axl inhibitors as cornerstone of combination cancer therapy1 axl inhibitors as cornerstone of...

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AXL inhibitors as cornerstone of combination cancer therapyFirst-in-class medicines to treat aggressive cancers

Third Annual Immuno-Oncology Summit Europe March 22nd 2018

Julia Schoelermann (PhD, MBA), Assoc. Dir BD & Partnering

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Disclaimer

Certain statements contained in this presentation constitute forward-looking statements. Forward-looking statements are statements that are not historical facts and they can be identified by the use of forward-looking terminology, including the words "anticipate", "believe", "intend", "estimate", "expect", "will", "may", "should" and words of similar meaning. By their nature, forward-looking statements involve a number of risks, uncertainties and assumptions that could cause actual results or events to differ materially from those expressed or implied by the forward-looking statements. Accordingly, no assurance is given that such forward-looking statements will prove to have been correct. They speak only as at the date of the presentation and no representation or warranty, expressed or implied, is made by BerGenBio ASA or its affiliates ("BerGenBio"), or by any of their respective members, directors, officers or employees that any of these forward-looking statements

or forecasts will come to pass or that any forecast result will be achieved and you are cautioned not to place any undue influence on any forward-looking statement. BerGenBio is making no representation or warranty, expressed or implied, as to the accuracy, reliability or completeness of this presentation, and neither BerGenBio nor any of its directors, officers or employees will have any liability to you or any other person resulting from the use of this presentation.

Copyright of all published material, including photographs, drawings and images in this presentation remain with BerGenBio and relevant third parties, as appropriate. Consequently, no reproduction in any form of the presentation, or parts thereof, is permitted without the prior written permission, and only with appropriate acknowledgements.

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Corporate snapshot

BackgroundLeaders in developing therapeutics that target AXL, a protein that makes cancers and their environment highly aggressive and which is associated with poorer outcomes across many cancers

Diversified pipeline, lead drug is tested in several indications of high unmet medical need and large market potential

Promising efficacy with sustained treatment benefit and confirmed favourable safety

Companion diagnostic supported by biomarker tests

Bemcentinib (BGB324)First-in-class highly selective small molecule AXL inhibitor

Broad phase II proof of concept clinical trials ongoing in NSCLC, TNBC, AML/MDS, melanoma.

PipelineBemcentinib (BGB324)

AXL antibody

AXL ADC (partnered)

Immunomodulatory small molecules

OSE:BGBIORaised $50m in IPO on OSE in April ’17

$320m market cap (Feb 18th 2018)

Corporate 35 staff

Headquarters and research in Bergen, Norway; Clinical Trial Management in Oxford, UK

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Antibody programs

BGB149 Oncology

BGB601(Partnered) Metastatic cancer

Discovery Pipeline – small molecule inhibitorsBGB002/BGB003 Oncology

Discovery Preclinical Phase I Phase II Phase IIIBemcentinib – Axl kinase inhibitor

NSCLC

adenocarcinoma

mutation driven

all comers*

TNBC

Melanoma*

AML / MDS

Advancing a broad development pipeline of innovative drugs

Small molecule

Anti-Axl mAb

ADC

Phase Ib / II – Single agent / Combination

Phase Ib / II – Combination with TARCEVA® (erlotinib)

Phase II Combination with KEYTRUDA® (pembrolizumab)


Phase II bemcentinib in combination with Docetaxel

Phase II bemcentinib in combination with current standard therapies, incl. CPIs

>350 Patients

*Investigator-sponsored trials

50 sites in Europe & US.

