Development of Small Molecule Checkpoint...
Transcript of Development of Small Molecule Checkpoint...
Development of Small Molecule Checkpoint Inhibitors
David Tuck, M.D. CMO Curis Inc
Immune Checkpoint Inhibitors Symposium March 14-16 2017
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Dru
g C
once
ntra
tion
Activity Level
Days D
rug
Con
cent
ratio
n
Activity Level
Days
Small molecule PK profile allows optimization of dose and administration schedule Usually less than 24 hour half-life (T1/2) permits
flexibility with dosing schedule – daily or intermittent dosing
Permits flexible adjustment of exposure as measured by Cmax and AUC – both parameters can be adjusted to match mechanism-of-action
Flexibility to adjust dose and schedule to address emergent adverse events
Flexibility to adjust for combinations
Untether patient from infusion chair – cost, convenience, access
Typical Small Molecule Drug PK Profile
Typical Antibody Drug PK Profile
Why Small Molecule Immune Checkpoint Blockade?
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Structural Features of PD-1 / PD-L1 Interaction
mPD1 hPDL1 hPDL1 hPD1
Lin et.al., 2008; PNAS. 105: 3011 Zak et.al., 2015; Structure. 23: 2341
Structural Features of PD-1 / PD-L1 Interaction
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Unbound PD1 Bound PD1 PDL1 Zak et.al., 2015; Structure. 23: 2341
Compounds Mechanism Reference Source
ENUM-C8 PD1 Non-blocking antibody AACR 2016 Enumeral
MQ-209,MQ-210 Non-blocking (Allosteric) antibody
ASCO 2016 Fenwick Abstract 3072
Mabquest
NP12 Peptide targeting PDL1 AACR 2013 Aurigene
(D) PPA-1 D peptides blocking PDL1-PD1 interaction
Chang 2015 Tsinghua Univ
high-affinity PD-1 Small non-antibody peptides
Maute PNAS 2015 Stanford
Small molecule BMS-202, BMS-8
Small molecule targeting PDL1
Zak et al 2016 BMS
CA170,CA327 Small molecules targeting immune checkpoints
AACR 2016 SITC 2016
Curis/Aurigene
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Small molecules, peptides, non-blocking antibodies
Peptides, small molecule and mAbs ICI may have different mechanisms
3/22/2017 6
Discovery, Characterization and Development of a New Class of Therapeutic Anti-PD-1 Antibody - Amirinia-Nave et al AACR 2016
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Aurigene discovery platform Small molecule design based on structure
of interaction hotspots
Small molecule library
Functional screening to identify compounds capable of selectively rescuing T cell proliferation and
activation in the presence of inhibitory checkpoints
VISTA TIM3 PD-L1
PD-1 PD-L1
Discovery process for small molecule immune checkpoint blockade
Pharmacophore derived
small molecule mimics
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Antagonism of PD-L1 and VISTA by CA-170 Ex-vivo activation of human PBMC
Dose dependent activation of PD-L1 or VISTA-inhibited T cells ex-vivo
PD-L1
Res
cue
(%)
IFN-γ production used as a marker for T cell activation
CA-170 Concentration (log nM)
VISTA
No activation of CTLA4-inhibited T cells
No activation of TIM3-inhibited T cells
Potent and selective rescue of human T cell activation (proliferation or IFN-γ production) Dose-dependent activation of T cells inhibited by exogenous PD ligands or by VISTA
• Similar to that observed using anti-PD1 or anti-VISTA antibodies as control
No rescue of T cells inhibited by CTLA-4, TIM3, BTLA, LAG3
EC50 = 17nM EC50 = 37nM
Curis Confidential
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CA-170 is Orally Bioavailable Multiple species
Oral exposure in all non-clinical species examined At 10mg/kg: Cmax ~ 500ng/ml, AUC ~ 3,500ng*hr/ml in mouse (efficacy animal model)
