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

2

Cancer Epigenetics

Cell & Gene Therapy

Immuno-Oncology

Reprogram cancer

cells

Stimulate anti-tumour

immunity

Cells as medicines

First-in-class medicines

Long-term survival &

cures

Combination therapy GS

K p

ipe

lin

e

Today CURE

SOC

replacements

Elimination of

chemotherapy

from SOC

regimens

Substantial survival

improvements

Across wide

populations

New

technologies

Expansion of the

toolbox

Complex

combinations

Maximise efficacy

Immune

profiling

Patient selection

to predict

response

Improved endpoints

Accelerated

development 3

Main Trends

Oncology – Pipeline Snapshot

4 † Collaboration with a third party.

Notch2/3 (tarextumab) † SCLC

BET inhibitor (GSK525762)

LSD-1 inhibitor (GSK2879552)

EZH2 inhibitor (GSK2816126)

Solid tumours, Heme Malignancies

AML, SCLC

Solid tumours, Heme Malignancies

PRMT5 inhibitor (GSK3326595) †

Solid tumours, Lymphoma

Novel small molecule targets

PI3K beta inhibitor (GSK2636771) Prostate cancer

CAR-T and TCR-Ts

NY-ESO-1 TCR-T † Sarcoma, Multiple Myeloma, NSCLC, Ovarian cancer, Melanoma

BCMA ADC (GSK 2857916) †

OX40 agonist (GSK3174998) † Solid tumours, Heme Malignancies

ICOS agonist (GSK3359609) †

TLR4 agonist (GSK1795091)

Novel small molecule targets

ImmTacs †

mAb-dAbs and dual-specific Abs

Solid tumours

Cancer

Multiple Myeloma

Immuno-Oncology

Epigenetics

Cell & gene therapy

Other targeted therapies

Mechanism Pre-clinical Phase I Phase II

5

Immuno-Oncology: 3 Generations of Therapies

Generation 1 Generation 2

PROVENGE

sipuleucel-T

(Cell Therapy)

YERVOY

ipilimumab (CTLA-4)

Generation 3

Multiple therapies

under

development

OPDIVO

nivolumab (PD-1)

2010 2011 2012 2015 2013 2014 2016 2017 2018 2019

KEYTRUDA

pembrolizumab (PD-1)

BLINCYTO

blinatumomab (BITE)

IMLYGIC

T-Vec (Oncolytic Virus) Under development

Approved

Hoos A, Nat Rev Drug Discov 2016

TECENTRIQ

atezolizumab (PD-L1)

3rd Generation Opportunities

Spectrum of immuno-oncology modalities

Cancer Vaccines

Cytokines

Cellular Therapies

T-cell Checkpoint Modulators

Oncolytic Viruses

NK Cells

Checkpoint Modulators

-

Adjuvants

“Connector” Bi-specific Abs -

Dual-specific Abs

Small Molecules

6

T-Cell Immunity

Innate Immunity

B-Cell Immunity

Adaptive Immunity

Approved therapies

3rd Generation Opportunities

GSK’s multi-modality pipeline

Cancer Vaccines

T-Cell Immunity

Cytokines

Cellular Therapies

T-cell Checkpoint Modulators

Innate Immunity

B-Cell Immunity

Adaptive Immunity

Oncolytic Viruses

NK Cells*

Checkpoint Modulators

-

Adjuvants

“Connector” Bi-specific Abs -

Dual-specific Abs

Small Molecules

GSK Pipeline 7 * in planning

B Cell maturation antigen (BCMA)

Antibody drug conjugate (ADC) with MMAF (auristatin derivative)

High-expression target in multiple myeloma and some NHL

Immunogenic cell death inducer

Phase I efficacy in refractory population: ~67% RR at > phase II dose

Next steps: - Rapid development for monotherapy - Combinations with SOC and novel agents

8

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%)

Safety observations:

Thrombocytopenia, transient

Corneal toxicity: dry eye, blurry vision, reversible

Phase I data presented at ASH December 2016

ASH: American Society of Hematology.

GSK2857916: First-in-class anti-BCMA-ADC,

proof of concept in multiple myeloma

GSK3174998 is one of several OX-40s in clinic

Dual mechanism: enhancing effector T-cell and suppressing T-regs

Phase I Study under way in eight cancers

Combination with Merck PD1 started 3Q16

Combination with GSK TLR4 expected to start in 2H2017

Collaboration with MD Anderson

GSK3174998 OX40 agonist mAb

aOX40

TLR4a

TLR4a / aOX40

control

Survival in animal model (CT26)

OX-40 + TLR-4

Pe

rce

nt su

rviv

al

Study day 0 50

0

50

100

100 150

Survival in animal model (CT26)

OX-40 + PD-1

control aPD-1

aOX40

aOX40 /aPD-1

Pe

rce

nt su

rviv

al

Time (days) 20 30 40 50 60

0

20

40

60

80

100

70 80 90

9 Source: GSK, data on file.

Uniquely engineered IgG4 mAb with agonist function and no cell depletion

Evolved from patient selection biomarker

Enhances T-cells associated with clinical benefit

Universal mechanism across multiple cancers: Phase I ongoing in 8 cancers

Possible use after CTLA-4 and PD-1 in unresponsive or refractory patients

Possible anchor for combinations: Expected start in combo with Merck PD-1 in 2Q17

