Miles Congreve, Head of Discovery
Discovery of A2AR Antagonist HTL1071/AZD4635 using SBDD
NON-CONFIDENTIAL
June 2019 | © Heptares Therapeutics Ltd.
3
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Disclaimer
Introduction to GPCRs
4
Agenda
1
GPCR Platform
A2AR and Immuno-Oncology
Summary
2
3
4
5
Introduction to GPCRs
1
6
G Protein-Coupled Receptors (GPCRs) Super Family
• Highly important family of drug targets in industry
• 800 GPCRs including ~400 olfactory
• 225 with known ligands, 150 ‘orphan’ receptors
• Compelling biology across wide range of diseases
• Many valuable yet challenging targets still untapped
Many Top-Selling Drugs Hit GPCRs ~ 30% of ALL prescription drugs
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GPCR Targets as a Source of Drugs
Christopher et al. Med. Chem. Rev. 2018, 69
FIC vs BIC GPCR ApprovalsFDA Drug Approvals
• 116 GPCR targeted drugs over 20 year period (1995-2015)
• Including 43 different GPCR targets
• No decline in target class drug discovery success over time
• 25% new GPCR targeting approvals were for first in class therapies
• Majority of new GPCR approvals demonstrate improvements over existing agents (PK, selectivity & safety)
• However, many notable GPCR drug failures (efficacy & safety attrition) e.g. CB1 (obesity), CGRP (migraine), mGlu5 (Fragile X & depression), GPR40 (diabetes)
25%
22%
12%
10%
5%4%4%3%3%7%
5%
FIC PK Selectivity PolypharmacyCombination Toxicology CNS penetration Phys ChemReceptor kinetics Route Potency
28
53
39
3035
2724
1721
36
20 2218
24 2621
30
39
27
4145
3
11
3 52 4
7 5 4 4 5 4 511
4 5 36
38
14
0
10
20
30
40
50
60
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
20
09
20
10
20
11
20
12
20
13
20
14
20
15
Total GPCR
8
GPCR Platform
2
9
Key to our Structure-Based Drug Discovery (SBDD)The Stabilised Receptor (StaR®)
-10
10
30
50
70
-10 10 30 50 70
Drug Candidates
StaRUnstableNativeGPCR
FragmentScreening
X-rayCrystallography
Receptor Kinetics
• Native receptor spans cell membrane – highly unstable when removed
• Aggregates and loses function when purified
• 4-10 point mutations in GPCR stabilise it by 10-30ºC to create StaR
• Stabilised receptor (StaR) can be purified and retains function and shape
• StaR is basis for integrated structure/chemistry/pharmacology platform
• 60+ Stabilised Receptors generated representing targets in agonist and/or antagonist conformations
10
Step-wise Receptor EngineeringSosei Heptares Unique Stabilisation Platform
• Step-wise stabilisation results in evolution of the receptor towards improved thermostability and recovery upon solubilisation
• Process flexibility to “harvest” StaR proteins for different purposes
11
StaR® Technology reliably delivers X-ray structures Semi-automated scout purification of multiple constructs/conditions
Milligram quantities of up to 6 proteins in 24 hours
S
E
C
Express Membrane Solubilise Purify SEC LCP/VD Setup Crystals Optimise StructureUnstable
Native
GPCR
StaR
Screening: Fusions Positions Ligands Detergents
Crystals grown in lipidic cubic phase
12
GPCR Structures now possible with high resolution
• Excellent definition of ligand, side chains and waters at 1.7 Å resolution
• Highest resolution GPCR structure solved to date
13
New era of GPCR Structure-Based Drug Design
GPCR structures
Sosei Heptares >260 structures• Different pockets and ligand properties• Orthogonal sites of receptor modulation
PAR2
Cheng et al.,
Nature (2017)
CCR9
Oswald et al.,
Nature (2016)
GCGR
Jazayeri et al.,
Nature (2016)
CRF1
Hollenstein et al.,
Nature (2013)C5a
Robertson et al.,
Nature (2018)
GPCR binding mode diversity
14
A2AR and Immuno-Oncology
3
15
Multiple GPCR families are commonly associated with the immune systemGPCRs and Immunology
COMPLEMENT
FORMYL PEPTIDE
CHEMOKINE
ADENOSINE
NEUROKININ
HISTAMINE PARS
EICOSINOID
CANNABINOID
LYSOPHOPHOLIPID (S1P)
pH-SENSING
16
Antigen Presentation – T-cell Trafficking/Activation – Tumor MicroenvironmentThe Immune Response to Cancer
Adapted from Immunity 2013 39, 1-10DOI: (10.1016/j.immuni.2013.07.012
• Many human cancers exploit inhibitory “immune checkpoint pathways” to evade the anti-tumorimmune response.
