1

Elizabeth Buck, PhDSociety for Neuro-Oncology’s 25th Annual Meeting and Education DayEXTH-59

Potent, selective, and brain penetrant inhibitors of extracellular domain EGFR oncogenic mutants expressed in GBM demonstrate efficacy in an intracranial patient derived xenograft model

2

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 – Selective MasterKey small-molecule inhibitor directed against allosteric EGFR/HER2 mutants expressed in solid tumors; Advancing through MasterKey-01 phase 1/2 clinical trial (NCT04209465)

GBM program – Selective and brain-penetrant small-molecule inhibitor directed against EGFR mutants expressed in glioblastoma; IND candidate nomination expected Q4’20

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

3

Erlotinib

Placebo

Time (months)

PFS

(%)

HR=0.10 (0.04-0.25)log-rank p<0.0001

NSCLC Trial1

KinaseDomain

Mutation

Allosteric mutation

Time (months)

p=0.003

PFS

(%)

GBM Trial2

Erlotinib in WT-EGFR GBM PatientsErlotinib in EGFR-Viii+ GBM Patients

1 Capuzzo et al Lancet 20102 Van den Bent et al JCO 2009

2

1

EGFR TKIs Do Not Extend PFS in

Allosteric Mutants in the Clinic

EGFR-TKI Extends Progression-Free Survival (PFS) in

Kinase Domain (KD) Mutants in the Clinic

Not All Oncogenic Mutations Are Alike

Dissecting Altered Pharmacology for EGFR Oncogenes In Glioblastoma

4

Designed to inhibit a spectrum of concurrently expressed allosteric EGFR mutations found in GBM

patients

AddressingGenetic Drivers

of GBM

Demonstrated potency against allostericEGFR mutants while sparing WT-EGFR,

providing a favorable safety profile

SelectivityOver WT-EGFR

Brain penetrating properties as a design ruleto ensure adequate drug exposures

BrainPenetrance

Development candidate nominationand IND-enabling studies expected in 2020

RapidPreclinical

Advancement

BDTX-GBM

BDTX-GBM Molecules Are Designed to be Potent, Allosteric EGFR Selective, and Brain Penetrant

5

Approximately 50% of GBM tumors express oncogenic EGFR variants

Extracellular region Intracellular region

Viii Vvi Vii

Tum

or fr

eque

ncy

(log)

• GBM cells express multiple allo-EGFR isoforms1

• Necessitates spectrum-selective TKIs1

39

36

18

13

9 9

6 5 42 2 1 1 1 1 1

0

10

20

30

40

CNA

SV

VviVvi

Vii

Viii

Set Size

Inte

rsec

tion

Size

0 50 100

Viii

A289

Vvi

Vii

G59

8

AA P

ositi

on 0

200

400

600

Tran

smem

bran

e re

gion

800

1000

1200

1 Based on data presented in supplementary figures for Brennan et al Cell 2013

GBM Tumors Express a Family of Allosteric EGFR Oncogenic Mutations in the Extracellular Domain

6

Allosteric EGFR Oncogenes Expressed in Glioblastoma Are Activated As Covalently Linked Homodimers

Mutations give rise to free cysteines at the extracellular dimer interface & result in covalently linked oncogenic dimers

covalent dimer

covalent dimer

Lysates derived from cells expressing EGFR-WT or EGFRvIII electrophoresed under non-reducing (-) or reducing (+) conditions to enable detection of high molecular weight covalent dimer

Dimer Interface

reductant

7

Ligand promotes dimerization to activate kinase

Monomers / dimers in equilibrium

Mutations line dimer interface

Form ligand-independent stabilized/locked dimers (LoDi-EGFR mutants)

WT-EGFR

Allo-ErbB oncogenes

Monomers Reversible Dynamic Dimers

Monomers Stabilized / Locked Dimers

Inactive Active

The Conformation of Allo-EGFR Locked Dimers Is Distinct From WT-EGFR

8

ATP mimetics can promote increased dimerization throughout EGFR

ProliferationDimerization – EGFR mutant

Erlotinib paradoxically stimulates cell proliferation in cells driven by LoDi-EGFR mutants

REVEAL

EGFR Mutant Covalent Dimer Conformation Affects The Pharmacology For Small Molecule Drugs

ATP mimetics(erlotinib/afatinib/osimertinib …)

9

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

Isogenic Panel of EGFR Mutants as Ba/F3 Transformants

Counterscreen vs cells driven by EGFR WT

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.

