anti-tumor activity of glutaminase inhibitor cb-839 in ... · anti-tumor activity of glutaminase...
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Anti-Tumor Activity of Glutaminase Inhibitor CB-839 in Solid Tumor Malignancies
Francesco Parlati, Ph.D.Calithera Biosciences
Keystone Tumor Metabolism January 25, 2018
Disclosure
• I am an employee and shareholder at Calithera Biosciences
Agenda
• Introduction to CB-839
• CB-839 combination with signal transduction inhibitors
• CB-839 combination with taxol in TNBC
• Novel combination strategies with CB-839
– CDK4/6 and PARP inhibitors
Agenda
• Introduction to CB-839
• CB-839 combination with signal transduction inhibitors
• CB-839 combination with taxol in TNBC
• Novel combination strategies
– CDK4/6 and PARP inhibitors
Cancer vs. Normal Cell Metabolism
GLUCOSE
Pyruvate
α-KG
Glutamate
GLUTAMINE
Lactate
TCACycle
Mitochondrion
Normal Cells Cancer Cells
Intermediates for biosynthesis
Glutathione
Glutaminase
GLUCOSE
Pyruvate
α-KG
Glutamate
GLUTAMINE
Lactate
TCACycle
Glutaminase
Mitochondrion
CB-839
aspartate
a-ketoglutarate(a-KG)
citrate
fumaratemalate
oxaloacetateTCAcycleglutamate
a-KGglutamate
glutamine
Glutaminase
CB-839 Suppresses Metabolic Pathways Downstream of Glutamate in vitro
glutathione
0 . 0 6 2 5
0 . 1 2 5
0 . 2 5
0 . 5
1
2
4
8
1 6
G l u t a m i n e
Fo
ld C
ha
ng
e i
n M
eta
bo
lite
0 . 0 6 2 5
0 . 1 2 5
0 . 2 5
0 . 5
1
2
4
8
1 6
G l u t a m a t e
0 . 0 6 2 5
0 . 1 2 5
0 . 2 5
0 . 5
1
2
4
8
1 6
G S H
0 . 0 6 2 5
0 . 1 2 5
0 . 2 5
0 . 5
1
2
4
8
1 6
M a l a t e
0 . 0 6 2 5
0 . 1 2 5
0 . 2 5
0 . 5
1
2
4
8
1 6
C i t r a t e
0 . 0 6 2 5
0 . 1 2 5
0 . 2 5
0 . 5
1
2
4
8
1 6
A s p a r t a t e
6
CB-839
NSCLC*24 h treatment 1 mM CB-839
* Average of 4 cell lines
- 3
- 2
- 1
0
1
2
3
4
5
6
mR
NA
ex
pr
es
sio
n (
log
2)
p = 0 . 0 7 * * * * * * * * * *
T N B C c c R C C N S C L C m e l a n o m a
no
rm
al
tum
or
no
rm
al
tum
or
no
rm
al
tum
or
no
rm
al
tum
or
Glutaminase is Overexpressed in Solid Tumors
Expression of GAC isoform in Clinical Samples
mRNA levels were obtained from Compendia Bioscience™ Translational Bioinformatics Services (Life Technologies, Ann Arbor, MI)
CB-839 Has Broad Anti-tumor Activity Across Multiple Tumor Cell Lines
Panel of Tumor Cell Lines Treated with CB-839 (1 mM) for 72 Hours• Effects of CB-839 on the growth/death of a panel of cancer cell lines
– % cell growth compared to untreated cells– % cell death compared to starting cell number
Incr
easi
ng
effe
ct o
f C
B-8
39
0
25
50
75
100
no drugeffect
completegrowthsuppression
completekilling
% c
ell g
row
th%
cel
l dea
th
Triple Negative Breast Cancer Non-Small Cell Lung CancerRenal Cell Carcinoma Melanoma
High Levels of GLS Expression in PatientsOn-study or Archival Tumor Samples
Non-Small Cell Lung Cancer
Triple Negative Breast Cancer
Renal CellCarcinoma
Melanoma
G l u t a m i n a s e E x p r e s s i o n ( I H C )H
Sc
or
e
TN
BC
RC
C
NS
CL C
me