2018 Key read-outs:

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Discovery Preclinical Phase I Phase II Phase IIIBemcentinib – Axl kinase inhibitor

NSCLC adenocarcinoma

TNBC

Melanoma*

Three combination trials of bemcentinib with KEYTRUDA



Phase II bemcentinib in combination with current standard therapies, incl. CPIs

*Investigator-sponsored trials

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background bemcentinib Phase II PoC programme

T-cell

Successful anti-cancer therapies depend on both tumour antigenicity and immune system adjuvanticity

Tumour antigenicity /

immunogenicity

Immune system adjuvanticity

Anti-tumour therapy:• Chemotherapy• Radiotherapy• Targeted therapy• Oncolytic viruses• Anti-PD-L1

Tumour cell

DC

NKTNK

- Interferon mediated -anti-tumour immune reaction

Tumour clearance

7


T-cell

Successful anti-cancer therapies depend on both tumour antigenicity and immune system adjuvanticity

Tumour antigenicity /

immunogenicity

Immune system adjuvanticity

- Interferon mediated -anti-tumour immune reaction

Anti-tumour therapy Immune activating therapy

Tumour cell

DC

NKTNK

Tumour clearance

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AXL is negative feedback mechanism: drives cancer immune escape via tumour intrinsic survival programme & suppression of immune adjuvanticity

Tumour survival programme

(EMT)

Tumour cell

T-cell

Innate immune suppression

DC

NKTNK

- AXL mediated -tumour immune escape

Aggressive cancer

Survival programme (EMT):• Therapy resistance• Metabolic programming• Reduced immunogenicity:

• Biophysical• PD-L1• autophagy

Immune suppression• SOCS → ↓DC • M2 macrophages• Tregs• ↓MHC

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Successful cancer drug combination strategies…

AXL driven tumour cell plasticity and immune suppression is a negative feedback mechanism

Boost tumour antigenicity

Effectively address feedback inhibition

Boost immune adjuvanticity and concomitantly

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AXL receptor tyrosine kinase

bemcentinibbinds the internal

kinase domain

IG-like domains

FN domains

Kinase domain

Immunosuppression & therapy resistance

• Member of the TAM (Tyro-AXL-Mer) family

• Ubiquitously expressed at low levels

• Epigenetically upregulated upon immune reaction or cellular damage (e.g. anti-cancer therapy, hypoxia)

o Innate immune checkpointo Tumour cell pro-survival programme:

Ø Therapy resistanceØ Metabolic reprogrammingØ Reduced immunogenicity

• Only TAM member that correlates with aggressive cancers

AXL is a surface receptor tyrosine kinaseAXL antibody BGB149binds IG domain

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AXL signalling in DCs, via INF/STAT pathway, leads to

expression of DC negative regulators SOCS1/32

Antigen presentation by DCs (red) to T-

cells (green) is reduced when AXL is

active1

AXL is off-switch for DCs

AXL is an innate immune checkpoint facilitating immune escape

Innate immune activation through toll-like receptor (TLR) signalling

triggers AXL upregulation in DCs1

Ø miR-34a downregulates AXL

Ø ↓miR-34a à↑AXL

Source: (1) Kurowska-Stolarska et al Nature Comm 2017 (2) Rothlin et al Cell 2007

AXLactive inactive

Immune response trigger

DC

DC inactive

DC DC activeantigen presentation

to T-cells

Toll like receptor

signalling

AXL signalling

DC self-regulatory

cycle1

1

2

2

AXL off = DC on AXL on = DC off

AXL activation

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AXL drives tumour cell escape from checkpoint inhibitors

Source: Chouaib, 2014; Hugo, 2016

Checkpoint inhibitors (CPIs) work only in a small proportion of patients

% r

espo

nder

s vs

non

-re

spon

ders

0 %

20 %

40 %

60 %

80 %

100 %

NSCLC TNBC Renal Cancer Head & Neck Melanoma

Responders Non-responders

AXL upregulated in CPI resistant melanomaAXL

Axl driven tumour EMT prevents CTL killing of cancer cells

EpiEpi

Epi

AJAJ

AJ

ICAM

CTL

LFA1

IS

MHC-II

TCR

• Effective synapse

• Immune mediated cell death

Robust immunological synapse between CTL and epithelial tumour cell

CTL MES

• impaired synapse

• Immune evasion

Impaired immunological synapse between CTL & mesenchymal tumour cell

AXL

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AXL is detected in patient tumour and immune cells (BerGenBio) IHC assay