• Immuno-oncology approaches seek to:
• Boost the presentation of cancer antigens to the immune system,
• Prime and activate the effector arm of the immune response,
• Augment migration of immune cells in to tumors
• Reduce activity of suppressor mechanisms
• High concentrations of adenosine in the tumormicroenvironment is a key immune inhibitory mechanism in many cancers
Tumor
Microenvironment
↓ immune cell suppression
↑ eff T-cellseT-cell
Treg
TAN
MDSC
TAM
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Role of adenosine in cancer immunotherapy
Computational and Structural Biotechnology Journal 13 (2015) 265–272
• Accumulation of extracellular
adenosine within the microenvironment is a strategy
exploited by tumors to escape
immune surveillance.
• Adenosine signaling through the high
affinity adenosine 2A receptor (A2AR) on immune cells elicits a
range of immunosuppressive effects
which can promote tumor growth and limit the efficacy of immune
checkpoint inhibitors.
• Blockade of the A2A receptor can
reverse adenosine mediated immune
suppression to enhance anti-tumorimmunity
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A2AR Historical Antagonists
Adapted from Manuel de Lera Ruiz; Yeon-Hee Lim; Junying Zheng; J. Med. Chem. 2014, 57, 3623-3650.Copyright © 2013 American Chemical Society
A2AR antagonism complementary approach to dopamine D2R agonism
for PD
19
Generation of A2A StaR® - Enabled SBDD
Segala et al. J. Med. Chem., 2016, 59, 6470–6479
• Excellent definition of ligand, side chains and waters at 1.7 Å resolution
• Perfect superposition of Sosei Heptares StaR structure (blue) with Stevens et. al. chimera structure (4EIY - red) with ZM241385 bound
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Adenosine A2AR Antagonist Hit ID
Langmead, C. et. al, J. Med. Chem., 2012, 55, 1904
N
N
N
NH2
S
CH3
OHN
N
N NH2
• A2AR homology models built from b1AR structure
• A2A StaR data used to refine models
• 545000 compounds screened in silico
• 372 compounds prioritised• 230 purchased
• 20 compounds IC50 < 55 µM• 9% hit rate• Top 10 all have LE > 0.27
scaffold hop
VS hit
• Highest LE hit from virtual screening
• A2AR pKi = 8.46• LE = 0.52, clogP 3.09
• A2AR pKi = 6.93• LE = 0.50, clogP = 2.74 • MW = 248.28• no analogues available
• Preladenant, istradefylline, vipadenant (BIIB014,Biogen/Vernalis) and Syn115 (Synosia) met key endpoints in Phase II validating A2A antagonism as a mechanism for Parkinson’s disease
21
Impact of SBDD on A2A Hit ID → LO → DCGPCR SBDD: Discovery A2A Receptor Antagonist – HTL1071/AZD4635
Langmead et al. J. Med. Chem. 2012, 1904; Congreve et al. J. Med. Chem. 2012, 1898
A2A pKi 8.5MW 310, clogP 3.1
LE 0.52, LLE 5.4CNS MPO 4.6
A2A pKi 6.9MW 248, clogP 2.7
LE 0.50, LLE 4.2CNS MPO 5.2
A2A pKi 8.8MW 503, clogP 2.4
