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
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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 – 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.
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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
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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
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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
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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
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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
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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 …)
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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.
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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
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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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