targeting critical immune drivers of cancer and inflammation · 2019. 5. 24. · 8 ©2019 flx bio...
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©2019 FLX Bio Inc.
Targeting Critical Immune Drivers of Cancer and Inflammation37th Annual J.P. Morgan Healthcare Conference
January 2019
©2019 FLX Bio Inc.2
FLX Bio: Unique Approach to Targeting Critical Immune Drivers of Cancer and Inflammation
▪ Robust pipeline of first-in-class oral small molecule agents▪FLX475 (Cancer): Selectively targeting tumor Treg in Phase 1/2 oncology study
mono/combo with Keytruda®
▪FLX193 (Allergy): Targeting validated Th2 pathway
▪GCN2 Program (Cancer)
▪HPK1 Program (Cancer)
▪ Growing pipeline driven by big data and machine learning
▪ Predictive biomarker approach to patient selection
▪ Supported by top tier investors, strong management team and a world-class SAB
©2019 FLX Bio Inc.3
FLX Bio Pipeline: Best-in-Class Compounds Targeting Critical Immune Drivers
P R O G R A M D I S C O V E R Y P R E C L I N I C A L P H A S E 1 P H A S E 2
FLX475 (CCR4) Cancer
FLX193 (CCR4) Inflammation
GCN2 Cancer
Discovery Targets(HPK1 & other undisclosed)
Monotherapy
Atopic Dermatitis
PD1 Combination
Asthma
©2019 FLX Bio Inc.4
FLX475: CCR4 Antagonist for CancerBest-in-Class Oral CCR4 Antagonist That Selectively Blocks Tumor Treg with Phase 2 Readout in 2019
©2019 FLX Bio Inc.5
CCR4 Protein on Treg Cells Drives Tumor Progression
▪Regulatory T cells (Treg) are critical drivers of immune suppression in tumor
▪Treg recruited into tumor by CCR4; suppress beneficial CD8 T cells
▪CCR4 antagonism blocks Treg recruitment and enhances tumor immunity
▪Highly selective approach to target tumor Treg without resorting to cell depletion
Treg
CCR4
CD8 T Cell
Anti-tumor immunity
Cancer
©2019 FLX Bio Inc.6
FLX475: Most Selective Approach to Targeting Tumor Treg
▪Potently binds to CCR4
▪Blocks interaction with ligands CCL22 and CCL17
▪Selectively inhibits Treg recruitment in tumor microenvironment ▪ Decreases tumor Treg without affecting Treg
in healthy tissues
▪ No impact on beneficial immune cells needed for anti-tumor response
▪Potential both as single-agent and in combination
Treg
CCL22
CCR4
CD8 T cell
Tumor
CCL17
©2019 FLX Bio Inc.7
FLX475: Excellent Exposure & Safety in Healthy Volunteer Study
▪ 75 mg QD exceeded target exposure corresponding to 90% inhibition of Treg recruitment and preclinical efficacy
▪No autoimmunity or immune-related AEs ▪ No changes in peripheral immune cell
populations
▪No significant clinical AEs or laboratory changes
▪No significant QTc prolongation at projected efficacious exposures
High Trough Exposures Excellent Safety Profile
0 5 10 150
100
200
300
24 hour Exposure Levels
Day
FL
X4
75 (
ng/m
L)
25 mg QD
50 mg QD
75 mg QD
Projected Efficacious Exposure
FLX
47
5 (
ng
/mL)
300
200
100
0
Day0 5 10 150 5 10 15
0
100
200
300
24 hour Exposure Levels
Day
FL
X4
75 (
ng/m
L)
25 mg QD
50 mg QD
75 mg QD
25 mg QD
50 mg QD
75 mg QD
©2019 FLX Bio Inc.8
FLX475: Strong Single Agent Activity in Preclinical Models
▪ Single agent efficacy in tumor model with high CCR4 ligand expression at baseline (Pan02)
Single Agent Efficacy
0
40
80
120
160 * *
CD8: Treg Ratio
Veh CCR4Antag
CPI Comb0 20 40 600
200
400
600
800
Days post-inoculation
Tu
mo
r V
olu
me (
mm
3)
0 20 40 600
200
400
600
800
Days post-inoculation
Tu
mo
r V
olu
me (
mm
3)
0 20 40 600
200
400
600
800
Days post-inoculation
Tu
mo
r V
olu
me (
mm
3)
0 20 40 600
200
400
600
800
Days post-inoculation
Tu
mo
r V
olu
me (
mm
3)
CD
8 :
Tre
gR
atio
Days Post-Inoculation
Tum
or
Vo
lum
e (
mm
3) 800
600
400
200
00 20 40 60
0 20 40 600
200
400
600
800
Days post-inoculation
Tu
mo
r V
olu
me (
mm
3) Vehicle
FLX CCR4 Antagonist
Checkpoint Inhibitor
Combination
Vehicle
FLX CCR4 Antagonist
Checkpoint Inhibitor
Combination
***
*
©2019 FLX Bio Inc.9
FLX475: Robust Combination Activity in Preclinical Models
▪ Robust combination activity in tumor models with checkpoint inhibitor-induced CCR4 ligand expression (CT26)
0 10 20 300
500
1000
1500
Me
dia
n T
um
or
Vo
lum
e (
mm
3)
Vehicle
Checkpoint Inhibitor
Checkpoint + CCR4 Antag.