GSK3359609 First-in-class ICOS agonist mAb

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ICOS in ipilimumab-treated patients GSK3359609

Cell

count/L

Ipilimumab Responders

Ipilimumab Non-Responders

Baseline W7 W12 W24 0

20

40

60

80 CD4 ICOS T cells

12 24 36 48 0

20

40

60

100

CD4 ICOS T cells

OS

(%

) 80

60

Time (months)

CD4 ICOS >4

0

CD4 ICOS ≤4

T cell Proliferation in-vitro

% o

f to

tal C

D4

T c

ells

ICOS Ab (ug/ml)

Ki67+ CD4 T cells 48hr after stimulation

0.01 0.1 1 10 100 0

5

10

15

20

25

% o

f to

tal C

D4

T c

ells

ICOS Ab (ug/ml)

T cell Activation in-vitro

CD69+ CD4 T cells 24hr after stimulation

0

20

40

60

80

100

0.01 0.1 1 10 100

DiGiacomo, Clin Immunol Immunother 2013

GSK1795091: TLR4 agonist

Pre-clinical combination synergy

TLR4 + OX40

TLR4 + ICOS

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Glycolipid TLR-4 agonist compound

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

Activates dendritic cells and innate immunity, positively modulates tumour microenvironment

Strong combination potential with several IO agents

Potential mechanistic synergies with OX40 and ICOS agonist mAbs

TCR T-cell therapy

50% ORR in synovial sarcoma

Ongoing studies in myeloma, ovarian cancer and other solid tumours

Planned studies in combination with checkpoint modulators

FDA Breakthrough designation

EMA PRIME designation

Collaboration with Adaptimmune

NY-ESO-1 TCR-T Cell Therapy

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Baseline Day 2: Inflammation Day 100: CR

Sarcoma Phase I/II: Best response in treated patients (N=12)*

Sarcoma Phase I/II: Individual patient complete response (CR)

Note: GSK3377794 subject to exercise of option by GSK

Excludes 3 subjects who did not receive a T-Cell Infusion.

One subject with disease progression is excluded because lesion could not be measured *Subjects did not receive the target cell dose

Stable disease

-15 -16 -26

-50 -55

-64 -58

-100

-70

15 17

Subject number

Confirmed complete or partial response

261* 230 206* 207 200 204 202 209 205 208 201

Best response

-120

-100

-80

-60

-40

-20

0

20

40

60

Cha

ng

e in

ta

rge

t le

sio

n fro

m

ba

se

line

(%

)

Source: GSK, data on file.

Partnerships

GSK partnerships in Cell Therapy and Clinical Translational Research

13

And others…

Cell Therapy Oncology Clinical & Translational Consortium

13

Dhanak et al Nature, 2013

14

Epigenetics clinical programs

LSD1 EZH2

PRMT5 BET

‘762 Blocks binding of BET family proteins (BRD2, 3 and 4) to acetylated histones

causing targeted changes in gene expression including oncogene silencing

Nature 2010;468:1119-1123

Preclinical data: Activity of GSK525762 in many cancer types (gIC50 < 1 M)

0.001

0.01

0.1

1

10

100

gIC

50, µ

M

15

Broad activity across multiple tumor types – preclinical cell line models

GSK525762: BET inhibitor

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† •Across all dose cohort (n=17):12% RR

•At 80/100 mg doses (n=9): 22% RR

Preliminary evidence of clinical activity in NUT midline carcinoma (NMC) (AACR 2016)

•Solid Tumor: CRPC and ER positive BC expansion cohorts completed; TNBC, SCLC, NMC cohorts ongoing

•Heme: Dose finding in AML completed; dose finding in NHL and MM ongoing; expansion cohorts commencing April 2017

•Anticipate presenting heme clinical data by YE 2017

Progress in Ph I since AACR 2016

•Pre-clinical data suggest combination synergy

•Combo in ER positive BC with fulvestrant (active)

•Combo in mCRPC with abiraterone or enzalutamide (start ~2Q)

•Other novel combos in 2017 and 2018

Expect start of combination studies in 2017

12 / 17 patients with NMC presented (5 non-evaluable ).

2 mg QD

4 mg QD

80 mg QD #5

80 mg QD #8

X

X

4 mg QD

16 mg QD

100 mg QD #1

80 mg QD #2

60 mg QD #4

100 mg QD #3

80 mg QD #7

80 mg QD #9

Study day

200

-40

100

80

60

40

20

0

-20

-60

-80

-100

Spider plot of % change from baseline in target lesion diameter

X

X X X

150

100 50 0

GSK525762: Potential First-in-class BET Inhibitor

Early clinical efficacy in NMC; Progress in many tumour types

Scientific Focus

• Optimise T-cell Immunity

• Re-program cancer cells

• Cells as medicines

• Synergies and transformational effects through combinations

Tactics

• Diversified pipeline

• Across key modalities

• Innovation

• 3rd generation targets, modalities & combinations

• Build world-class discovery and development team

• Fully-integrated programs from early discovery through licensure

• Partnerships

• Best science

• Access to combinations

Goals

• Transformational effects for patients

• Maximise survival

• Pipeline sustainability

• Long-term leadership position in Oncology

Mission: Maximise patient survival Achieve a long-term leadership position in Oncology

Oncology at GSK

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