l an
om
a
0
5 0
1 0 0
1 5 0
2 0 0
2 5 0
3 0 0h i g h e s t
e x p r e s s i o n
l o w e s t
e x p r e s s i o n
Tumor FFPE stained with a-GLS antibody
[ C B - 8 3 9 @ 4 h ] ( n g / m L )
% G
lut
am
ina
se
Ac
tiv
ity
1 1 0 1 0 0 1 0 0 0
0
2 0
4 0
6 0
8 0
1 0 01 0 0 T I D
1 5 0 T I D
2 5 0 T I D
4 0 0 T I D
6 0 0 T I D
8 0 0 T I D
e x v i v o p l a t e l e t
d o s e r e s p o n s e
8 0 0 B I D
6 0 0 B I D
L L O Q
CB-839 Monotherapy in Patients
• Well tolerated at active doses
– MTD not reached
– 800 mg PO BID selected as RP2D
• Clear PK/PD relationship
– Glutaminase inhibition tested in patients with solid tumors (n=88)
– Sustained and near-complete inhibition of glutaminase in platelets and tumors
• CB-839 monotherapy was active in RCC pts (n=21)
– 1 PR; on study 356 days
– 52% SD, 2 longest ongoing at 25 mo and 15 mo
Tumor GIST NSCLC colon meso RCC
662 1384 1945 2352 11530
C1D15 AUC (0-8h) (ng*hr/mL)
Approximately 3 weeks on study drug
Glu
ta
min
as
e A
ct
ivit
y
(n
mo
l/m
in/
mg
pr
ot
ein
)
5
1 0
1 5
2 0
2 5
3 0
3 5
- 8 6 %
- 7 5 %
- 8 4 %- 5 7 %
U n i n h i b i t e d
I n h i b i t e d
- 9 6 %
C1D1 4 hours post dose
Platelets
Pharmacodynamic Glutaminase Inhibition
Tumors
Meric-Bernstam F. et. al, European Journal of Cancer, Vol. 69, S12–S13
Agenda
• Introduction to CB-839
• CB-839 combination with signal transduction inhibitors
• CB-839 combination with taxol in TNBC
• Novel combination strategies
– CDK4/6 and PARP inhibitors
CB-839 is Synergistic with Growth Factor Signaling Pathway Inhibitors• Signal Transduction inhibitors indirectly decrease glucose and glutamine utilization
• CB-839 is synergistic with multiple growth factor signaling pathway inhibitors
CB-839
Erlotinib(EGFRi)
Everolimus(mTORi)
= Inhibition
Growth Factor Receptor
Ras/RafPathway
PI3K/mTOR Pathway
↑ Glutamine Utilization
↑ Glucose Utilization
Metabolic Rewiring Supporting Tumor Growth
Crizotinib(ALKi/ROSi)
12
Cabozantinib(VEGFRi/METi)
Synergistic Anti-Proliferative Activity of CB-839 and Everolimus in Renal Clear Cell Carcinoma
0 .4
0 .6
0 .8
1 .0
Ce
ll S
urv
iva
l
(re
alt
ive
to
DM
SO
)
A C H N
CB-839 (nM)Everolimus (nM)Mixture (Comb. Index)
3001000.38
18.81.6
0.19
15050
0.33
7525
0.20
37.53.1
0.36
Plating Density
72 hTreatment
0 .0
0 .5
1 .0
G lu c o s e
C o n s u m p tio n
Nu
trie
nt
Co
ns
um
pti
on
(re
lati
ve
to
DM
SO
)
G lu ta m in e
C o n s u m p tio n
D M S O
C B -8 3 9
E v e ro lim u s
C o m b o
24 h Treatment
CB-839 Enhances the Anti-tumor Activity of Signal Transduction Inhibitors
D a y P o s t I m p l a n t
Tu
mo
r V
olu
me
(m
m3
)
8 1 6 2 4 3 2
3 0 0
6 0 0
9 0 0
1 2 0 0
1 5 0 0
V e h i c l e
C B - 8 3 9
C o m b o
E v e r o l i m u s
D o s i n g
s t a r t
* * *
D a y P o s t I m p l a n t
Tu
mo
r V
olu
me
(m
m3
)
1 0 2 0 3 0 4 0
2 0 0
4 0 0
6 0 0
8 0 0
1 0 0 0
1 2 0 0
1 4 0 0
V e h i c l e
C B - 8 3 9
C o m b o
C a b o z a n t in ib
*D o s i n g
s t a r t
D a y s P o s t I m p l a n t