1/10 Tumor-Free
5/10 Tumor-Free
Activity in Combo with Checkpoint Inhibitor
CCR4 Ligand Expression in CT26 Tumors
0
20000
40000
60000
Tota
l CC
L22
in T
um
or
lysa
te (
pg)
Vehicle Checkpoint Inhibitor Days Post Inoculation
Treatment initiation
***
©2019 FLX Bio Inc.10
FLX475: Big Data Analysis Identified “Charged” Tumors Most Likely to Respond
▪“Charged” tumors: Tumors expressing high levels of CCR4 ligands and Treg
▪ Non-Small Cell Lung Cancer
▪ Triple Negative Breast Cancer
▪ Head and Neck
▪“Charged” tumors tend to be “hot” with high levels of Treg likely holding back the anti-tumor immune response
**Data from in-house analysis of TCGA database; Confirmed in > 400 tumor microarrays
“Heat” (CD8 Signature)
T re
g(F
OX
P3
)
Cervical
Lung SC
Lung AD
H&N
Breast
Esophageal
Gastric
©2019 FLX Bio Inc.11
Prospectively-Selected “Charged” Tumors Include EBV and HPV-Associated Tumors
▪ High concordance of EBV and CCL22
▪ Similar pattern for CCL17
▪Prospectively-selected “charged” tumors identified using big data and confirmed using in situ hybridization
▪EBV and HPV directly drive CCR4 pathway to recruit Treg
▪ Nasopharyngeal (EBV+)
▪ Hodgkin Lymphoma (EBV+)
▪ Cervical, Oropharyngeal cancers (HPV+)
▪Potential for accelerated approval in tissue-agnostic cancers
Hodgkin LymphomaIn situ hybridization
Nuclear Stain
EBER1
CCL22
©2019 FLX Bio Inc.12
Addressable Opportunity: “Charged” Cancers
Additional Upside in 1st Line Patients
Addressable Opportunity: Charged TumorsMetastatic, second-line+ patients in NSCLC, H&N, TNBC
Addressable Opportunity: EBV/HPV TumorsMetastatic, second-line+ patients in NPC, GC, cHL, Cervical
US/EU5 Japan China Total
13,271
113,348
Rest of Asia
13,816
51,335
34,926
NSCLC H&N TNBC Total
43,347
34,393
14,852
15,306
12,333
14,349
77,740
30,158
26,682 134,580
EU5
US
©2019 FLX Bio Inc.13
FLX475 Monotherapy
FLX475 + Keytruda®
FLX475 Phase 1/2 Trial: Seamless, Rapid Path to PoC in 2019
▪ Phase 2: Gated 2-stage design, PoC in 2019, biomarkers, ORR
▪ EBV+/HPV+ tumors▪ Charged tumors
Phase 1 Dose Escalation Phase 2 Dose Expansion
~18-24 patients
▪ Charged tumors
80 patients
▪ Charged tumors▪ EBV+/HPV+ tumors
1Q
20
19
4Q
20
19
Po
C
Additional Expansion
Additional Expansion
Escalating Dose
Escalating Dose
FLX475 Monotherapy
FLX475 + Keytruda®
▪ Phase 1: Safety, PK/PD, biomarkers, overall response rate (ORR)
©2019 FLX Bio Inc.14
FLX475: Best-in-Class CCR4 Inhibitor with Phase 2 PoC in 2019
▪Highly specific tumor Treg inhibitor spares normal tissues and beneficial immune cells
▪ Excellent PK/PD and safety with oral dosing
▪ Phase 1/2 study with prospective patient selection and efficacy readout in 2019
▪Data supports development as single agent and in combination therapy with multiple IO agents
▪Wholly-owned IP, long patent life
©2019 FLX Bio Inc.15
FLX193: CCR4 Antagonist for Allergic DisordersBest-in-Class Oral CCR4 Inhibitor In Highly Validated Pathway for Allergic Disorders with Phase 2 Readout 1Q20
©2019 FLX Bio Inc.16
