Upload
others
View
3
Download
0
Embed Size (px)
Citation preview
Targeting tumor suppressor lossto unmask vulnerabilities in cancer
for the next generation of precision medicines
Corporate overview
November 2021
Confidential | 2
Disclaimer and Safe Harbor Statement
Certain statements in this Presentation may be considered forward-looking statements. Forward-looking statements generally relate to future events, Tango’s future financial and operating performance, goals, expectations,
beliefs, development plans and development objectives for Tango’s product pipeline. In some cases, you can identify forward-looking statements by terminology such as “may”, “should”, “expect”, “intend”, “will”, “achievable”,
“milestones”, “goal”, “forecast”, “estimate”, “anticipate”, “believe”, “predict”, “potential” or “continue”, or the negatives of these terms or variations of them or similar terminology. For example, statements concerning the
following include or constitute forward-looking statements: Tango’s ability to identify, develop and commercialize drug candidates; the future anticipated benefits and future product candidates identified through the Tango
discovery platform; the expected timing of: (i) development candidate declaration for certain targets, (ii) initiating IND-enabling studies; (iii) filing INDs, (iv) clinical trial initiation and (v) the release of preliminary safety and
efficacy data and final safety and efficacy data from clinical trials; expected paths to clinical proof of concept for pipeline products; potential future product registrations for treatment of certain cancer tumor types; the initiation,
cost, timing, progress and results of research and development activities, preclinical and/or clinical trials with respect to PRMT5 and potential future drug candidates; TNG908 is a potentially first in class PRMT5 inhibitor that
is synthetic lethal with MTAP deletion; the various steps to be taken in Tango’s comprehensive development plan; the expected benefits and the timing of development and launch of the next generation PRMT5 inhibitors; in-
licensed and internal chemical matters provides what is expected to be an optimized IP position for USP1 pipeline product; recent improvements in crystal structure may drive future potency gains in USP1; the STK11
mutation enables the first potential genetic patient selection for an immuno-oncology clinical trial; estimates of Tango’s total addressable market and patient opportunity, future revenue, expenses, capital requirements and
the need for additional financing; Tango’s ability to advance TNG908/PRMT5 or other future product candidates into, and successfully complete, preclinical studies and clinical studies; the multiple key milestones identified in
this Presentation that are considered achievable; the projected milestones for TNG908/PRMT5 (including the completion of phase 1/2 trials, registrational studies start up and development of additional next generation
inhibitors); the projected milestones for the product pipeline; the discovery pipeline has the potential to deliver one new IND every 12 to 18 months; the TNG908 composition of matter patent application that has been filed
with patent offices will provide meaningful patent protection through at least 2041; and Tango has a cash balance that provides a runway into second half of 2024. Such forward-looking statements are subject to risks,
uncertainties, and other factors which could cause actual results to differ materially from those expressed or implied by such forward looking statements. These forward-looking statements are based upon estimates and
assumptions that, while considered reasonable by Tango and its management are inherently uncertain. Drug development and commercialization involves a high degree of risk, and only a small number of research and
development programs result in commercialization of a product. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. Factors that may cause actual results to
differ materially from current expectations include, but are not limited to: Tango has a limited operating history and has not generated any revenue to date from drug sales, and may never become profitable; Tango has
incurred significant operating losses and anticipates continued losses for the foreseeable future; we will need to raise capital in the future and if we are unable to raise capital when needed or on attractive terms, we would be
forced to delay, scale back or discontinue some of our development programs or future commercialization efforts; we may be unable to advance our preclinical development programs into and through the clinic for safety or
efficacy reasons or commercialize our product candidates or experience significant delays in doing so as a result of factors beyond Tango’s control; Tango’s approach to the discovery and development of product candidates
is novel and unproven, which makes it difficult to predict the time, cost of development, and likelihood of successfully developing any products; Tango may not identify or discover additional product candidates (including next
generation products) or may expend limited resources to pursue a particular product candidate or indication and fail to capitalize on product candidates or indications that may be more profitable or for which there is a greater
likelihood of success; delays or difficulties in the initiation or enrollment of patients in clinical trials could delay or prevent receipt of regulatory approvals; our products candidates may cause adverse or other undesirable side
effects that could, among other things, delay or prevent regulatory approval; even if we obtain regulatory approval to market a product, we will be subject to ongoing obligations and continued regulatory review, which may
result in significant expense; our dependence on third parties for conducting clinical trials and producing drug product; our ability to obtain and maintain patent and other intellectual property protection for our technology and
product candidates or the scope of intellectual property protection obtained is not sufficiently broad; and delays and other impacts on product development and clinical trials from the COVID-19 pandemic. Additional
information concerning risks, uncertainties and assumptions can be found in Tango’s filings with the SEC, including the risk factors referenced in Tango’s Quarterly Report on Form 10-Q for the quarter ended September 30,
2021 as filed with the SEC on November 9, 2021. You should not place undue reliance on forward-looking statements in this presentation, which speak only as of the date they are made and are qualified in their entirety by
reference to the cautionary statements herein. Tango specifically disclaims any duty to update these forward-looking statements.