LE 0.32, LLE 6.4CNS MPO 3.3
A2A pKi 8.0MW 316, clogP 2.7
LE 0.49, LLE 5.3 CNS MPO 5.2
Structure-based Virtual Screen (VS)
BPM & VSSBDD
Design vector+
Core hop
SBDDLipophilic hotspots
water networks
• Poor CNS physchem properties• Furan containing
• Novel non-furan containing• Mod. selectivity (vs A1)
• Novel triazene template• No structural alerts• Low selectivity (vs A1)• Mod. metabolic selectivity
• Improved LLE• Improved selectivity• Improved metabolic stability
Hit 1Preladenant Hit 2 HTL1071 / AZD4635
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Full SBDD project from virtual screening through hit optimization to clinical compoundsWater network controls A2A receptor antagonist binding kinetics
WaterFLAP: MIF based water networks post short MD relaxation
Compounds designed to interact with lipophilic hotspots, to displace
‘unhappy’ waters
Poor network with the phenyl.Good network with the pyridine. (GRID water probe only shown)
Potent: Slower off-rate Less potent: Very fast off-rate
WaterMap: MD based hydration site thermodynamics
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High-Throughput GPCR Crystallography
Soak crystals with any other higher
affinity ligand
Theophylline180 Da
Affinity: ~2 µM for A2A StaRKinetics: very fast
2.0 Å structure
Multiple co-structures
A2A in complex with theophylline
Co-crystallisation
with one 96 well crystallisation plate (150 µg protein) can soak 96 new ligands
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Soaking A2A Crystals
Rucktooa et al. Sci Rep. 2018
25
Crystal structure of HTL1071/AZD4635 with A2AR
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Optimised as a CNS drug benchmarked vs PreladenantAdenosine A2A Antagonist Profile: HTL1071/AZD4635
Hal
oper
idol
Istrad
efyl
line
Pre
lade
nant
HTL
0
20
40
60
80
1001h post-dose
2h post-dose
Effect of istradefylline, preladenant or HTL(1 mg/kg, PO) on haloperidol-induced catalepsy in rats
% 0
.8 m
g/k
g h
alo
peri
do
l re
sp
on
se
Candidate is highly efficacious from oral dosing(PK/PD model of Parkinson’s Disease)
ED50 0.2 mpk
• Improved oral bioavailability and PK in multiple species• Low metabolic clearance • Good CNS exposure in rat (not shown)• Excellent in vivo efficacy
HTL A2A antagonistPreladenant (Ph. III)
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HTL1071/AZD4635 A2A RO in cynomologus monkey using PET
Johnström et al., AACR 2017, Cancer Research 2017
PK/PD modelling of cyno PET occupancy dataBinding of [18F]MNI-444 to striatal regions in the NHP brain was reduced in a dose-dependent
manner by AZD4635
Occupancy-time course data reveal reduction of AZD4635 A2A receptor blockade with time
Data generated by
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HTL1071/AZD4635 is active against human and mouse A2AR