CCR4 Protein on Th2 Drives Allergic Inflammation
▪CCR4 recruits Th2 cells into tissues and drives allergic inflammation
▪CCR4 antagonist suppresses allergic inflammation
▪Pathway highly validated with approved biologics
IL-4IL-5IL-13
Eosinophilia
High IgE
Skin and airway thickening
Atopic Dermatitis, Asthma
Th2
CCR4
©2019 FLX Bio Inc.17
FLX193: Second CCR4 Molecule Advancing in Allergic Disorders
▪Highly potent oral CCR4 antagonist targeting allergic disorders: atopic dermatitis, asthma, others
▪Oral convenience provides substantial competitive advantage to injectables and topical agents
▪Rapid path to clinical proof of concept
©2019 FLX Bio Inc.18
FLX193: Efficacious in Th2-Driven Inflammation Preclinical Model
24 Hrs After Day 23 ChallengeBALF Collection and Cell Count
Sensitisation Day 1
OVA ChallengeDays 20-23
p.o. compound Days 19 - 23
Boost Day 14
Allergic Airway Inflammation Model
0
5 0
1 0 0
1 5 0
I L - 1 3
G r o u p s
IL
-1
3
[p
g/
ml
]
V e h i c l e
O V A
F L X 1 9 3 [ 3 0 m g / k g ]
F L X 1 9 3 [ 1 0 0 m g / k g ]
******
IL-13
IL-1
3 p
g/m
l
0
1 0 0
2 0 0
3 0 0
4 0 0
I L - 5
G r o u p s
IL
-5
[
pg
/m
l]
V e h i c l e
O V A
F L X 1 9 3 [ 3 0 m g / k g ]
F L X 1 9 3 [ 1 0 0 m g / k g ]
****
*
IL-5
IL-5
pg/
ml
0
2
4
6
8
E o s i n o p h i l s
G r o u p s
Eo
si
no
ph
il
s
in
BA
LF
[
x1
06
]
V e h i c l e
O V A
F L X 1 9 3 [ 3 0 m g / k g ]
F L X 1 9 3 [ 1 0 0 m g / k g ]
Eosinophils
Eosi
no
ph
ils (
x10
6) **
©2019 FLX Bio Inc.19
FLX193 MAD FLX193 AD
• Mod-Severe AD• Readout 4 weeks
~20-30 AD Patients~40-50 HV
Phase 1a/1b Healthy Volunteer/Atopic Dermatitis Study
Phase 2a/2b Studies
Phase 2 Atopic Dermatitis
Phase 2 Allergic Asthma
Other Allergic Disorders
Escalating Dose
Escalating Dose
FLX193: Clinical Plan
PoC
(mid
-20
20
)
▪ Phase 2: Studies in AD, asthma, and other allergic disorders
▪ Phase 1a/1b: Safety, PK/PD, PoC in small atopic dermatitis (AD) cohort
FLX193 SAD
©2019 FLX Bio Inc.20
FLX193: Potentially Disruptive Convenience and Safety Profile
Atopic Dermatitis (AD) US Prevalence**
**2018 Data, Decision Resources
Mild AD~40%
Severe AD~24%
Moderate AD~36%
48%
FLX193 Target Population
Total US AD Prevalence(~19 M)
US Diagnosed Prevalence(~9 M)
©2019 FLX Bio Inc.21
GCN2Targeting Key Metabolic Pressure Point in Tumor Microenvironment
©2019 FLX Bio Inc.22
GCN2: Key Driver of Immunosuppression in TME
▪TME harbors significant metabolic stress
▪GCN2: key target driving immunosuppression caused by metabolic stress
▪GCN2 inhibitors have potential to:▪ Reactivate the immune response
▪ Increase tumor cell death
▪ Act in the TME resulting in better therapeutic index
▪ Generate greater efficacy
▪Preclinical candidate 2Q19
Mellor and Munn, 2008; Ye et al, 2010; Wang et al, 2013
GCN2
CD8 T cell
Tumor Microenvironment
Decrease Survival and Tumor Killing
Increase Tumor
Survival
IncreaseImmune
Suppression
MDSC
↓Tryptophan↓ Arginine
↓ Asparagine ↓ Glucose
©2019 FLX Bio Inc.23