MethodsEstablishment of a validated, automated immuno-histochemistry (IHC) assay for the detection of AXL in human formalin-fixed paraffin-embedded (FFPE) tissue: IHC was implemented on the Discovery XT staining platform (Roche Diagnostics/Ventana Medical Sys-tems) using a rabbit monoclonal anti-AXL antibody. FFPE tissue samples and FFPE TMAs were sliced into 3-5 μm sections and mounted and the method was verified for linerity and precision using a semi-quantitative H-score performed by a pathologist. Between 28 and 33 patient samples of TNBC, adeno-carcinoma of the lung and squamous cell carcinoma, respectively, were pathologist scored for presence of AXL expression on either tumour tissue or tumour infil-trating immune cells.

Shown are squamous cell carcinoma FFPE patient samples stained for AXL (brown) as per BerGenBio’s proprietary AXL IHC assay

AXL expression in tumour adjacent alveolar macrophages

AXL expression in NSCLC patient tumour sample

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AXL is independent negative prognostic factor in a broad variety of cancers

1 Gjerdrum, 2010; 2 Ishikawa, 2012; 3 Ben-Battala, 2013; 4 Song, 2010, 5 supported by > 100 publications

Therapy resistance

Breast carcinoma1

Acute Myeloid Leukaemia3 Pancreatic ductal adenocarcinoma4

Lung adenocarcinoma (NSCLC)2Astrocytic brain tumors

Breast cancer

Gallbladder cancer

GI

• Colon cancer

• Esophageal cancer

• Gastric cancer

Gynaecological

• Ovarian cancer

• Uterine cancer

HCC

HNC

Haematological

• AML

• CLL

• CML

Months after primary treatment20 40 60 80 100

0

0.2

0.4

0.6

0.8

1

Prob

abilit

y of

sur

viva

l

AXL expressionLog Rank Test, P=0.035

Strong AXL (64/11)

Weak AXL (90/6)

0 24 36 48 600

20

40

60

80

100

12Months after operation

AXL IHC high (n=29)

AXL IHC low (n=59)

P <0.001

Time after diagnosis (years)0 4 8 12

0

20

40

60

80

100

Ove

rall

surv

ival

(%)

AXL > median

AXL < median

0 100 1500

20

40

60

80

100

50Time (months)

AXL IHC high (n=38)

AXL IHC low (n=16)

P=0.02

Ove

rall

surv

ival

(%)

Prob

abilit

y of

sur

viva

l

Strong AXL expression correlates with poor survival rate Broad evidence of AXL linked with poor prognosis5

Melanoma

Mesothelioma

NSCLC

Pancreatic cancer

Sarcomas

• Ewing Sarcoma

• Kaposis sarcoma

• Liposarcoma

• Osteosarcoma

Skin SCC

Thyroid cancer

Urological

• Bladder cancer

• Prostate cancer

• RCC

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Bemcentinib, first in class highly selective AXL inhibitor

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Bemcentinib is active throughout the complete cancer immunity cycle reversing immune suppression

Reversal of immune

suppression

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Bemcentinib is an immune modulator that enhances anti-tumourimmunity

Source: Ludvig, Cancer Research, 2017; Guo, OncoTarget, 2017

Cytokines that mediate immune suppression

• Recruitment (CCL2, CCL3, CCL4, CCL5) and

• Activity (CCL11, IL-7, IL-1β, and IL-6)

Bemcentinib decreases immune suppression

• Recruitment (CXCL9, CXCL10 and CXCL11) and

• Functionality (IFN-γ, IL-12p40, T-bet)

While enhancing T cell responses

T cell activity increased T cell activity increased

CCL11

Cntl Gem BGB Combo

1750150012501000750500250

0

pg/m

L

IL-710

5

0

pg/m

L

Cntl Gem BGB Combo

IL-1β50

40

30

20

10

0

pg/m

L

Cntl Gem BGB Combo

IL-6350300250200150100500

pg/m

L

Cntl Gem BGB Combo

MyeloidSuppression decreased

MyeloidSuppression decreased

IC8 ovarian carcinoma

Vehiclebemcentinib

Vehiclebemcentinib

Pancreatic model

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Bemcentinib is an immune modulator that enhances anti-tumourimmunity

