blu-285: a potent and highly selective inhibitor designed ... · 4/2/2017 · 10 cell line kit...
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BLU-285: A potent and highly selective inhibitor designed to target malignancies driven by KIT and
PDGFRα mutations
Erica Evans Ph.D.
New Drugs on the Horizon
2017 AACR Annual Meeting
April 2, 2017
2
Disclosures
Employee and shareholder of Blueprint Medicines
BLU-285 is an investigational agent currently in development by Blueprint Medicines
3
Activating mutations in KIT and PDGFRα are disease drivers
Mutation Disease
PDGFRα Fusion MDS, MPN, Eosinophilic leukemia
PDGFRα Exon 12 GIST
PDGFRα Exon 18 GIST
KIT Exon 9 GIST
KIT Exon 11 GIST, Melanoma
KIT Exon 13 GIST, Melanoma imatinib-resistant GIST
KIT Exon 17 Systemic Mastocytosis
Acute Myeloid Leukemia
Germ Cell Tumors
imatinib/sunitinib-resistant GIST
KIT and PDGFRα • Highly-related class III receptor tyrosine kinases • Kinase activity normally requires ligand-induced dimerization • PDGFRα activity: organogenesis, angiogenesis, vascular integrity • KIT activity: hematopoeisis, melanocytes, germ cells
Kinome illustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com) imatinib-sensitive
4
KIT activation loop mutations abrogate type II inhibitor binding Imatinib binds inactive conformation of KIT/PDGFRα
Inactive conformation
Activation loop closed, DFG-out Type II inhibitors active
Active conformation
Activation loop open, DFG-in
Type II inhibitors inactive
5
imatinib
regorafenib
sunitinib
Annotated library highlights type 1 inhibitor activity on KIT exon 17 and exon 11 activating mutations
Type II
Type I
UNIQUE KINASE-DIRECTED
COMPOUND LIBRARY
• Designed to balance novelty, potency, selectivity
• Broad and deep kinome coverage
• High quality, differentiated medicinal chemistry starting
points fully annotated across human kinome
KIT
Exon 17
D816V
KIT
Exon 11
V559D
KIT
WT
Gatekeeper
To solvent
Gatekeeper
“Selectivity” pocket
6
BLU-285 is a potent type 1 KIT/PDGFRα inhibitor that binds to the active conformation of the kinase
BLU-285
Imatinib
Activation loop open
BLU-285
Activation loop open
[chemical structure for BLU-285 removed]
[chemical structure
for BLU-285 removed]
7
BLU-285 is a potent, highly selective inhibitor of KIT and PDGFR activation loop mutants
Compound PDGFR D842V
IC50 nM
KIT D816V
IC50 nM
KIT
V560G/D816V
IC50 nM
BLU-285 0.24 0.27 0.10
imatinib 759 8150 6145
sunitinib 120 207 97.2
regorafenib 810 3640 1685
midostaurin 4.9 2.8 1.4
crenolanib 0.2 1.5 1.2
Exon 17 Exon 11/17
Activation loop
Exon 18
JM domain/
activation loop
crenolanib BLU-285 imatinib sunitinib regorafenib midostaurin
Kinome illustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com)
Type II inhibitors
Non-selective Type I inhibitors
Kinome screening at 3 µM
8
Activation Loop
Exons 17 and 18
JM Domain
Exon 11
ATP binding pocket
Exons 13 and 14
BLU-285 potently inhibits a broad spectrum of disease relevant KIT mutants
9
BLU-285 inhibits a broad spectrum of disease relevant KIT mutants more potently than imatinib
Activation Loop
Exons 17 and 18
JM Domain
Exon 11
ATP binding pocket
Exons 13 and 14
10
Cell Line KIT mutation Exon Tissue BLU-285 Imatinib
M-07e Wild type - human megakaryoblastic leukemia 192 336
HMC1.1 V560G 11 human mast cell leukemia 100 31
Kasumi N822K 17 human acute myeloid leukemia 40 126
P815 D816Y 17 murine mastocytoma 22 1235.6
HMC1.2 V560G/D816V 11/17 human mast cell leukemia 4 9143.5
CHO PDGFR D842V 18 engineered 30 3145
BLU-285 biochemical activity is recapitulated in cells
P-KIT inhibition IC50 (nM)
M-07e Wild-type KIT
HMC1.2 KIT V560G/D816V
P-KIT
T-KIT
P-AKT
T-AKT
Β-ACTIN
0
1
3
10
30
10
0
30
0
10
00
0
1
3
10
30
10
0
30
0
10
00
nM
11
BLU-285 is active in a primary activation loop mutant in vivo model
Tumor Growth
KIT Exon 17-driven P815 mastocytoma allograft: • Mutation in KIT exon 17 equivalent to human KIT D816Y
• Tumor regression observed with 10 and 30 mg/kg BLU-285 once daily, oral dosing • BLU-285 well tolerated at all doses
PK-PD
12
BLU-285 is active in imatinib-resistant GIST PDX models
Tumor Growth Exon 11/17 mutant GIST PDX
Tumor Growth Exon 11/13 mutant GIST PDX
KIT Exon 11/17 mutant (del556-558/Y823D) GIST PDX: • Tumor regression observed with 10 and 30 mg/kg BLU-285 KIT Exon 11/13 mutant (V559D/V654A) GIST PDX: • Tumor regression observed with 30 mg/kg BLU-285
13
BLU-285 is active in a primary exon 11 mutant GIST PDX model
KIT Exon 11 mutant (del557-559insF) GIST PDX: • Tumor regression observed with 30 mg/kg BLU-285, stasis with 10 mg/kg BLU-285 once daily, oral dosing • BLU-285 active against primary KIT exon 11 mutants, suggests reemergence of primary clone is unlikely
• Collaboration with P. Schoffski, (KU Leuven) Abstract #687 Monday April 3, 1- 5pm.