FLX GCN2 Inhibitor: Restores Human CD8 T Cell Proliferation and Effector Function in Presence of MDSCs
Tolerogenic MDSC Human CD8 cells
+/- GCN2i+ Assess T cell proliferation
and effector functions
CD8 T Cell
GCN2 Inhibitor Restores CD8 T Cell Proliferation
GCN2 Inhibitor Restores CD8 T Cell IFNg Expression
GCN2i
+ MDSC
0
20
40
60
80
%C
D8
a T
Ce
ll P
rolif
erat
ion
CD
8-F
ITC
IFNg-APC
Control +GCN2i
IFNg, CD8A Subset35.0
IFNg, CD8A Subset2.55
©2019 FLX Bio Inc.24
Key Upcoming Milestones
T I M I N GM I L E S T O N E S
F L X 4 7 5 F L X 1 9 3 G C N 2
20191H ▪ Ph 2 dose selection
(monotherapy & combo)▪ IND Filing
▪ Preclinical candidate selection
2H ▪ Ph 2 PoC ▪ First in humans study
2020
1H ▪ Additional expansion cohorts
▪ Clinical POC in Ph 1b ▪ IND filing
2H ▪ Initiate registrational studies
▪ Initiate Ph 2 in AD & additional indications
▪ First in humans
©2019 FLX Bio Inc.25
Management, Board, Advisors, & Investors
©2019 FLX Bio Inc.26
Alexander Rudensky, Ph.D.Chairman, FLX Scientific Advisory Board
Chairman, Immunology Program, Sloan-Kettering Institute,
Director, Ludwig Center at MSKCC; Member Natl. Acad. Sci.
Antoni Ribas, M.D., Ph.D.Professor, Medicine, Hematology/Oncology & Director,
JCCC Tumor Immunology, UCLA
Scott J. Antonia, M.D., Ph.D.Chair, Thoracic Oncology, H. Lee Moffitt Cancer Center and
Research Institute; Professor of Oncologic Sciences,
University of South Florida College of Medicine
Drew Pardoll, M.D. Ph.D.Professor, Johns Hopkins University, Director; Bloomberg-Kimmel
Institute for Cancer Immunotherapy
Philip Greenberg, M.D.Professor, Medicine (Oncology) &Immunology, University of
Washington; Head of Immunology, Fred Hutchinson Cancer
Research Center
Robert Zamboni, Ph.D.Adjunct Professor of Chemistry, McGill University;
Former VP of Research at Merck & Co.
David V. Goeddel, Ph.D.Founder & CEO Tularik; Founder & Partner The Column Group;
Member Natl. Acad. Sci.
World Class Scientific and Clinical AdvisorsLeading Clinicians and Scientific Researchers
©2019 FLX Bio Inc.27
Experienced Board of Directors & Strong Investor Base
David V. Goeddel, Ph.D. Managing Partner, The Column Group
Beth Seidenberg, M.D. General Partner, Kleiner Perkins
Linda KozickFormer VP and Head of Immuno-Oncology/Oncology Product & Portfolio Strategy, Bristol-Myers Squibb
Michael F. Giordano, M.D.Former SVP and Head of Development, Oncology & Immuno-Oncology, Bristol-Myers Squibb
William Rieflin, J.D. CEO, NGM Biopharmaceuticals Inc.
Brian Wong, M.D., Ph.D. CEO, FLX Bio
B O A R D O F D I R E C T O R S M A J O R I N V E S T O R S
©2019 FLX Bio Inc.28
Brian Wong, M.D., Ph.D. Chief Executive Officer
Rekha Hemrajani Chief Operating Officer
William Ho, M.D., Ph.D. Chief Medical Officer
Dirk Brockstedt, Ph.D. Senior Vice President of Biology
Paul Kassner, Ph.D.Vice President, Quantitative and Computational Biology
David Wustrow, Ph.D. Vice President, Drug Discovery
Proven Management Team
©2019 FLX Bio Inc.29
Thank You
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