GSK Oncology Axel Hoos, MD, PhD Senior Vice President, Oncology - PowerPoint PPT Presentation

GSK Oncology Axel Hoos, MD, PhD Senior Vice President, Oncology R&D March 8, 2017

Oncology R&D Strategy Maximizing survival through transformational medicines and combinations Cancer Epigenetics Reprogram cancer Long-term survival & cells cures Stimulate anti-tumour GSK pipeline immunity Cells as medicines Immuno-Oncology First-in-class medicines Combination therapy Cell & Gene Therapy 2

Main Trends SOC Immune New replacements profiling technologies Elimination of chemotherapy Patient selection Expansion of the from SOC to predict toolbox regimens response CURE Today Substantial survival Complex improvements combinations Across wide Maximise efficacy populations Improved endpoints Accelerated development 3

Oncology – Pipeline Snapshot Mechanism Pre-clinical Phase I Phase II OX40 agonist (GSK3174998) † Solid tumours, Heme Malignancies ICOS agonist (GSK3359609) † Solid tumours BCMA ADC (GSK 2857916) † Multiple Myeloma TLR4 agonist (GSK1795091) Cancer Novel small molecule targets Immuno-Oncology ImmTacs † Epigenetics mAb-dAbs and dual-specific Abs Cell & gene therapy BET inhibitor (GSK525762) Solid tumours, Heme Malignancies Other targeted therapies LSD-1 inhibitor (GSK2879552) AML, SCLC EZH2 inhibitor (GSK2816126) Solid tumours, Heme Malignancies PRMT5 inhibitor (GSK3326595) † Solid tumours, Lymphoma PI3K beta inhibitor (GSK2636771) Prostate cancer Novel small molecule targets NY-ESO-1 TCR-T † Sarcoma, Multiple Myeloma, NSCLC, Ovarian cancer, Melanoma CAR-T and TCR-Ts Notch2/3 (tarextumab) † SCLC 4 † Collaboration with a third party.

Immuno-Oncology: 3 Generations of Therapies Generation 2 Generation 3 Generation 1 Multiple therapies TECENTRIQ atezolizumab (PD-L1) under development YERVOY KEYTRUDA ipilimumab (CTLA-4) pembrolizumab (PD-1) 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 PROVENGE BLINCYTO sipuleucel-T blinatumomab (BITE) (Cell Therapy) OPDIVO nivolumab (PD-1) Approved IMLYGIC T-Vec (Oncolytic Virus) Under development Hoos A, Nat Rev Drug Discov 2016 5

3 rd Generation Opportunities Spectrum of immuno-oncology modalities Adaptive Immunity Innate Immunity T-Cell Immunity B-Cell Immunity Cytokines Cellular Therapies - NK Cells Cancer Vaccines T-cell Checkpoint Modulators Checkpoint Modulators “Connector” Bi -specific Abs - Dual-specific Abs Small Molecules Oncolytic Viruses Adjuvants Approved therapies 6

3 rd Generation Opportunities GSK’s multi -modality pipeline Adaptive Immunity Innate Immunity T-Cell Immunity B-Cell Immunity Cytokines Cellular Therapies - NK Cells* Cancer Vaccines T-cell Checkpoint Modulators Checkpoint Modulators “Connector” Bi -specific Abs - Dual-specific Abs Small Molecules Oncolytic Viruses Adjuvants GSK Pipeline * in planning 7

GSK2857916: First-in-class anti-BCMA-ADC, proof of concept in multiple myeloma All doses: ORR = 8/30 (27%; 95% CI: 12.3%, 45.9%) At >Ph2 dose 3.4 mg/kg: ORR= 6/9 ( 66.7 %; 95% CI: 0.29, 0.92%) B Cell maturation antigen (BCMA) High-expression target in multiple myeloma and some NHL Phase I data presented at ASH December 2016 Antibody drug conjugate (ADC) with MMAF (auristatin derivative) Immunogenic cell death inducer Phase I efficacy in refractory population: ~67% RR at > phase II dose Next steps: - Rapid development for monotherapy Safety observations: - Combinations with SOC and novel agents Thrombocytopenia, transient Corneal toxicity: dry eye, blurry vision, reversible ASH: American Society of Hematology. 8

GSK3174998 OX40 agonist mAb Survival in animal model (CT26) OX-40 + PD-1 GSK3174998 is one of several OX-40s in clinic 100 Percent survival 80 Dual mechanism: enhancing effector T-cell and aOX40 /aPD-1 60 suppressing T-regs 40 aOX40 20 Collaboration with MD Anderson aPD-1 control 0 20 30 40 50 60 70 80 90 Time (days) Phase I Study under way in eight cancers Survival in animal model (CT26) OX-40 + TLR-4 100 Percent survival Combination with Merck PD1 started 3Q16 TLR4a / aOX40 Combination with GSK TLR4 expected to start 50 in 2H2017 TLR4a aOX40 control 0 0 50 100 150 Study day 9 Source: GSK, data on file.

