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Elizabeth Buck, PhD32nd EORTC-NCI-AACR Virtual Symposium; October 24–25, 2020INV-006

BDTX-189, a Potent and Selective Inhibitor of Allosteric EGFR and HER2 Oncogenic Mutations

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MasterKey Precision Medicine;Novel Cancer Therapy Against Families of Mutations

Allosteric EGFR and HER2 oncogenic mutations represent an undrugged opportunity

Our proprietary MAP (Mutation-Allostery-Pharmacology) platform enables us to:• Identify oncogenic allosteric mutations • Aggregate these mutations into families• Discover small-molecule spectrum selective (MasterKey) therapies

BDTX-189 – Designed to be a selective MasterKey small-molecule, irreversible, orally available inhibitor

BDTX-189 – Advancing through MasterKey-01 phase 1/2 clinical trial (NCT04209465)

EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2.

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The Allosteric HER2/EGFR Mutant Oncogene Family Represents an Undrugged Opportunity for MasterKey Precision Medicine

48a allosteric oncogenic mutations in HER2 and EGFR(includes EGFR/HER2 exon 20 insertion mutants)

Amino Acid Position

Prev

alen

ce

NGS reveals thousands of undrugged ERBB mutations

MAP Scoring: An in silico approach to reveal oncogenic spectra

Amino Acid Position

Prev

alen

ce

MAP Score

DimerInterface

StructuralMotifs

Conservation

MutationExclusivity

MutationLandscape

ProteinDynamics

a Additional rare mutations continue to be aggregated into the family.EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; NGS, next-generation sequencing.

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10-8 10-7 10-6-0.4

0.0

0.4

0.8

1.2

Lapatinib Concentration

Frac

tion

of M

axim

alIn

hibi

tion

HER2 WT HER2 S310F

Allosteric EGFR/HER2 Mutations Share a Unique Activation Mechanism and Are Resistant to Current Drugs

Allosteric mutations share a unifying activation mechanism

• Mutations positioned along dimer interface

• Mutations drive activated stabilized dimer conformation

Allosteric mutations confer drug resistance

(Current-generation inactive/nonselective inhibitors)

Dimer interface

EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; WT, wild type.

10-8 10-7 10-60.0

0.4

0.8

1.2

Erlotinib Concentration

Frac

t ion

ofM

axim

alIn

h ib i

t ion

EGFR ASVEGFR WT

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Unique Pharmacology Imparted by Protein Allostery Necessitates Cell-Based Screening in Drug Discovery

Isogenic Panel of ERBB Mutants as Ba/F3 Transformants

Counterscreen vs cells driven by EGFR WT

Extracellular domain13 mutants

Juxtamembrane domain2 mutants

Exon 20 insertions21 mutants

Kinase domain12 mutants

Screen mutant panel in cellular proliferation assay

Potent, selective MasterKey therapy against family of mutations

Screen in cellular phenotypic assays

EGFR, epidermal growth factor receptor; WT, wild type.

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BDTX-189 Is a MasterKey Inhibitor of the ERBB Allosteric Mutant Oncogene FamilyPotent, selective, irreversible active site inhibitor

Average selectivity: >50 fold

Extracellular domain

Juxtamembrane domain

Exon 20 insertion

Kinase domain

EGFR WT

BDTX-189

Fold selectivity

EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; IC50, half-maximal inhibitory concentration; WT, wild type.

A431

H292

EGFR

A76

3-Y7

64in

sFQ

EAEG

FR A

767-

V769

dupA

SVEG

FR A

767-

V769

dupS

VAEG

FR S

768-

D770

dupS

VDEG

FR D

770-

N771

insG

EGFR

D77

0-N7

71in

sGYN

EGFR

D77

0-P7

72du

pDNP

EGFR

N77

1-H7

73du

pNPH

EGFR

P77

2-H7

73du

pPH

EGFR

H77

3-V7

74du

pHV

EGFR

H77

3-V7

74in

sAH

EGFR

H77

3dup

HH

ER2

A775

-G77

6ins

SVM

AH

ER2

A775

-G77

6ins

VVM

AH

ER2

P780

-Y78

1ins

GSP

HER

2 V7

77-G

778i

nsV

HER

2 A7

75-G

776i

nsYV

MA

HER

2 G

778-

S779

insG

HER

2 G

778-

S779

insC

PGH

ER2

G77

6ins

VCH

ER2

V777

-G77

8ins

CH

ER2

G58

RH

ER2

R103

QH

ER2

P122

LH

ER2

V219

IH

ER2

G22

9RH

ER2

G29

2CH

ER2

G29

2RH

ER2

A293

TH

ER2

S310

FH

ER2

S310

YH

ER2

A516

TH

ER2

A588

VH

ER2

G60

3CH

ER2

G66

0DH

ER2

R678

QH

ER2

Q70

9LH

ER2

E717

VH

ER2

T733

IH

ER2

L755

SH

ER2

D769

HH

ER2

D769

YH

ER2

G77

6VH

ER2

V777

LH

ER2

V842

IH

ER2

T862

AH

ER2

L869

RH

ER2

R123

0Q

1

10

100

1000

Antip

rolif

erat

ive

IC50

(nM

)

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EGFRHER2ERBB3ERBB4

BLK

RIPK2

Kinase KD, nM

EGFR 0.20

HER2 0.76

ERBB3 ND

ERBB4 ND

BLK 13

RIPK2 1.2

BLK, B lymphocyte kinase; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; KD, dissociation constant; ND, not determined; RIPK2, receptor-interacting serine/threonine-protein kinase 2 .