Certain information contained in this Presentation relates to or is based on studies, publications, surveys and Tango’s own internal estimates and research. In addition, the market data included in this presentation involve a
number of assumptions and limitations, and there can be no guarantee as to the accuracy or reliability of such assumptions. Finally, while Tango believes its internal research is reliable, such research has not been verified
by any independent source.
Confidential | 3
COMPANY OVERVIEW
Confidential | 4
Tango summary
Precision oncology company based on synthetic lethality, combining discovery and clinical
development in the same genetic context
Expanding oncology target space into tumor suppressor gene loss with a productive,
state-of-the-art discovery platform
Sustainable pipeline of novel drug programs for cancers with specific tumor
suppressor gene loss and bringing precision medicine to immuno-oncology
TNG908 is a potentially first-in-class synthetic lethal PRMT5 inhibitor for MTAP-deleted
tumors with IND filing planned for 4Q 2021
Broad strategic collaboration with Gilead based on immune evasion effects of tumor
suppressor gene loss
Management team with deep expertise in cancer genetics, drug discovery, clinical development
and extensive pharmaceutical experience backed by top-tier investors
Confidential | 5
BOARD OF DIRECTORS
Reid Huber, PhD
Barbara Weber, MD
Malte Peters, MD
Mace Rothenberg, MD
Alexis Borisy
Chairman
Aaron Davis
Lesley Calhoun
Leaders in drug discovery, cancer biology, functional genomics and translational medicine
LEADERSHIP
John Maxwell, PhDChemistry
Barbara Weber, MDCEO
Alan Huang, PhDCSO
Daniella BeckmanCFO
Jannik Andersen, PhDBiology
Bill Mallender, PhDBiochemistry
Heather
DiBenedetto, MSDevelopment Operations
Charles Davis, PhDPharmaceutical Sciences
Doug BarryGeneral Counsel
Marc Rudoltz, MDCMO
Confidential | 6
José Baselga, MD PhDHead of Oncology R&D
AstraZeneca
Alan Ashworth, PhD FRSPresident
UCSF Cancer Center
Bill Kaelin, MD Professor, Dana Farber
Cancer Institute
Ulrich Elling, PhDInvestigator
Institute of Molecular Biotechnology, Vienna
Leaders in cancer genetics, synthetic lethality, CRISPR technology and immuno-oncology
Scientific advisors
In memoriam
1959-2021
John Doench, PhDInstitute Scientist
Broad Institute
Antoni Ribas, MD PhD Professor
UCLA
Confidential | 7
$125MUPFRONT
$6BMILESTONES
$410M/program
Up to $110M through
clinical POC
LOW
DOUBLE DIGIT
ROYALTIES
$20MEQUITY
15 TARGETSIMMUNE EVASION
50/50US PROFIT/LOSS
ON CO-CO
PROGRAMS
5 PROGRAMSCO-DEVELOP
AND CO-PROMOTE
TANGOFULL RIGHTS RETAINED
TO THREE LEAD
PROGRAMS
All new cell autonomous targets
TANGOTARGET VALIDATION
TO CLINICAL POC
GILEADMULTIPLE
TIMEPOINTS TO
LICENSE A
PROGRAM
Funded by milestone
payments during option
extension
GILEADLICENSE RIGHTS
All immune evasion
targets
SCOPERESEARCH AND DEVLOPMENT
RIGHTSSHARED
ECONOMICS DEAL TERMS
2 licensed,
2 option-extended
to date
A strong strategic partnership with Gilead
Confidential | 8
A sustainable precision oncology pipeline of novel targets
PROGRAMPATIENT
SELECTIONDISCOVERY
IND-ENABLING
CLINICAL TRIALSANTICIPATED MILESTONES
Phase 1 Phase 2 Phase 3
PRMT5
TNG908
MTAP-del
cancersIND filing 4Q 2021
USP1BRCA1-mut
cancersIND filing 2022
TARGET 3STK11-mut
lung cancerIND filing 2023
Multiple wholly owned targets in discovery phase
Gilead options and licensed targets not listed
Confidential | 9
SYNTHETIC LETHALITY FOR CANCER THERAPEUTICS
Confidential | 10
Most cancer targets are not drugged yet
SYNTHETIC LETHALITY
is currently the only way
to target tumor
suppressor gene loss
makes large scale
synthetic lethal
discovery efforts
feasible
CRISPR TECHNOLOGY
TUMOR SUPPRESSOR GENES
• Important drivers of cancer inactivated or deleted in almost all human cancers