Tu
mo
r V
olu
me
(m
m3
)
2 0 3 0 4 0 5 0
2 5 0
5 0 0
7 5 0
1 0 0 0V e h i c l e
C B - 8 3 9
C r i z o t in ib
C o m b o
* *
D o s i n g
s t a r t
D a y P o s t I m p l a n t
Tu
mo
r V
olu
me
(m
m3
)
0 2 5 5 0 7 5 1 0 0 1 2 5
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
V e h i c l e
C B - 8 3 9
E r lo t i n ib
C o m b o
* * * *
D o s i n g
s t a r t
Everolimus Combination Cabozantinib Combination
Crizotinib Combination Erlotinib Combination
RCCCaki-1 xenograft
RCCCaki-1 xenograft
NSCLCH2228 xenograft
NSCLCHCC827 xenograft
CB-839 + Everolimus in RCC
Phase 1b Dose escalation and expansion
15
Escalation in Advanced RCC
Expansion in clear cell and papillary
RCC
CB-839 + Everolimus in RCC Clinical Outcomes in Phase 1b
N=17 patients (14 ccRCC and 3 papillary RCC)
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14
Median PFS is 8.5 moSu
rviv
al P
rob
abili
ty (
%)
Months
Number at risk: 16 10 8 5 4 2 1 0
Median PFS (95% C.I.)8.5 mo (5.3 - 11 mo)
^*
Ever
olim
us
med
ian
PFS
^ Motzer et al, NEJM 2015* Choueiri et al, NEJM 2015
Meric-Bernstam F. et. al, European Journal of Cancer, Vol. 69, S12–S13
Clinical Studies in RCC with CB-839
• Phase 2: CB-839 + Everolimus vs. Everolimus
– Placebo control double blind study in RCC patients
• Phase 1b: CB-839 + Cabozantinib in RCC patients
• Phase 1/2: CB-839 + Nivolumab in RCC patients
Combination Partner
Nivolumab
Ph 2: Renal Cell Carcinoma Everolimus
Ph 1b: Renal Cell Carcinoma Cabozantinib
Ph 1/2: Renal Cell Carcinoma
Agenda
• Introduction to CB-839
• CB-839 combination with signal transduction inhibitors
• CB-839 combination with taxol in TNBC
• Novel combination strategies
– CDK4/6 and PARP inhibitors
CB-839 Has Broad Anti-tumor Activity Across Multiple Tumor Cell Lines
Panel of Tumor Cell Lines Treated with CB-839 (1 mM) for 72 Hours• Effects of CB-839 on the growth/death of a panel of cancer cell lines
– % cell growth compared to untreated cells– % cell death compared to starting cell number
Incr
easi
ng
effe
ct o
f C
B-8
39
0
2 5
5 0
7 5
1 0 0
n o d r u g
e f f e c t
c o m p l e t e
g r o w t h
s u p p r e s s i o n
c o m p l e t e
k i l l i n g
% c
ell
gr
ow
th
% c
ell
de
at
h
T N B C N S C L CR C C M e l a n o m a
CB-839 in TNBC PatientsMonotherapy
• CB-839 was well tolerated in TNBC patients
• 19 patients were treated
– 3 patients had stable disease
• 2 patients with stable disease greater than 8 months
CB-839 plus Paclitaxel Exacerbates Cell Cycle Defect in TNBC cells
21
• Paclitaxel targets tubulin and blocks cell cycle progression at mitosis (G2/M-phase) • CB-839 treatment causes cells to accumulate in G1 or S-phase • The combination of CB-839 plus paclitaxel causes cells to accumulate in G2/M or S-phase• Synergy between CB-839 and Paclitaxel in 8 out of 11 TNBC cell lines
DM
SO
CB
- 83
9
Pa
cl i
t ax
el
Co
mb
o
0
2 5
5 0
7 5
1 0 0
J I M T - 1
% C
ell
s
% G 1
% S
% G 2 / M
0 . 0 0
0 . 2 5
0 . 5 0
0 . 7 5
1 . 0 0