Source: Guo, OncoTarget, 2017

ID8 ovarian carcinoma, 5 day bemcentinib monotherapyVehiclebemcentinib

Increased T Cell infiltration Increased T cell proliferation Increased T cell activity

Decreased myeloid

suppressors

Increased dendritic

cells

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Bemcentinib therapy targets immune suppressive M-MDSC and tumor associated macrophages

Source: Ludvig et al., Can Research, 2017

bemcentinib monotherapy (2 wk) PDAC cells (subQ)Monocytic myeloid-derived suppressor cell immature myeloid cells with pathologic activation, immune suppressive

Tumour associated macrophagePro-tumoural macrophage, promote proliferation, invasion, and metastasis of tumour cells, and inhibit T cell response

ArginaseMetabolises L-arginine to L-ornithine and urea - myeloid cell arginase-mediated L-arginine depletion suppresses T cell responses

M-MDSC

TAM

Arg1

Source: Ludvig, Cancer Research, 2017

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Bemcentinib promotes dendritic cell tumour-infiltration and activation

ID8 ovarian carcinoma, 5 day bemcentinib monotherapy

Control bemcentinib

Source: Guo, OncoTarget, 2017

Control bemcentinib Control bemcentinib

Peripheral, cross-presenting dendritic cell (DC)

Mature DC

IL-12 secreting DC

CD103+ DC

CD40+CD86+ DC

IL-12p40+ DC

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Orthotopic 4T1 in Balb/c

! CTLA4/PD1 CTLA4/PD1 + BGB324!Lung Liver Spleen Lung Liver Spleen

Non-responders! 11/15 10/15 12/15 14/16 9/16 10/16

Responders! 0/1 0/1 0/1 3/8 0/8 1/8

!!! CTLA4 CTLA4 + BGB324!

Lung Liver Spleen Lung Liver Spleen Non-responders! 6/8 5/8 5/8 6/7 5/7 4/7

Responders na na na 0/2 0/2 0/2

!

P=0.0009P=0.006 P=0.02

Bemcentinib enhances immune checkpoint inhibitor efficacyM

emb

ran

e ex

pre

ssio

n

AX

L

0

2

4

6

8

10

CTLA4/P

D-1

Control

Source: Davidsen ,Wnup-Lipinska, et al, in prep

100

Perc

ent s

urvi

val

50

00 10 20 30 40 50

Time (days)

Anti-CTLA + Anti-PD1 + bemcentinibAnti-CTLA-4 + Anti-PD1Control

re-challenge

Checkpoint inhibitor treatment induces aggressive tumour AXL

programmeAbrogation of metastases in

respondersDurable response to bemcentinib +

CPI treatment

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Bemcentinib phase II PoCprogramme:

designed to evaluate potential of bemcentinib to increase efficacy of anti-cancer therapies

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Bemcentinib recently reported interim PoC Phase II data

Bemcentinib (BGB324) foundation therapy

monotherapy

BGBIL006: Melanoma

BGBC007: TNBC

BGBC008: NSCLC

BGBC004: NSCLC

BGBIL006: Melanoma

BGBIL005: NSCLC

BGBC003: AML

BGBC003: AML/MDS

+ chemotherapy+ checkpoint inhibitors + targeted therapy

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AXL inhibition to increase efficacy of anti-PD-1 therapy

BGBC007, BGBC008, BGBIL006

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science bemcentinib Phase II PoC programme

Combination with bemcentinib to increase efficacy of anti-PD1 therapy

BerGenBio trials including anti-PD1 therapy

TNBCNSCLC Melanoma

2nd line (no prior CPIs) 1st & 2nd line2nd line

(no prior CPIs)

Combination therapy: bemcentinib + KEYTRUDA to increase response rates

AXL driven immune evasion and drug resistance

• A significant proportion (up to 95% in 2L TNBC) of patients do not respond to checkpoint inhibitor therapy