BDTX-189 Achieves a Favorable Kinase Selectivity Profile –Improved vs Current-Generation ERBB-Targeted Agents

468 kinases tested

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BDTX-189 Achieves a Superior Selectivity Profile vs Current-Generation DrugsHead-to-Head Assessment in Cell-Based Assays

Mutations assessed: HER2 S310F, HER2 P95, HER2 R678Q, HER2 L755S, HER2 V777L, HER2 YVMA, HER2 GSP, EGFRvIII, EGFR NPH, EGFR ASV. Fold selectivity derived from head-to-head cellular proliferation assays conducted to compare compounds.EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; WT, wild type.

Poor selectivity

Targeted selectivity

Erlo

tinib

Pozi

otin

ib

Afa

tinib

Osi

mer

tinib

CLN

-081

/TA

S641

7

Mob

ocer

tinib

/TA

K78

8

BD

TX-1

89

0.1

1

10

100Fo

ld S

elec

tivity

(EG

FR W

T/M

utan

t)>

9

BDTX-189 is designed to achieve rapid and sustained target occupancy

Ba/F3 HER2 S310F Transformants

BDTX-189 is designed with rapid clearance to achieve a long biological PD effect while minimizing

potential toxicities

Ba/F3 HER2 S310F Allograft Tumors

Ctrl, control; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; PD, pharmacodynamics; PK, pharmacokinetics.

0 6 12 18 240

20

40

60

80

100

Time, h

Site

Occ

upan

cy, %

MonomerDimer

0 10 200.00.20.40.60.81.01.2

01000200030004000500060007000

Time Postdose, h

Frac

tion

of C

ontro

l Act

ivity

(HER

2 Ph

osph

oryl

atio

n) PD PK

Ctrl

Plasma Exposure, ng/m

LBDTX-189 Achieves Rapid and Sustained Active Site OccupancyProfile Supports “Hit-and-Run” PK Strategy

50mpk acute dose

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BDTX-189 Is Differentiated by Potent, Sustained Inactivation of Multiple Allosteric ERBB Mutants In Vivo

Note: Once-daily oral dosing: 50 mg/kg.Ctrl, control; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; IC50, half-maximal inhibitory concentration; PD, pharmacodynamics; PDX, patient-derived xenograft; PK, pharmacokinetics; WT, wild type.

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Ctrl 4 8 12 16 20 24Frac

tion

of C

ontr

ol A

ctiv

ity(H

ER2

Phos

phor

ylat

ion)

Time Postdose, h

HER2 S310F

0.0

0.5

1.0

1.5

Ctrl 4 8 12 16 20 24

Time Postdose, h

EGFRvIII

EGFRvIII (Ba/F3)

EGFRvIII (PDX)Fr

actio

n of

Con

trol

Act

ivity

(EG

FRvI

II Ph

osph

oryl

atio

n)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Ctrl 4 8 12 16 20 24Frac

tion

of C

ontr

ol A

ctiv

ity(H

ER2

Phos

phor

ylat

ion)

Time Postdose, h

HER2 YVMA

PK/PD Properties Afford Target Coverage Across a Range of IC50 Values

IC50, nM

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BDTX-189 Achieves Dose-Dependent Regression of Allosteric HER2 and EGFRTumors at Well-Tolerated Doses

a Daily dosing of BDTX-189 was evaluated in athymic nude mice bearing HER2 S310F Ba/F3 allograft tumors up to 100 mg/kg daily dose; b Daily dosing of BDTX-189 at an oral dose of 1 to 50 mg/kg was evaluated in athymic nude mice bearing CUTO-14 PDX tumors that express the EGFR mutation EGFR ASV. ED90, 90% effective dose; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; PDX, patient-derived xenograft; QD, once daily.

Allosteric HER2 Tumors (HER2 S310F)a

Tumor Growth Regression

ED90 = 10 mg/kg

Dose-dependent tumor growth inhibition and regression in PDX models

Dose-dependent tumor growth inhibition and regression in engineered HER2 S310F tumors

QD

ED90 = 34 mg/kg

(lung adenocarcinoma)b

Tumor Growth Inhibition and Regression

10 100

-100-75-50-25

0255075

100

BDTX-189 Dose, mg/kgRel

ativ

eT u

mor

Vol

ume ,

%HER2 S310F

4 6 8 100

200

400

600

Days

Med

ian

T um

orVo

lum

e,m

m3

Vehicle Control

BDTX-189 (50 mg/kg QD)

1 10 100

-50

-25

0

25

50

75

100

BDTX-189 Dose, mg/kgRel

ati v

eT u

mor

Vol

ume,

%

EGFR A767-V769dupASV (CUTO-14)

0 5 10 15507090

110130150170190

Dosing Duration, Days

Med

i an

Tum

orVo

l um

e,m

m3

Vehicle

50 mg/kg30 mg/kg10 mg/kg3 mg/kg1 mg/kg

Limit of palpation

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BDTX-189: A Mutation Spectrum-Selective MasterKey ERBB Inhibitor Clinical Development Is Ongoing

Strong Preclinical ActivityPotent and selective

Spectrum activity against family of mutantsDose-dependent anticancer activity

BDTX-189

Ongoing Phase 1/2 MasterKey-01 Trial Estimated completion of phase 1 portion: 1H 2021

Favorable Preclinical Toxicology ProfileDesigned to spare EGFR WT-associated toxicities

Tumor Agnostic Clinical Development

EGFR, epidermal growth factor receptor; WT, wild type.

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