Tumor Growth Exon 11 mutant GIST PDX
vehicle imatinib 10 mg/kg BLU-285
30 mg/kg BLU-285
pY703 KIT
pY719 KIT
KIT
pAKT
AKT
pMAPK
MAPK
p-Histone H3 IHC
vehicle imatinib
10 mg/kg
BLU-285 30 mg/kg
BLU-285
BLU-285 Achieves Rapid Clinical Proof of Concept in Diseases Driven by KIT/PDGFRα Mutants
15
• Advanced systemic mastocytosis is a rare and severe disease that shortens life expectancy with a wide range of debilitating symptoms and organ damage
KIT D816V is a key driver in 90-95% of systemic mastocytosis
C-findings
Blood
MC degranulation MC mediator Sx
↑tryptase
Skin
Urticaria
pigmentosa Liver function abnormalities,
Ascites, or Hypersplenism
CD117 (KIT)
Osteolytic bone lesions
Cytopenias
CD117 (KIT)
GI tract
Hypoalbuminemia Weight loss
CD117 (KIT)
Bone and bone marrow Liver and Spleen
16
Encouraging clinical activity in phase 1 AdvSM study Objective decreases in mast cell burden and serum tryptase
Decreased bone marrow mast cells in 6 of 8 patients Decreased serum tryptase in 10 of 12 patients
Data cut-off date: November 11, 2016 Drummond et al. 2016 ASH Annual Conference The values above/below the bars denote the dose level (mg) QD received by each patient
17
Molecular response observed in blood and bone marrow of SM patients treated with BLU-285
Droplet digital PCR with allele specific primers measures KIT D816V allele burden in blood and BM aspirate
Data cut-off date: November 11, 2016 Drummond et al. 2016 ASH Conference
18
Cancer of the interstitial cells of Cajal
Chemotherapy has no impact
Activating KIT or PDGFRα mutations drive metastatic GIST
Most common GI sarcoma
Primary mutational hotspots
– KIT Exons 9 or 11
– PDGFR Exons 12 and 18 (D842V)
Resistance mutations
– KIT Exons 13 and 17
– PDGFR Exon 18 (D842V)
KIT ~ 80% PDGFR ~ 8%
Extracellular
Domain
JM Domain
Kinase Domain-1
Kinase Domain-2
(activation loop)
TM Domain
Exons
9
11
17
12
18
13
Colon and rectum 5%
Small intestine 30%
Stomach 60%
Duodenum 5%
19
65 year old female, Primary Gastric GIST, PDGFR D842V – Previous surgical de-bulking: stomach; peritoneal metastases x 2; colon
– Prior response to crenolanib followed by progression
– Progression on prior dasatinib (no response)
– Ongoing at Cycle 13 with confirmed partial response (-52% per RECIST1.1)
Radiographic response per RECIST 1.1 in PDGFR D842V GIST in phase 1 testing (dose level 1, 30 mg)
BASELINE WEEK 8: PARTIAL RESPONSE
(-42% per RECIST1.1)
Rapid PDGFR D842V ct-DNA decline
0 5 0 1 0 0 1 5 0 2 0 0 2 5 0 3 0 0
0
5 0
1 0 0
1 5 0
0 .0 0
0 .0 1
0 .0 2
0 .0 3
0 .0 4
0 .0 5
1 -2 0 0 3 -0 0 3
D a y s o n s tu d y
Tu
mo
r [
mm
]
PD
GF
RA
D8
42
V [%
]
C T s c a n c tD N A
PD
GF
Rα
D842V
[%]
Days on study
Tu
mo
r [m
m]
Data cut-off date: November 1, 2016 Heinrich et al. 2016 EORTC-NCI-AACR Conference
20
Strong clinical activity against PDGFR D842-mutant GIST at all dose levels
Maxim
um
re
du
ction –
su
m o
f dia
me
ter
ch
an
ge fro
m B
ase
line (
%)
30 PDGFRα Exon 14
PDGFRα D842
20
10
0
–10
–20
–30
–40
–50
–60
200
60
60
60
60
135 200 90
90 135
200 135 90
135 30
PR
SD
PD
14 out of 14 D842-mutant patients with tumor reductions
ORR = 42%, DCR = 100%