J I M T - 1
Re
lativ
e C
ell
Gr
ow
th
CB-839 (nM)Paclitaxel (nM)Combination Index
50050.10
25025.16
12512.5.15
62.56.25.07
31.33.13.11
15.61.56.16
7.80.78.19
00-
CB-839 plus Paclitaxel Shows Enhanced Anti-tumor Activity In Vivo
22
T N B C
J I M T - 1 X e n o g r a f t
S t u d y D a y
Tu
mo
r V
olu
me
(m
m3
)
0 5 1 0 1 5 2 0 2 5
5 0 0
1 0 0 0
1 5 0 0 V e h i c l e
C B - 8 3 9 , B I D
P a c l i t a x e l , I P Q O D x 5
C o m b o
*
v s p a c l i t a x e l
T N B C
J I M T - 1 X e n o g r a f t
S t u d y d a y
Tu
mo
r V
olu
me
(m
m3
)
0 7 1 4 2 1 2 8 3 5
0
2 0 0
4 0 0
6 0 0
8 0 0
P a c l i t a x e l , I V Q O D x 5
C o m b o
* *
* *v s p a c l i t a x e l
v s v e h i c l e
C B - 8 3 9 , B I D
V e h i c l e
CB-839 + Paclitaxel in TNBCStudy Design
23
Advanced TNBC
CB-839 400 – 800 mg BIDPaclitaxel 80 mg/m2 IV D1,8,15 Q28
Expansion in TNBC pts with and without prior taxane in
the metastatic setting
CB-839 + Paclitaxel in TNBCKey Demographics
• Median of 3 prior lines of therapy for metastatic disease
– 35% ≥ 5L therapy
• Prior taxane exposure
– 88% any line of therapy• 51% advanced/metastatic
• 37% adjuvant/neoadjuvant
24
Kalinsky et al. SABCS 2017
CB-839 + Paclitaxel in TNBCBest Change in Target Lesions
25
% c
ha
ng
e i
n t
ar
ge
t t
um
or
s
60
0
80
0
60
0
40
0
80
0
80
0
80
0
80
0
40
0
80
0
80
0
80
0
80
0
80
0
60
0
80
0
40
0
60
0
80
0
80
0
80
0
80
0
60
0
80
0
80
0
40
0
60
0
40
0
80
0
60
0
80
0
60
0
80
0
80
0
60
0
80
0
60
0
80
0
80
0
- 1 0 0
- 8 0
- 6 0
- 4 0
- 2 0
0
2 0
4 0
6 0
8 0
1 0 0
P r i o r T a x a n e
[ A d v / M e t ]
P r i o r T a x a n e
[ N e o / A d j o n l y ]
N o P r i o r
T a x a n e
D o s e ( m g )
Kalinsky et al. SABCS 2017
Patients were dosed with CB-839 400-800 mg BID and Paclitaxel 80 mg/m2 IV D1,8,15 Q28
CB-839 + Paclitaxel in TNBCResponse Table CB-839 ≥ 600 mg dose
26
Adv/Met^
Neo/Adj only
None
22 16 3
20 14 3
4 (20) 3 (21) 1 (33)
7 (35) 5 (36) 2 (67)
9 (45) 6 (43) 0
11 (55) 8 (57) 3 (100)
4 2 6
Patients:
Total Enrolled (N)
RECIST Evaluable [N (%)]*
PR
SD
PD
DCR (CR + PR + SD)
Lines of Prior Adv/Met Therapy
By Prior Taxane (≥600 mg)
400mg
≥600mg
7 42
7 37
0 8 (22)
3 (43) 14 (38)
4 (57) 15 (41)
3 (43) 22 (59)
3 4
By CB-839 Dose
*pts receiving a post-baseline tumor assessment, discontinued due to drug-related AE, or died due to diseasehaving received 16 days of treatment
^Includes 3 pts that progressed on neo-adjuvant taxane therapy
Kalinsky et al. SABCS 2017
Molecular Subtyping of TNBC Patients on CB-839 + Pacitaxel Combination
• RNA expression analysis typically used to subtype TNBC tumors:
– TNBC-type:
• Tumor-intrinsic and tumor-extrinsic gene signature
• 6 subtypes identified (LAR, BL1, BL2, M, MSL, IM)
– Stroma-Axis:
• Tumor-extrinsic gene signature
• 4 subtypes identified (T, B, E, D)
3 6 9 1 2 1 8 2 4
T i m e o n S t u d y ( M o n t h s )
P R
S D
P D
Trend between Clinical Benefit and LAR Subtype in TNBC Patients on CB-839 + Pacitaxel
28