GSK3359609 First-in-class ICOS agonist mAb ICOS in ipilimumab-treated patients GSK3359609 Uniquely engineered IgG4 mAb with agonist CD4 ICOS T cells function and no cell depletion T cell Activation in-vitro 80 Cell count/  L % of total CD4 T cells 100 CD69+ CD4 T cells 24hr after stimulation 60 80 Evolved from patient selection biomarker 40 60 20 40 Enhances T-cells associated with clinical 0 20 Baseline W7 W12 W24 benefit 0 Ipilimumab Responders 0.01 0.1 1 10 100 Ipilimumab Non-Responders ICOS Ab (ug/ml) Universal mechanism across multiple cancers: T cell Proliferation in-vitro Phase I ongoing in 8 cancers CD4 ICOS T cells % of total CD4 T cells 100 Ki67+ CD4 T cells 48hr after stimulation 25 80 OS (%) Possible use after CTLA-4 and PD-1 in 20 CD4 ICOS >4 60 unresponsive or refractory patients 15 40 10 20 CD4 ICOS ≤4 Possible anchor for combinations: Expected 5 0 start in combo with Merck PD-1 in 2Q17 0 12 24 36 48 60 0 Time (months) 0.01 0.1 1 10 100 ICOS Ab (ug/ml) DiGiacomo, Clin Immunol Immunother 2013 10

GSK1795091: TLR4 agonist Pre-clinical combination synergy Glycolipid TLR-4 agonist compound TLR4 + OX40 Activates dendritic cells and innate immunity, positively modulates tumour microenvironment Strong combination potential with several IO agents TLR4 + ICOS Potential mechanistic synergies with OX40 and ICOS agonist mAbs Phase I in healthy volunteers under way to determine dose and PD effects Phase I combination with OX-40 in cancer patients expected to start 2H17 11

NY-ESO-1 TCR-T Cell Therapy Sarcoma Phase I/II: Individual patient complete response (CR) TCR T-cell therapy Baseline Day 2: Inflammation Day 100: CR 50% ORR in synovial sarcoma Ongoing studies in myeloma, ovarian cancer and other solid tumours 60 Sarcoma Phase I/II: Best response in treated patients (N=12)* Planned studies in combination with Change in target lesion from 40 Best response Stable disease Confirmed complete or partial response checkpoint modulators 17 15 20 baseline (%) 0 FDA Breakthrough designation -20 -15 -16 -26 -40 -50 EMA PRIME designation -60 -55 -58 -64 -70 -80 Excludes 3 subjects who did not receive a T-Cell Infusion. -100 One subject with disease progression is excluded because lesion could not be measured 
 -100 Collaboration with Adaptimmune *Subjects did not receive the target cell dose -120 261* 230 206* 207 200 204 202 209 205 208 201 Subject number Note: GSK3377794 subject to exercise of option by GSK 12 Source: GSK, data on file.

Partnerships GSK partnerships in Cell Therapy and Clinical Translational Research Cell Therapy Oncology Clinical & Translational Consortium And others… 13 13

Epigenetics clinical programs Dhanak et al Nature, 2013 EZH2 LSD1 BET PRMT5 14

GSK525762: BET inhibitor Broad activity across multiple tumor types – preclinical cell line models ‘762 Blocks binding of BET family proteins (BRD2, 3 and 4) to acetylated histones causing targeted changes in gene expression including oncogene silencing Preclinical data: Activity of GSK525762 in many cancer types (gIC50 < 1  M) 100 10 gIC50, µM 1 0.1 0.01 0.001 Nature 2010;468:1119-1123 15

GSK525762: Potential First-in-class BET Inhibitor Early clinical efficacy in NMC; Progress in many tumour types Spider plot of % change from baseline in target lesion diameter 100 Preliminary evidence of clinical activity in NUT midline carcinoma (NMC) (AACR 2016) 80 60 † • Across all dose cohort (n=17):12% RR 40 • At 80/100 mg doses (n=9): 22% RR 20 X X Progress in Ph I since AACR 2016 0 X X -20 • Solid Tumor: CRPC and ER positive BC expansion cohorts -40 completed; TNBC, SCLC, NMC cohorts ongoing • Heme: Dose finding in AML completed; dose finding in NHL and -60 MM ongoing; expansion cohorts commencing April 2017 -80 • Anticipate presenting heme clinical data by YE 2017 -100 0 50 100 150 200 Study day Expect start of combination studies in 2017 2 mg QD 4 mg QD 60 mg QD #4 • Pre-clinical data suggest combination synergy 4 mg QD 16 mg QD 100 mg QD #3 X 80 mg QD #5 100 mg QD #1 80 mg QD #7 • Combo in ER positive BC with fulvestrant (active) 80 mg QD #8 80 mg QD #2 80 mg QD #9 X • Combo in mCRPC with abiraterone or enzalutamide (start ~2Q) • Other novel combos in 2017 and 2018 12 / 17 patients with NMC presented (5 non-evaluable ). 16

Oncology at GSK Mission: Maximise patient survival Achieve a long-term leadership position in Oncology Scientific Focus Tactics Goals • Optimise T-cell Immunity • Diversified pipeline • Transformational effects for • Across key modalities patients • Maximise survival • Re-program cancer cells • Innovation • Pipeline sustainability • Cells as medicines • 3 rd generation targets, modalities & combinations • Long-term leadership position • Synergies and transformational • Build world-class discovery in Oncology effects through combinations and development team • Fully-integrated programs from early discovery through licensure • Partnerships • Best science • Access to combinations 17