• Non-responders to checkpoint therapy have been shown to express AXL at higher rates

• Inhibiting AXL may increase the number of patients responding to checkpoint therapy

• Comprehensive biomarker programme analysing AXL, PD-L1 and immune signature

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ASCO-SITC Clinical IO Symposium 2018Favourable safety reported for bemcentinib / pembro combo across all three trials

Source: Yule et al ASCO-SITC Clinical IO Symposium (January 2018)

• 34 patients evaluable for safety

• SAE profile of combination similar to pembro alone

TNBCNCT03184558

NSCLCNCT03184571

Melanoma*NCT02872259 total

19 9 6 34

SOC n n n n %

Skin and subcutaneous tissue disorders 4 0 0 4 12

General disorders and administration site conditions 3 0 1 4 12

Gastrointestinal disorders 3 0 0 3 9

Investigations 3 3 9

Blood and lymphatic system disorders 1 0 0 1 3

Cardiac disorders 1 0 0 1 3

Hepatobiliary disorders 0 1 0 1 3

Respiratory, thoracic and mediastinal disorders 1 0 0 1 3

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BGBC008 trial in NSCLCKeytruda monotherapy showed 18% response rate in previously treated NSCLC patients. PD-L1 negative patients remain particularly challenging.

The BGBC008 trial is designed to test the hypothesis whether AXL inhibition can

Enhance responses to immunotherapy

when given in combination with pembrolizumab in previously treated, immunotherapy-naïve NSCLC patients.

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Bemcentinib increases immune checkpoint inhibitor efficacy in NSCLC models in vivo

Bemcntinib reverses CPI induced EMT

0.7

0.8

0.9

1.0

1.1

1.2

0.0

0.5

1.0

1.5Vimentin N-cadherin

mR

NA

fold

cha

nge

(rela

tive

to c

ontro

l)

mR

NA

fold

cha

nge

(rela

tive

to c

ontro

l)

Bemcentinib PD1/PDL1 Bemcentinib + PD1/PDL1 Bemcentinib PD1/PDL1 Bemcentinib +

PD1/PDL1

**

Tum

our v

olum

es (m

m3 )

0

300

600

900

1200

1500

1800

Control Bemcentinib PD1/PDL1

PD1/PDL1Bemcentinib

Bemcentinib increases CPI efficacy

Source: Wnuk-Lipinska et al AACR 2017 – LLC model

*******

****

0

0.5

1

1.5

2

2.5

CD

3+

CD

8+

CD

4-

Control BGB324PD1/PDL1PD1/PDL1BGB324

Tumour CTLs

*******


0

0.5

1

1.5

2

2.5

CD

3+

NK

p4

6+ 3

3.5

NKT cells

*

mMDSCs


0

20

40

60

CD

11

b+

Ly6

G L

y6C

hig

h

Bemcentinib reverses immunosuppression in tumour microenvironment

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BGBC008: Phase II trial in NSCLC of bemcentinib in combination with KEYTRUDA

BGBC008 Phase 2 – NSCLC Adenocarcinoma of the lung

Initial read-out expected 2H 2018

Previously treated, unresectable adenocarcinoma of the lung

up to 48 ptsany PD-L1 expressionany AXL expressionno prior IO

Simon two stage (interim after 22 pts)

ORR

Safety, DoR, TtP, OS at 12 mo, response by biomarker expression

Expected readout

Single arm

bemcentinib 200mg/dKeytruda 200mg/3w

Mandatory pre-treatment biopsies

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BGBC007 trial in TNBCKEYTRUDA monotherapy showed 4% response rate in previously treated TNBC patients.

The BGBC007 trial is designed to test the hypothesis whether AXL inhibition with bemcentinib can

Enhance responses to immunotherapy

when given in combination with pembrolizumab in previously treated, immunotherapy-naïve TNBC patients.