Trend between clinical benefit (PR or SD> 4 mo):• LAR subtype (3 of 6 patients w/benefit; 0 of 7 w/o benefit)
• Expression of androgen receptor and several metabolic enzymes
• e.g. TCA cycle, GSH biosynthesis, amino acid metabolism
LAR
LAR
MSL
IM
LAR
M
IM
M
M
BL2
IM
BL2
BL1
BL1
BL1
IM
Clin
ical
Ben
efit
No
Cli
nic
al
Ben
efi
t
Kalinsky et al. SABCS 2017
TNBC-Type
3 6 9 1 2 1 8 2 4
T i m e o n S t u d y ( M o n t h s )
P R
S D
P D
Trend between Clinical Benefit and Stroma Axis D in TNBC Patients on CB-839 + Paclitaxel
29
Stromal axis D “high” subtype • 5 of 6 pts with “high” stromal D had clinical benefit
– Characterized by expression of collagens and collagen modifying enzymes associated with desmoplasia
– Recent publication linking collagen production by fibroblasts to glutaminolysis
High
High
High
Intermed
High
High
Intermed
Low
Low
Intermed
Intermed
High
Low
Low
Low
Low
Clin
ical
Ben
efit
No
Clin
ical
B
enef
it
Stroma-D Score
Kalinsky et al. SABCS 2017
SummaryCombination of CB-839 with Paclitaxel
• CB-839 is well tolerated in combination with paclitaxel in TNBC patients
• Clinical benefit demonstrated in heavily pre-treated TNBC population
• Strongest clinical benefit in pts with LAR and/or Desmoplastic Stromal gene expression biomarker signatures
• Phase 2 Study initiated to further evaluate CB-839 + Paclitaxel combination in patients with TNBC
Agenda
• Introduction to CB-839
• CB-839 combination with signal transduction inhibitors
• CB-839 combination with taxol in TNBC
• Novel combination strategies
– CDK4/6 and PARP inhibitors
Cancer vs. Normal Cell Metabolism
GLUCOSE
Pyruvate
α-KG
Glutamate
GLUTAMINE
Lactate
TCACycle
Mitochondrion
Normal Cells Cancer Cells
Intermediates for biosynthesis
(e.g. nucleotides)
Glutaminase
GLUCOSE
Pyruvate
α-KG
Glutamate
GLUTAMINE
Lactate
TCACycle
Glutaminase
Mitochondrion
CB-839
CB-839 Decreases Nucleotide Pools In Vivo
D a y s P o s t - I m p l a n t
Tu
mo
r V
olu
me
(m
m3
)
1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5
2 0 0
4 0 0
6 0 0
8 0 0
1 0 0 0
V e h i c l e
C B - 8 3 9
D o s i n g
S t a r t
* * * *
A M P
Sc
ale
d I
nte
ns
ity
Ve
hi c
l e
CB
- 83
9
0
2
4
6
* *
G M P
Ve
hi c
l e
CB
- 8
39
0 . 0
0 . 5
1 . 0
1 . 5* *
U M P
Ve
hi c
l e
CB
- 83
9
0
1
2
* *
C M P
Ve
hi c
l e
CB
- 83
9
0
1
2
*
T M P
Ve
hi c
l e
CB
- 83
9
0
1
2
* *
PDn
RPMI-8226 Xenograft Model
aspartate
a-KG citrate
fumaratemalate
oxaloacetateTCAcycleglutamate
glutamine
glutathione
CB-839succinate
nucleotides
DMSO
EdU
Inco
rpo
rati
on
CB-839
DNA Content
CB-839 Induces G1/S Cell Cycle Defect in TNBC cells
34
SUM159PT
Hs 587T
• CB-839 treatment causes cells to accumulate in G1 or S-phase (9 out of 11 cell lines)
Cells were treated with 1 mM CB-839 for 24 hours and labelled with EdU for 2 hours
DM
SO
CB
- 83
9
0
2 5
5 0
7 5
1 0 0
H s 5 8 7 T
G 1 - p h a s e
G 2 / M - p h a s e
S - p h a s e
% p
op
ula
tio
n
DM
SO
CB
83
9
0
2 5
5 0
7 5
1 0 0
S U M 1 5 9 P T