Borodovsky et al AACR 2017 Cancer Research 2017
• CHO cells stably expressing human or mouse A2AR• Incubated with adenosine in the presence of
AZD4635 (10 min)• cAMP measured by CatchPointTM cAMP Fluorescent
Assay Kit
Adenosine concentration (µM) mouse A2AR human A2AR
0.1 10 ± 2 0.8 ± 0.7
1 20 ± 4 10 ± 6
10 97 ± 13 143 ± 12
AZD4635 IC50, nM
A Z D 4 6 3 5
h u m a n A 2 A s ta b le lin e
n = 2
lo g 1 0 [A Z D 4 6 3 5 ] M
cA
MP
(n
M)
-1 2 -1 1 -1 0 -9 -8 -7 -6 -5 -4 -3
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
1 0 0 M A d e n o s in e , IC 5 0 = 1 ,6 9 4 .4 n M
1 0 M A d e n o s in e , IC 5 0 = 1 3 4 .9 n M
1 M A d e n o s in e , IC 5 0 = 1 4 .7 n M
0 .1 M A d e n o s in e , IC 5 0 = 1 .4 n M
A Z D 4 6 3 5
m o u s e A 2 A s ta b le lin e
n = 2
lo g 1 0 [A Z D 4 6 3 5 ] M
cA
MP
(n
M)
-1 2 -1 1 -1 0 -9 -8 -7 -6 -5 -4 -3
0
1 0
2 0
3 0
4 0
5 0
6 0
1 0 0 M A d e n o s in e , IC 5 0 = 1 ,0 7 8 .9 n M
1 0 M A d e n o s in e , IC 5 0 = 8 8 .1 n M
1 M A d e n o s in e , IC 5 0 = 1 7 .1 n M
0 .1 M A d e n o s in e , IC 5 0 = 8 .6 n M
Mouse A2AR Human A2AR
Data generated by
29
Reversal of NECA-mediated suppression of IFNγ secretion in mouse CD8+ T cellsHTL1071/AZD4635 reverses adenosine mediated T cell suppression
Borodovsky, et al. AACR 2018 Cancer Research 2018
Key NECA (µM)AZD4635 EC50 (µM)
±SD
10 >10
1 0.598 ± 0.067
0.1 0.053 ± 0.015
UT N/A
L o g A Z D 4 6 3 5 c o n c e n tra tio n (M )
Ac
tiv
ity
[%
]
-9 -8 -7 -6 -5
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
Data generated by
30
Total adenosine concentrations are high in mouse syngeneic tumors compared to corresponding cell lines
Borodovsky, et al. AACR 2018 Cancer Research 2018
M
C3
8 C
el l
s
M
C3
8 M
ed
i a
B1
6 C
el l
s
B1
6 M
ed
i a
M
CA
20
5 C
el l
s
M
CA
20
5 M
ed
i a
0 . 0 1
0 . 1
1
1 0
To
ta
l A
de
no
sin
e
Co
nc
en
tr
atio
n (
M)
CT
26_100m
m
CT
26_200m
m
CT
26_800m
m
MC
38_100m
m
MC
38_200m
m
MC
38_800m
m
EL4_100m
m
EL4_200m
m
EL4_800m
m
B16_100m
m
B16_200m
m
B16_800m
m
MC
A205 1
00m
m
MC
A205_200m
m
MC
A205_800m
m
1
1 0
1 0 0
1 0 0 0
To
tal
Ad
en
os
ine
Co
nc
en
tra
tio
n (
M)
Data generated by
31
Activity seen for HTL1071/AZD4635 monotherapy and in combination with anti-PD-L1 mAb
Borodovsky, et al. AACR 2018 Cancer Research 2018
D a y s o f T r e a t m e n t
Tu
mo
r
Vo
lu
me
(
mm
3
)
Ge
oM
ea
n
S
E
0 5 1 0
0
5 0 0
1 0 0 0
1 5 0 0V e h i c l e
A Z D 4 6 3 5 ( 5 0 m g / k g , B I D )
a n t i - P D - L 1 ( 1 0 m g / k g , B I W )
a n t i - P D - L 1 + A Z D 4 6 3 5
MC38 model: high adenosine ~100 µM
0 5 1 0 1 5
0
5 0 0
1 0 0 0
1 5 0 0
D a y s o f T r e a t m e n t
Tu
mo
r
Vo
lu
me
(
mm
3
)
Ge
oM
ea
n
S
E
V e h i c l e
A Z D 4 6 3 5 ( 5 0 m g / k g , B I D )
a n t i - P D - L 1 ( 1 0 m g / k g , B I W )
A Z D 4 6 3 5 + a n t i - P D - L 1