Clinical collaboration with Merck & Co. (MSD)

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Bemcentinib increases immune checkpoint inhibitor efficacy in TNBC models in vivo

Bemcntinib reverses CPI induced EMT – correlates with response Bemcentinib increases CPI efficacy

Source: Wnuk-Lipinska et al AACR 2017 – 4T1 model

Bemcentinib reverses immunosuppression in tumour microenvironment

0

2

4

6

8

10

mR

NA

fold

cha

nge

(rel

ativ

e to

Ctrl

)

Non-responders Responders

*

0

2

4

6

8 Non-responders Responders

mR

NA

fold

cha

nge

(rel

ativ

e to

Ctrl

)

VimentinAXL

CTLA4/PDL1 Bemcentinib + CTLA4/PDL1 CTLA4/PDL1 Bemcentinib +

CTLA4/PDL1

0 10 20 30 40 50 60 70 130 140 1500

50

100

*********

control

Bemcentinib mono

anti-CTLA4/PD-1

anti-CTLA4/PD-1 + bemcentinib

0

2

4

6

CD

3+,

CD

8a

+,

CD

4-

Ctr Bemcentinib CTLA4/PD1

CTLA4/PD1Bemcentinib

Tumour CTLs

0

0.02

0.04

0.06

0.08

0.10

CD

4- , C

D3

- , N

Kp

46

+ 0.12

Tumour NK cells

splenicmMDSCs

0

2

0

6

CD

11

b+,

Ly6

G,

Ly6

Ch

igh

Ctr Bemcentinib CTLA4/PD1

CTLA4/PD1Bemcentinib Ctr Bemcentinib

CTLA4/PD1CTLA4/

PD1Bemcentinib

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BGBC007: Phase II trial in TNBC of bemcentinib in combination with KEYTRUDA

BGBC007 Phase 2 – TNBC


Previously treated, unresectable or metastatic TNBC

up to 56 ptsany PD-L1 expressionany AXL expressionno prior IO

Simon two stage (interim after 28 pts)

ORR


Expected readout

Single arm

bemcentinib 200mg/dKeytruda 200mg/3w

Mandatory pre-treatment biopsies

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BGBIL006 trial in melanomaAlthough responses to TKIs are rapid, resistance ultimately emerges. Monotherapy checkpoint inhibitor responses can be further improved.

The BGBIL006 trial is designed to test the hypothesis whether AXL inhibition can

Enhance responses to immunotherapyEnhance responses to targeted therapy

when given in combination with pembrolizumab or dabrafenib/trametinib in treatment naïve melanoma patients

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Dabrafenib+trametinib

+/- bemcentinib200mg/d

Treatment naïve,

BRAF mutant (high tumourburden)

up to 40 pts

BRAF mutation driven

any AXL expression

BGBIL006 : Randomised Phase II trial of BGB324 in combination with targeted and I/O therapies in Melanoma

Source: Straume et alWorld Conference on Melanoma (October 2017)

BGBIL006 Phase II – Melanoma, randomised SoC (Keytruda or BRAF/MEKi) +/- BGB324


First Line

ORR


Expected readoutEndpointsSecond Line

Pembrolizumab200mg/3w


Dabrafenib+trametinib


Pembrolizumab 200mg/3w


R

Treatment naïve,

BRAF mutant (low tumourburden), BRAF-

up to 40 pts

any AXL expression

any PD-L1 expression

R

*

* Only BRAF mutant pts will be allowed to cross-over at progression on first line KEYTRUDA +/- bemcentinib)

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Summary

The potential of bemcentinib to enhance efficacy of KEYTRUDA is being explored in three phase II trials in NSCLC, TNBC and melanoma with interim readouts expected during the coming months

AXL drives tumour immune evasion & immune suppression = negative feedback

Bemcentinib synergises with ICB in preclinical models

Bemcentinib is a first-in-class selective AXL inhibitor in phase II clinical development

Interim PoC clinical data available for bemcentinib monotherapy and in combination with targeted- and chemotherapy

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Thank you.For further information please visit www.bergenbio.com

axl inhibitors as cornerstone of combination cancer therapy1 axl inhibitors as cornerstone of...

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