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

▶
gsk oncology
SMART_READER_LITE
LIVE PREVIEW

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

Nov 29, 2023 135 likes •310 views

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

slide-1
SLIDE 1

GSK Oncology

Axel Hoos, MD, PhD Senior Vice President, Oncology R&D

March 8, 2017

slide-2
SLIDE 2

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

GSK pipeline

slide-3
SLIDE 3

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

slide-4
SLIDE 4

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

slide-5
SLIDE 5

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)

slide-6
SLIDE 6

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

slide-7
SLIDE 7

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

slide-8
SLIDE 8

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

slide-9
SLIDE 9

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 Percent survival

Study day

50 50 100 100 150

Survival in animal model (CT26) OX-40 + PD-1

control aPD-1 aOX40 aOX40 /aPD-1

Percent survival

Time (days)

20 30 40 50 60 20 40 60 80 100 70 80 90 9 Source: GSK, data on file.

slide-10
SLIDE 10

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

10

ICOS in ipilimumab-treated patients GSK3359609

Cell count/L

Ipilimumab Responders Ipilimumab Non-Responders Baseline W7 W12 W24 20 40 60 80

CD4 ICOS T cells

12 24 36 48 20 40 60 100

CD4 ICOS T cells OS (%)

80 60 Time (months)

CD4 ICOS >4 CD4 ICOS ≤4

T cell Proliferation in-vitro

% of total CD4 T cells

ICOS Ab (ug/ml)

Ki67+ CD4 T cells 48hr after stimulation

0.01 0.1 1 10 100 5 10 15 20 25

% of total CD4 T cells

ICOS Ab (ug/ml)

T cell Activation in-vitro

CD69+ CD4 T cells 24hr after stimulation

20 40 60 80 100 0.01 0.1 1 10 100

DiGiacomo, Clin Immunol Immunother 2013

slide-11
SLIDE 11

GSK1795091: TLR4 agonist

Pre-clinical combination synergy TLR4 + OX40 TLR4 + ICOS

11

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

slide-12
SLIDE 12

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

12

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

20 40 60

Change in target lesion from baseline (%)

Source: GSK, data on file.

slide-13
SLIDE 13

Partnerships

GSK partnerships in Cell Therapy and Clinical Translational Research

13

And others…

Cell Therapy Oncology Clinical & Translational Consortium

13

slide-14
SLIDE 14

Dhanak et al Nature, 2013 14

Epigenetics clinical programs

LSD1 EZH2 PRMT5 BET

slide-15
SLIDE 15

‘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

gIC50, µM

15

Broad activity across multiple tumor types – preclinical cell line models

GSK525762: BET inhibitor

slide-16
SLIDE 16

16

†

  • 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

  • 20
  • 60
  • 80
  • 100

Spider plot of % change from baseline in target lesion diameter

X X X X

150 100 50

GSK525762: Potential First-in-class BET Inhibitor

Early clinical efficacy in NMC; Progress in many tumour types

slide-17
SLIDE 17

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

17