MCA205: lowadenosine ~5 µM
0 5 1 0
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
D a y s o f T r e a t m e n t
Tu
mo
r
Vo
lu
me
(
mm
3
)
Ge
oM
ea
n
S
E
V e h i c l e
A Z D 4 6 3 5 + a n t i - P D - L 1
MCA205(NSG)
• Goal to identify preclinical model sensitive to AZD4635 +/- anti-PD-L1 and understand criteria for sensitivity• Greatest sensitivity observed in MCA205 and MC38 models• Efficacy abrogated when tumors grown in immune compromised animals (NSG) - consistent with IO mechanism
Data generated by
32
Assessment of Sensitivity in Syngeneic Models
Lyne, AACR Spotlight 2018
CD8+ tumor infiltration Flow cytometry of tumors (1000-2000mm3)
DAPI-CD45+CD8+
MCA205MC38
CT26 EL4
TRAMP-C1
Tumor Mutational BurdenEstimation by total “putative somatic” Non-synonymous mutations
CD8+ tumor infiltration IHC
anti-CD8
LL2
• Models sensitive to AZD4635 have high levels of infiltrating CD8+ T Cells
• Sensitive models have high tumor mutational burden
Data generated by
33
HTL1071/AZD4635 enhances the expression of genes associated with T-cell and antigen presenting cell functions
Borodovsky et al AACR 2017 Cancer Research 2017
-1 0 1 2
1
AZ
D4635
AZ
D4635.1
AZ
D4635.2
AZ
D4635.3
Veh
Veh.1
Veh.2
Veh.3
Cd207 / CD molecules
Gbp2b / Basic Cell Functions
Ccr8 / Adaptive, Chemokines and Receptors
Klrb1c / NK Cell Functions
H2-Ea-ps / Antigen Processing
Fcer1a / Adaptive, Inflammation, Interleukins, Macrophage Functions, Mast Cell Functions
Cr2 / B-Cell Functions, CD molecules, Complement Pathway, Dendritic Cell Functions, Innate
F13a1 / Basic Cell Functions
Ccr6 / Adaptive, CD molecules, Chemokines and Receptors, Humoral Response, Innate, T-Cell Functions
Cd1d2 / Antigen Processing, CD molecules, Innate, Interleukins, T-Cell Functions
Fasl / Adaptive, Cytokines and Receptors, Inflammation, T-Cell Functions, TNF Superfamily
Ptgdr2 / CD molecules
Cd28 / Adaptive, B-Cell Functions, CD molecules, Humoral Response, Inflammation, Interleukins, T-Cell Functions
Chil3 / Basic Cell Functions
Il12rb2 / Cytokines and Receptors, Interferon, T-Cell Functions
Arg1 / Basic Cell Functions
Oas2 / Basic Cell Functions
Ifi44 / InterferonAZD4635 Vehicle
Interferon functions
Basic cell functions
Basic cell functions
T-cell functions
Basic cell functions
T-cell functions
CD molecules
T-cell functions
T-cell functions
T-cell functions
Basic cell functions
Dendritic cell functions
Macrophage functions
Antigen processing
NK cell functions
Chemokines and receptors
Basic cell functions
CD molecules
Decreased
Increased
Log 2 expression
• MC38 tumors treated for 14 days with AZD4635
• Gene expression changes evaluated with the NanoString Mouse PanCancer Immune Profiling Panel.
• Unsupervised clustering of gene expression changes revealed upregulation of antigen processing and T-cell function.
