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

– s

um

of

dia

met

er

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

dia

me

ter

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