Approximately 50% of GBM tumors express oncogenic EGFR variants

Extracellular region Intracellular region

Viii Vvi Vii

Tum

or fr

eque

ncy

(log)

Viii

A289

Vvi

Vii

G59

8

AA P

ositi

on 0

200

400

600

Tran

smem

bran

e re

gion

800

1000

1200

10

BDTX-GBM Candidates Achieve Potent & Selective Inhibition of the Family of Allosteric EGFR Variants Expressed in GBMPotency & selectivity not similarly captured by current generation TKIs

Anti-proliferative activity against BaF3 transformants expressing allosteric EGFR oncogenes versus EGFR-WT expressing A431 cells

BDTX-700 BDTX-1535

BDTX-700 and BDTX-1535: potent, selective, irreversible active site inhibitors of allo-EGFR mutants expressed in GBM

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Mean [Brain]

Mean [Plasma]

BDTX-GBM Leads Designed For Brain Penetrant PK Profile

1

10

100

1000

10000

0.250 1.00 2.00 4.00 8.00

Conc

entr

atio

n (n

g/m

L) o

r (ng

/g)

Time (h)

Mean Plasma and Brain Concentration of BDTX-700 in Mouse (15.0 mg/kg PO)

Kpuu = 0.19

1

10

100

1000

10000

0.250 1.00 2.00 4.00 8.00

Conc

entr

atio

n (n

g/m

L) o

r (ng

/g)

Time(h)

Mean Plasma and Brain Concentration of BDTX-1535 in Mouse (15 mg/kg PO)

Kpuu = 0.265

PK was conducted in fasted, male Balb/C mice. Plasma was collected , prepared and analyzed by LC-MS/MS analysis. Brain homogenate samples were prepared after homogenizing brain with homogenizing solution, then analyzed by LC-MS/MS. Kp = AUCbrain/AUCplasma. Kpuu was calculated using the formula Kpuu = Kp*Fubrain/Fuplasma.

12

BDTX-GBM Leads Achieve Engagement Of Allosteric EGFR Mutants In Vivo

BDTX-700 BDTX-1535

Mice bearing BaF3 allograft tumors expressing EGFR-Viii treated with a single oral dose of 50mg/kg, followed by determination of phosphorylation state of EGFR at 4, 8, 10, 12 and 24 hours following dosing

BDTX-700 and BDTX-1535 achieve complete and sustained inhibition of pEGFR in allo-EGFR mutant expressing tumors following a single oral dose

13

Imaging of GBM6 orthotopic brain patient derived xenograft tumors expressing EGFR-Viii

BDTX-GBM Leads Achieve Tumor Growth Inhibition Of Intracranial PDX Tumors Expressing Allosteric EGFR Mutants

• Dr. David Raleigh• Dr. Tomoko Ozawa

Bioluminescence imaging in mice expressing intracranial GBM6 patient derived tumors. Mice were treated orally with 50mg/kg of BDTX-700 or BDTX-1535

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BDTX-GBM Molecules Are Designed to be Potent, Allosteric EGFR Selective, and Brain Penetrant

Target Multiple Mutations in GBMCandidates designed to inhibit full

spectrum of allosteric-EGFR mutationvariants expressed in GBM

Selectivity Over WT-EGFRDemonstrated potency against allosteric

EGFR mutants while sparing WT-EGFR, providing a favorable safety profile

Brain PenetranceBrain penetrant properties as a design rule to ensure adequate drug exposures

Rapid Pre-Clinical AdvancementDevelopment candidate nomination andcommencement of IND-enabling studiesexpected in 2020

BDTX-GBM

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