G 1 - P h a s e
G 2 / M - P h a s e
S - p h a s e
% p
op
ula
tio
n
S%
29
20.6
Rationale for Combining CB-839 with CDK4/6 and PARP Inhibitors
• CB-839 decreases in glutamate and aspartate
• Lower aspartate decreases the pool of nucleotides in tumors
• Decreased nucleotides lead to decreased rate of DNA synthesis and increased DNA damage
• We hypothesized that this effect by CB-839 on DNA synthesis and DNA damage may enhance the activity of CDK4/6 and PARP inhibitors
35
CB-839 Potentiates the Activity of CDK 4/6 Inhibitor in TNBC
36
0 . 0
0 . 5
1 . 0
Ce
ll S
ur
viv
al
(r
ela
tiv
e t
o
DM
SO
)
C B - 8 3 9
C o m b o
P a l b o c i c l i b
CB-839 (mM)
CDK4/6 inh. (mM)
plating density Day 0
1
10
.5
5
.25
2.5
.13
1.3
.063
.63
.031
.31
0
0
.0156
.16
HCC1569
DMSO CB-839 (1 mM) Palbo (2.5 mM) Combination
DNA Content
Edu
Inco
rpo
rati
on
M C F 7 ( E R+
b r e a s t c a n c e r )
C D K 4 / 6 i
C B - 8 3 9
C o m b o
1
10
37
CB-839 Enhances the Activity of CDK4/6 Inhibitor in ER+ Breast Cancer
plating density Day 0
0
.5
5
.25
2.5
.13
1.3
.063
.63
.031
.31
.016
.16
0CB-839 (mM)
Palbociclib (mM)
D a y s P o s t I m p l a n t
Tu
mo
r V
olu
me
(m
m3
)
5 1 0 1 5 2 0 2 5 3 0 3 5 4 0
4 0 0
6 0 0
8 0 0 V e h i c l e
C B - 8 3 9
P a l b o c i c l i b
C o m b o
* * * *
M C F - 7 X e n o g r a f t
No calculated CI values due to lack of dose response
CB-839 Synergizes with PARP Inhibitor in Ovarian and Breast Cancer Cell Lines
38
0 . 0
0 . 5
1 . 0
U W B 1 . 2 8 9
O v a r i a n C a n c e r
Re
lativ
e C
ell
Gr
ow
th
C B - 8 3 9
P A R P i
C o m b o
CB-839 (µM)PARP inh. (µM)Combination Index
.252.5.03
.06
.63
.02
.131.3.04
.03
.31
.04
00-
.02
.16
.02
UMB1.2896 d CellTiterGlo assayPAPR inh.=Niraparib
.01
.08
.03
.004.04.02
0 . 0
0 . 5
1 . 0
H C C 1 3 9 5
T N B C
.252.5
.06
.63.131.3
.03
.3100
plating density Day 0
.55
110
No calculated CI values due to lack of dose response
HCC13953 d CellTiterGlo assayPAPR inh.=Talazoparib
Summary
• CB-839 is an oral, highly selective inhibitor of GLS with in vitro and in vivo anti-tumor activity
• Glutaminase inhibition has several downstream effects rationalizing novel combinations – Signal transduction inhibitors: everolimus, cabozantinib, crizotinib,
erlotinib
– Cell cycle inhibitors: paclitaxel and CDK4/6 inhibitors
– DNA repair inhibitors: PARP inhibitors
• Phase 1 clinical studies have shown promising clinical activity– Renal cell carcinoma in combination with everolimus
– Triple-negative breast cancer in combination with paclitaxel
Acknowledgements
BiologyEthan Emberley
Clarissa LeeAndy MacKinnonGisele Marguier
Silinda NeouSusanne Steggerda
Sandra Spurlock
PharmacologyMatthew Gross
Jason ChenTony Huang
Amani Makkouk
DMPKWeiqun LiYong Ma
Jing ZhangWinter Zhang
ChemistryEric Sjogren
Jim LiRoland Billedeau
Lijing ChenGuy Laidig
Tim Stanton
Pharm. Dev.Peter Shwonek
Natalija Sotirovska
Clinical TeamKeith OrfordSam Whiting Mark BennettSacha Holland
Yu LiangAlison Pan