BI mrna-based ICV NSCLC PD-1 BI NBE iv Immune cell redirection Immune cell priming Growth signalling BET BI NCE po NHL LAG-3 IAPs BI NBE iv BI NCE po Apoptosis regulation Immune cell reactivation/ infiltration Epigenetic and transcriptional regulation *In the EU, afatinib is indicated as a monotherapy for EGFR TKI-naïve adult patients with locally advanced or metastatic NSCLC with activating EGFR mutation(s) and locally advanced or metastatic NSCLC of squamous histology progressing on or after platinum-based chemotherapy; it is not approved in other indications; Nintedanib is indicated in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy; These are investigational compounds and have not been approved. Their safety and efficacy have not been established. 7

8 BI Oncology: Lung Cancer Pipeline Compound Class Status Setting Giotrif ErbB family blocker Approved Vargatef BI Angiokinase inhibitor VEGF/ANG2 nanobody Approved PhIII Phase EGFR M+ NSCLC Squamous NSCLC Lung Adenocarcinoma Mesothelioma Combination with PD1 BI BI PD-1 mab, LAG-3 mab immune checkpoint inhibitors Phase I Combi PD-1/LAG-3 PD-1 as backbone BI mrna vaccine Phase I Combi PD-(L)1, CTLA4 BI SMAC mimetic Phase I Combi with PD1 BI _ p53 reactivator Preclinical BI _ Inhibitor of Wnt signaling Preclinical 8

9 Strategic Research Collaborations and Partnerships MD Anderson 1 Novel therapeutic concepts and targets Biomarkers for pancreatic cancer BI research collaborations NCC Japan and BI Japan 6 Early drug discovery and translational research focusing on biomarkers and tumor types frequent in Asia Dundee University 3 Development of a new class of medicine involving PROTACS Yale University 4 Identification of new immune-modulatory agents and novel therapeutic targets for oncology, autoimmune and respiratory disorders BI, Boehringer Ingelheim; PROTACs, proteolysis targeting chimeric molecules; NCC, National Cancer Center Eureka Therapeutics 5 Identification of next generation cancer immunotherapies targeting intracellular oncogenes Vanderbilt University (Cancer Drug Discovery Laboratory) 2 The development of small molecule inhibitors of Ras February 2017); (Accessed: 20 February 2017); 4. (Accessed: 20 February 2017);

10 Strategic Clinical Collaborations and Partnerships The Leukemia & Lymphoma Society s The BEAT AML Master Trial 1 One sub-study arm within the trial offers therapy with BI (CD33 mab) in combination with azacitidine CureVac 4 BI (CV9202), an mrna-based ICV in combination with existing treatments for NSCLC Merck 5 Afatinib in combination with pembrolizumab for squamous cell NSCLC BI clinical collaborations Philogen 2 F16IL2 (Teleukin) in combination with BI (CD33 mab) in patients with AML relapse after allogeneic HSCT Sarah Cannon Research Institute 6 BI (PD-1 mab) in combination with BI (LAG-3 mab), and BI (SMAC mimetic) for multiple cancers, including NSCLC Eli Lilly 3 Novel combination therapy for HR+/HER2 mbc: xentuzumab with Lilly s CDK4/6 inhibitor abemaciclib will be investigated ViraTherapeutics 7 Development of next generation oncolytic virus therapy platform AML, acute myeloid leukaemia; BI, Boehringer Ingelheim; CD, cluster of differentiation; CDK, cyclin-dependent kinase; HER2, human epidermal growth factor receptor 2 negative; HR+, hormone receptor positive; HSCT, haematopoietic stem cell transplantation; LAG-3, lymphocyte activation gene 3 protein; mab, monoclonal antibody; mbc, metastatic breast cancer; mrna-based ICV, messenger ribonucleic acid-based immunotherapeutic cancer vaccine; NSCLC, non-small cell lung cancer; PD-1, programmed cell death (Accessed: 20 February 2017); 2. (Accessed: 20 February 2017); 3. boehringer-ingelheim.com/pressrelease/boehringer-ingelheim-and-lilly-announce-clinical-trial-collaboration-metastatic-breast (Accessed: 20 February 2017); 4. (Accessed: 20 February 2017); (Accessed: 20 February 2017); 7. (Accessed: 20 February 2017).

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