• Genes filtered for significance (p≤0.05) and magnitude (fold change>2)
Data generated by
34
HTL1071/AZD4635 enhances immune activation and CD8+ infiltration
Borodovsky et al AACR 2017 Cancer Research 2017 Borodovsky et al AACR 2018 Cancer Research 2018
Dendritic Cells(CD45+/CD11c+/F4/80-)
Macrophages(CD45+/F4/80+)
Vehicle
AZD4635
Vehicle
AZD4635
Vehicle
AZD4635
Vehicle
AZD4635
***
*** ***
De Koker S. et al. (2011) Chem. Soc. Rev. 40, 320-339
MC38
MCA205
• Efficient antigen presentation by APCs requires expression of MHCII and a co-stimulatory signal (CD80/86)
• AZD4635 increases expression of MHCII and CD86 in dendritic cells and macrophages
• AZD4635 in combination with anti-PD-L1 increases intratumoral CD8 infiltration
Data generated by
35
Clinical A2AR Antagonists for Immuno-Oncology
Miles Congreve, Giles A. Brown, Alexandra Borodovsky & Michelle L. Lamb (2018): Targeting adenosine A2A receptor antagonism for treatment of cancer, Expert Opinion on Drug Discovery, DOI: 10.1080/17460441.2018.1534825
CompoundAZD4635
(HTL-001071)
Ciforadenant
(CPI-444, V81444)
NIR178
(PBF-509)
Preladenant
(MK-3814, SCH-420814)
Development
(Discovery)
AstraZeneca
(Heptares)
Corvus
(Vernalis)
Novartis
(Palobiofarma)
Merck
(Schering Plough)
h A2A pKi 8.77 8.46 7.92 8.95
MW / ClogP 315.7 / 2.7 407.4 / 1.1 306.1 / 1.5 503.6 / 2.4
Latest Phase
ClinicalTrials.gov
I/Ib Ib/II II Ib/II (terminated)
Clinical Trials
single agents and
combinations:
Anti-PD-L1
(durvalumab)
Anti-CD73(oleclumab)
Anti-PD-L1
(atezolizumab)
Anti-CD73 (CPI-006)
Anti-PD1
(spartalizumab)
Anti-CD73(NZV730)
Anti-PD1 (pembrolizumab)
ClinicalTrials.gov Identifier: NCT02740985
ClinicalTrials.gov Identifier: NCT03381274
AZD4635 as monotherapy or in combination in tumors of high unmet needAstraZeneca testing HTL1071/AZD4635 in Phase 1b/2 studies
Partnered with:AZD4635
(A2aR)
MonotherapyAZD4635
(A2aR antagonist)
Primary completion date 2020
Combo with oleclumab(anti-CD73)
Primary completion date 2021
• I-O naïve and post immunotherapy tumors
Combo with durvalumab(anti-PD-L1)
Primary completion date 2020
• I-O naïve and post immunotherapy tumors
• Locally advanced/metastatic NSCLC with EGFR mutation
AZD4635Post IO NSCLC
AZD4635 IO naïve mCRPC
AZD4635IO naïve CRC
AZD4635Other IO naïve
AZD4635Post IO other
AZD4635 + DurvalumabPost IO NSCLC
AZD4635 + DurvalumabIO naïve mCRPC
AZD4635 + OleclumabNSCLC with EGFRmut
36
37
Summary
4
38
Discovery of A2A Receptor Antagonist - HTL1071/AZD4635
Langmead et al. J. Med. Chem. 2012, 1904; Congreve et al. J. Med. Chem. 2012, 1898
Impact of SBDD on A2A Hit ID → LO → DC
Preladenant Hit 1 Hit 2 HTL1071 / AZD4635
A2A pKi 8.5MW 310, clogP 3.1
LE 0.52, LLE 5.4CNS MPO 4.6
A2A pKi 6.9MW 248, clogP 2.7
LE 0.50, LLE 4.2CNS MPO 5.2
A2A pKi 8.8MW 503, clogP 2.4
LE 0.32, LLE 6.4CNS MPO 3.3
Virtual Screen
BPM & further VS‘core hop’
SBDD
A2A pKi 8.8MW 316, clogP 2.7
LE 0.49, LLE 5.2 CNS MPO 5.1
• Poor CNS physchem properties• Furan containing
• Novel non-furan containing• Mod. selectivity (vs A1)
• Novel triazene template• No structural alerts• Low selectivity (vs A1)• Mod. metabolic selectivity
• Improved LLE• Improved selectivity• Improved metabolic stability
• High efficiency leads identified using ‘enhanced homology model’ directed virtual screening• SBDD guided approach used to drive LLE & selectivity enhancements
SBDD platform approach significantly impacted identification & design of highly differentiated A2a ligands