Proportional increase in Cmax and AUC with increased oral dosing of CA-170 From 10mg/kg to 1000mg/kg dose tested in mouse and monkey (safety animal model)
Parameter Oral PK Profile
Species Mice Rat Dog Monkey
T1/2 (hr) 3.5 3.6 3.8 3.8
Tmax (hr) 1.0 1.0 1.0 3.3
Cmax (µg/ml) 0.52 0.59 4.3 0.86
AUC (0-t) (µg*hr/ml) 3.45 3.88 22.5 4.54
Single-dose Exposure in Mouse
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CA-170 Anti-Tumor Activity In Vivo Syngeneic mouse tumor models sensitive to anti-PD1 antibodies
CT26 Colon Carcinoma Model B16/F10 Melanoma Model MC38 Colon Carcinoma Model
* **
*** * *
* *
In vivo activity in tumor models grown in immuno-competent C57BL/6 mouse strain CT26 and MC-38 CRC tumors grown subcutaneously and change in tumor size measured B16/F10 melanoma tumor cells injected intravenously and number of lung metastatic nodules measured
Day 13 post tumor cell inoculation
*p<0.05
* p<0.05, **p<0.01, ***p<0.001 J43 at 100ug/animal, ip, q7d
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In vivo Activity Requires Intact Immune System
No anti-tumor activity observed in immune-deficient SCID/beige mice Provides evidence for immune response-mediated anti-tumor mechanism of CA-170
MC38 Model Syngeneic Mice
MC38 Model SCID/beige Mice
* **
* p<0.05, **p<0.01 J43 at 100ug/animal, ip, q7d
Vehicle CA-170 10mpk
Days
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CA-170 is Active In Vivo Syngeneic mouse tumor models where anti-PD1 antibodies are inactive
CA-170 Daily Oral Treatment Anti-PD1 Bi-weekly Injection Anti-VISTA Bi-weekly Injection
In vivo activity in 4T1 breast cancer tumor model Dose dependent response to CA-170
Tumor model is non-responsive to anti-PD1 antibody treatment
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CA-170 is Active In Vivo Syngeneic mouse tumor models insensitive to anti-PD1 antibodies
In vivo activity in B16/F1 melanoma tumor model Dose dependent response to CA-170
Tumor model is non-responsive to anti-PD1 antibody treatment
CA-170 Daily Oral Treatment Anti-PD1 Twice-weekly Injection
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Predictable Dose Exposure, T cell Activation and Efficacy in anti-PD-1 Non-responsive Mouse Models with CA-170
Mouse single dose exposure T Cell Activation – In Tumor
T Cell Activation – In Blood Efficacy in the B16/F1 Model
CA-170
CA-170 In vivo Effect on Immune Profile
Increased T cell activation in tumor-bearing animals following CA-170 administration Increase in CD8+ T cell activation markers (CD69) in tumor and in tumor draining lymph nodes
Increase in peripheral circulation of active CD4+ and CD8+ T cells
↑ Activation – Tumor Infiltrating CD8+ T cells
↑ Number – Peripheral Circulating CD8+ & CD4+ T cells
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Tumor CD69+ T cells
↑ Activation – Tumor-draining Lymph Node CD8+ T cells
Tumor CD69+/PD1+ T cells Lymph Node CD69+/PD1+ T cells
Cells
/ ml
Blood CD8+/CD69+ T cells
Cells
/ ml
Blood CD4+/CD69+ T cells
↑ Activation – Peripheral Circulating CD8+ & CD4+ T cells
Blood CD69 on CD4+ T cells Blood CD69 on CD8+ T cells
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CA-170 has Clean Preclinical Safety Profile GLP 28-day repeat oral dosing safety profile – mice and monkeys
Mortality : No mortality
Clinical Signs of Toxicity : No abnormalities detected
Body weight : No test item related changes
Food Consumption : No test item related changes
Hematology : No test item related changes
Clinical Chemistry : No test item related changes
Gross Pathology : No treatment related changes