The values above/below the bars denote the dose level (mg) QD received by each patient
Data cut-off date: November 1, 2016 Heinrich et al. 2016 EORTC-NCI-AACR Conference
21
Imatinib/sunitinib-resistant GIST are enriched for KIT exon 17 mutants
4L BSC or trial
1L imatinib
2L sunitinib regorafenib
Exon 9 Exon 11
Exon 13 Exon 14
Exon 17 Exon 18
9% 67%
60-70%
20%
90%
KIT
1%
22
Significant anti-tumor activity in TKI-resistant KIT-driven GIST at higher doses M
axim
um
red
uct
ion
– su
m o
f d
iam
eter
chan
ge
fro
m b
asel
ine
(%)
80
70
60
50
40
30
20
10
0
-10
-20
-30
-40
-50
-60
-70 #: off treatment
BLU-285
30 – 90 mg BLU-285
135 – 300 mg
90
60 30
30 90 30
60
300
135 200 300
300
135
PD
SD
PR
# #
# # #
#
# • 4 of 6 patients with tumor reduction
• 5 of 6 patients remain on treatment ≥ 5 cycles
The values above/below the bars denote the dose level (mg) QD received by each patient.
Data cutoff date: November 1, 2016 Data cut-off date: November 1, 2016 Heinrich et al. 2016 EORTC-NCI-AACR Conference
The values above/below the bars denote the dose level (mg) QD received by each patient
23 *Exposures adjusted for free fraction
• PDX data suggest active dose range for KIT mutant GIST at levels ≥ 135 mg • Expansion cohorts for GIST phase 1 trial recently initiated with RP2D of 400 mg QD
*
BLU-285 demonstrates dose dependent human pharmacokinetics PDX studies suggest clinical exposures in therapeutic range
24
KIT/PDGFRα activation loop mutants are unaddressed by approved therapies
Insights from BPMC library catalyzed design of BLU-285, a potent, highly-selective type 1 inhibitor of KIT/PDGFRα activating mutants
Potent activity of BLU-285 on KIT/PDGFR activation loop mutants has informed initial clinical development strategy resulting in early clinical proof of concept in several patient populations
Ma
xim
um
re
duction –
su
m o
f d
iam
ete
r ch
ange fro
m B
aselin
e (
%) 30
PDGFRα Exon 14 PDGFRα D842
20
10
0
–10
–20
–30
–40
–50
–60
200
60
60
60 60
135 200 90
90 135
200 135 90 135
30
PR
SD
PD
Type 1
KIT Exon 17 D816V
KIT Exon 11 V559D
KIT WT
Type 2
In summary, mechanistic and structural understanding of disease-driving
mutations paired with tailored inhibitors can accelerate drug development
[chemical structure
for BLU-285 removed]
25
Thanks to all participating patients and their families
Thanks to all study investigators, nurses and research coordinators
- Abramson Cancer Center at the University of Pennsylvania
- Dana-Farber Cancer Institute
- Fox Chase Cancer Center
- MD Anderson Cancer Center
- Oregon Health & Science University
- Stanford University
- University of Colorado
- University of Michigan Comprehensive Cancer Center
- University of Utah, Huntsman Cancer Institute
- Centre Leon Berard
- Erasmus MC Cancer institute
- Gartnavel General Hospital, Beatson West of Scotland Cancer Center
- Guy's & St Thomas NHS Trust
- Institut Gustave Roussy
- Leuven Cancer Institute
- Royal Marsden Hospital / Institute for Cancer Research
- University of Essen
Thanks to our collaborators - Michael Heinrich (Oregon Health & Science University)
- Patrick Schöffski (Leuven Cancer Institute)
Thanks to all colleagues at Blueprint Medicines
Acknowledgements