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Conclusions
AZD4635 (HTL-1071) is a potent and selective antagonist of A2AR, the result of a innovative and thorough structure-based design effort against this GPCR
Inhibition of A2AR signaling by AZD4635 led to an increase in expression of co-stimulatory markers on APCs and increased intratumoral infiltration of CD8+T cells in combination with anti-PD-L1
AZD4635 enhances expression of genes associated with T-cell and APC function
Treatment with AZD4635 alone and in combination with an anti-PD-L1 Ab led to a reduction in tumor growth in both adenosine high and adenosine low syngeneic tumor models
AZD4635 is currently in clinical trials as a single agent and in combination with durvalumab (anti-PD-L1 Ab) in patients with solid malignancies (NCT02740985), and in combination with oleclumab (anti-CD73 Ab, NCT03381274)
1
2
3
4
5
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Our partnered pipeline has advanced across multiple programs
1 Note: SME = small molecule; mAb = monoclonal antibody
Product/Program Modality1 Indication Partner Discovery Preclinical Phase 1 Phase 2 Phase 3 Marketed
Japan Marketed Products (Out-licensed to Marketing / Distribution / Commercialization Partners)
NorLevo® SME Emergency contraception
ORAVI® SME Oropharyngeal candidiasis
Partnered Pipeline - Respiratory Products (Traditional out-licensing)
Seebri®/Ultibro® SME COPD
QVM149 SME Asthma
Partnered GPCR Pipeline (Traditional out-licensing/collaboration projects)
A2a antagonist SME Multiple solid tumors
A2a antagonist SME EGFRm NSCLC
M1 agonist SME Alzheimer’s disease
M4 agonist SME Alzheimer’s disease
M1/M4 dual agonist SME Alzheimer’s disease
Single target SME Pain
Multiple targets SME Multiple indications
Multiple targets mAb Inflammation
Partnered GPCR Pipeline (Co-development/profit share)
CXCR4 mAb mAb Immuno-oncology
Single target mAb Immuno-oncology
Single target Peptide Inflammation
Asset-centric Companies
Orexin agonists SME Narcolepsy
Orexin agonists SME Narcolepsy
: Next 12–18 months progress
: Current stage
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Our proprietary pipeline now has 3 programs in clinical development
1 Note: SME = small molecule; mAb = monoclonal antibody
Product/Program Modality1 Indication Originator Discovery Preclinical Phase 1 Phase 2 Phase 3 Marketed
Proprietary GPCR Pipeline (Go-to-market/commercialize)
M1 agonist SME DLB (Japan)
mGlu5 NAM SME Neurology
SSTR agonist Peptide Endocrine disorders
CGRP antagonist SME Migraine
GLP-1 antagonist Peptide Metabolic diseases
GLP-2 agonist Peptide Intestinal failure
Orexin-1 antagonist SME Cocaine-use disorders
Apelin agonist Peptide PAH
GPR35 agonist SME Inflammatory bowel disorders
EP4 agonist SME Inflammatory bowel disorders
H4 antagonist SME Atopic dermatitis
PAR2 mAb mAb Atopic dermatitis
: Next 12–18 months progress: Current stageMultiple candidates entering clinical development and next wave of targets in advanced discussions
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• Sosei Heptares
• Oncology R&D AstraZeneca
• Oncology iMED and Clinical Development
• Patients and Families
Acknowledgements
Locations
SOSEI HEPTARES
PMO Hanzomon 11F
2-1 Kojimachi, Chiyoda-ku
Tokyo 102-0083
Japan
Steinmetz Building
Granta Park, Cambridge
CB21 6DG
United Kingdom
North West House
119 Marylebone Road
London NW1 5PU
United Kingdom