Organ weights : No treatment related changes
Histopathology : No treatment related changes
NOAEL at over 1,000 mg/kg/day : In vivo active dose = 10 mg/kg/day
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CA-327 Selectively Inhibits PDL1 and TIM3 Activation of human T cells in culture
Activation of PD-L1 or VISTA-inhibited T cells ex-vivo
No activation of CTLA4-inhibited T cells
No activation of VISTA-inhibited T cells
Potent and selective rescue of human T cell activation ex-vivo (proliferation or IFN-γ production) Dose-dependent activation of isolated human T cells inhibited by exogenous PD-ligands or by TIM3
Specificity: no rescue of T cells inhibited by CTLA-4, LAG3, VISTA
Res
cue
(%)
PDL1 TIM3
uM CA-327 uM CA-327
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CA-327 is Orally Bioavailable Multiple species
PK parameters at 10 mpk PO dose using water as vehicle under fed condition
Parameters Units BALB/c Mouse Wistar Rat Beagle Dog
AUC0-LAST h*ng/ml 5069 4631 12568
AUC0-inf h*ng/ml 5178 4702 12721
Beta t1/2 h 4.49 3.9 3.5
Cmax ng/ml 755 481 1450
Tmax h 1.0 3.3 2.6
P K p ro f ile o f A U -B G D -1 2 8 9 2 a c ro s s s p e c ie sa t 1 0 m p k d o s e u s in g w a te r a s v e h ic le
T im e (h )
Plas
ma
conc
entr
atio
n (n
g/m
L)
0 4 8 1 2 1 6 2 0 2 41 0
1 0 0
1 0 0 0
1 0 0 0 0
B A L B /c m o u s e
W is ta r ra t
B e a g le d o g
CA-327 PK Profile
CA-327 can inhibit tumor growth of multiple syngeneic tumor models in an immune dependent manner
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Tu
mo
r v
olu
me
(m
m3
)
V e h ic leC o n tr o l
J 4 31 0 0 µ g
a T im 31 0 u g
1 0 m g /k gP M 3 2 7 , Q D , P O
0
1 0 0 0
2 0 0 0
3 0 0 0
p < 0 .0 5
B16F10 melanoma CT26 colon carcinoma
Tu
mo
r v
olu
me
(m
m3
)
V e h ic leC o n tr o l
J 4 31 0 0 µ g
1 0 m g /k gP M -3 2 7 , Q D , P O
0
5 0 0
1 0 0 0
1 5 0 0
p < 0 .0 1
MC38 colon carcinoma
Tu
mo
r v
olu
me
(m
m3
)
V e h ic leC o n tr o l
J 4 31 0 0 µ g
1 0 m g /k gP M 3 2 7 , Q D , P O
0
5 0 0
1 0 0 0
1 5 0 0
p < 0 .0 5
CA-327 Effect on Immune Profile In Vivo CT-26 syngeneic colorectal cancer mouse model
Increased T cell activation in tumor-bearing animals with oral CA-327 administration Increased percentage of activated (CD69+ marker) CD8+ and CD4+ T cells in circulation and in tumors
↑ Percent Active – Tumor Infiltrating CD8+ & CD4+ T cells
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↑ Percent Active – Circulating CD8+ & CD4+ T cells
Blood CD8+/CD69+ T cells Blood CD4+/CD69+ T cells Tumor CD8+/CD69+ T cells Tumor CD4+/CD69+ T cells
% C
D8+
T C
ells
% C
D8+
T C
ells
% C
D4+
T C
ells
% C
D4+
T C
ells
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CA-327
Additional compounds with distinct targets in preparation for clinical study demonstrate the robustness of this discovery platform Potent and selective, oral small molecule immune checkpoint inhibitor ex-vivo Targets PDL1 and TIM3 immune checkpoints Activates isolated T cells that are inhibited by PDL1 or TIM3 in culture
Potent immune checkpoint inhibitor in vivo in mouse tumor models with oral dosing Biologically active in mouse: Oral administration results in T cell activation in circulation and in tumor tissue Significant anti-tumor activity in multiple syngeneic tumor models
IND-enabling studies ongoing
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CA-170 Phase 1 Trial (CA-170-101) Dose escalation design
Dose Level 1 50 mg QD
n=1
DLT or treatment-related Grade ≥ 2 AE
100%
33-40%
-50%
Dose Level -1 25 mg QD
Dose Level 2 100 mg QD
n=1
Dose Level 3 200 mg QD
n=1
100%
Dose Level 4 400 mg QD
n=1
100%
50% Dose Level 5 600 mg QD
n=3
Dose Level 6 800 mg QD
n=3
33% Dose Level 7 and beyond QD
n=3
33-40%
Standard 3+3 Dose Level X
QD
Open-label, dose escalation and dose expansion trial Up to 300 patients with advanced solid tumors
or lymphoma 6 centers in US enrolling patients for dose
escalation stage Currently in 3+3 stage of dose escalation
Objectives Safety, tolerability, PK, PD, clinical effects, and
recommended Phase 2 dose (RP2D)
Treatment Oral, once daily administration in continuous
21-day cycles
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CA-170 Oral Exposure in Patients Initial five dose cohorts – continuous once daily dosing
Dose proportional increase in exposure with increasing doses in patients Near-linear doubling in Cmax and AUC with dose doubling: 50mg – 400mg daily dose
50
mg
10
0 m
g
20
0 m
g
40
0 m
g (
n=
2)
60
0 m
g (
n=
3)0
2 .5 ×1 0 0 4
5 .0 ×1 0 0 4
7 .5 ×1 0 0 4
1 .0 ×1 0 0 5
1 .3 ×1 0 0 5
1 .5 ×1 0 0 5
hr*
ng
/ml
D a y 1 C y c le 1
D a y 1 5 C y c le 1
Parameter Units 50 mg 100 mg 200 mg 400 mg (n=2)
600 mg (n=3)
Tmax hr 7.4 4.0 3.0 8.0 7.3
Cmax ng/mL 412.4 1107.2 1997.6 3522.3 8976.3
AUClast hr*ng/mL 5196.7 11018.7 27487.8 57342.1 123669.3
Parameter Units 50 mg 100 mg 200 mg 400 mg (n=2)
Tmax hr 7 7 7 7
Cmax ng/mL 724.6 1078.4 2337.1 7087.3
AUClast hr*ng/mL 7953.9 13652.9 33997.6 102392.9
Day 1
Day 15
PK parameters
00
5 0 0 0
1 0 0 0 0
1 5 0 0 0
1 2 4 6 8 0 60 2 4 8 2 42 4
5 0 m g (N = 1 )
1 0 0 m g (N = 1 )
2 0 0 m g (N = 1 )
4 0 0 m g (N = 2 )
6 0 0 m g (N = 3 )
T im e (h r)
D a y 1 D a y 8 D a y 1 5
Con
cent
ratio
n (n
g/m
L)
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First dose levels in patients are consistent with Preclinical Predictable Dose Exposure and T Cell Activation ( NCT02812875 )
CD69+ CD134+ Granzyme B+
Day 1 Day 15
CA-170 exposure in humans
Change in the percentage of circulating CD8+ T cells expressing:
Human PK (200 mg/day)
Summary
• CA170 is a potent and selective, oral small molecule checkpoint inhibitor, and the first to enter the clinic
• Preclinical data demonstrate dose-dependent oral exposure, immune modulation and anti-tumor activity
• Clinical PK profile is similar to non-clinical and human exposure appears predictable on oral dosing
• CA-170 appears to be biologically active in patients, supporting continued clinical development
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CA-170 (PD-L1 / VISTA Antagonist): Summary
First-in-Class orally available small molecule antagonist of PD-L1 and VISTA
Induces proliferation of T-cells and IFN-gamma production Selective rescue in response to PD-L1, PD-L2, and VISTA inhibition and not other immune
checkpoint molecules
Clean off-target profile (enzyme, receptors, ion channels, kinases)
Orally bioavailable with good PK properties in mice & monkeys
Anti-tumor activity in multiple syngeneic tumor models
Clean in vivo safety profile – GLP toxicology in mice and monkeys
Phase 1 trial underway
Summary
Immune checkpoints of the immunoglobulin superfamily are amenable to small molecule targeting Transient interaction, not pre-formed complexes Structural information for receptor-ligand interaction is available Defined regions provide contact sites for small molecule interaction
This chemistry has identified key interaction regions for targeting Proposed interaction model is consistent with the structure-based design
This chemistry appears to extend to multiple checkpoint inhibitors PDL1, VISTA and TIM3 targeting compounds identified
Chemistry has translated to multiple drug candidates Successful conversion of design to an orally available, active and safe molecule