• Not directly druggable
• Indirectly targeted with synthetic lethality
• PARP inhibitors are the first examples of synthetic lethal targeting
Confidential | 11
Synthetic lethality provides a path to targeting undruggable tumor suppressor gene loss
barglass
or
barglass
Tumor suppressor gene
Synthetic lethal
partner gene Inhibitor
No effect
Normal cell
Tumor suppressor gene
Synthetic lethal
partner geneInhibitor
Cell death
Cancer cell
X
Synthetic lethality was first described in fruit flies…
…and is now applied to cancer therapies
Confidential | 12
BRCA1/2 mutation and PARP inhibition are a synthetic lethal pair
PARP inhibitors are approved in
BRCA mutant breast, ovarian
and prostate cancer
Niraparib
Placebo
BRCA-mut
cancer cell
CELL
DEATH
+ PARPi
Normal
cell
NO
EFFECT
+ PARPi
• PARP inhibitors are clinical validation for synthetic lethal drug targeting
• Synthetic lethal drugs inherently have a wide therapeutic index
• Multiple analyses suggest hundreds of synthetic lethal pairs exist in human cancer
PARP is the first synthetic lethal drug target
Confidential | 13
A unique approach to target discovery and clinical development in the same genetic context
DISCOVERdrugs against
context-specific
target
IDENTIFYdrug targets dependent
on genetic context for
activity “context-specific”
DEVELOPdrugs in same genetic
context used for target
discovery
DISCOVERY AND
DEVELOPMENT
IN THE
SAME GENETIC
CONTEXT
SELECTcancer subtypes with
high unmet need
DEFINEgenetic alterations
in cancer subtype
“genetic context”
Confidential | 14
Cancer types with high unmet medical need
Genetic selection from the first patient dosed
Increased probability of meaningful clinical
resultsProprietary genetic
perturbation data from hundreds of CRISPR screens
Efficient screening,actionable hits
Leveraging massive public data sets from Broad, NIH
and Sanger Institute
Combinatorial, T cell co-culture and in vivo genetic screens
NOVEL TARGET DISCOVERYCOMPUTATIONAL
ANALYSISPRECISIONMEDICINE
Multiple, highly optimized CRISPR systems
Druggable genome, paralog and genome-wide CRISPR libraries
Cancer genetics Functional data
Sophisticated and proprietary
Linking large Tango and public datasets
Integrating target, genetic context &
functional data
TANDEM
Tango cancer dependency map
A robust discovery platform linked to a precision medicine approach
Confidential | 15
PRMT5 inhibition in MTAP-deleted cancers
Confidential | 16
Lead program is a potential first-in-class synthetic lethal PRMT5 inhibitor
TNG908
MTA-cooperative PRMT5 inhibitor that is synthetic lethal with MTAP deletion
DIFFERENTIATED MECHANISM
Novel MTA-cooperative mechanism targeting tumor cells with MTAP deletion enables
stronger target inhibition than non-selective PRMT5 inhibitors currently in clinical
development
LARGE PATIENT OPPORTUNITY
10-15% of all human cancers have MTAP deletion
NEAR TERM MILESTONES
Expected IND filing 4Q 2021, clinical trial initiation 1H 2022, preliminary safety and efficacy
data 1H 2023
MT
AP
Confidential | 17
MTAP DELETION
FREQUENCY
TCGA
PanCancer
Atlas
• MTAP co-deleted with tumor
suppressor gene CDKN2A
• Clear path to clinical POC in
MTAP-null solid tumors with
multiple histologies
• Potential for histology-
agnostic registration with
broad-based activity across
tumor types
10-15% of all human cancers are MTAP-null
Confidential | 18
MTAP-deleted cancer cell lines are sensitive to PRMT5 knockdown
Cell d
ea
th e
ffect s
ize
Mavrakis et al., Science 2016; Kryukov et al., Science 2016
Project DRIVE1
0.5
0
-0.5
-1
-1.5
-2
-2.5
MTAP-intact
MTAP-deleted
Cancer cell lines (n= 400)
MTAP is deleted in 10-15% of human cancers and leads to PRMT5 inhibition
MTA MTA
MTAMTA
SDMAPRMT5-specific
methyl mark
MTAP
PRMT5
SAMPRMT5 methyl donor
X
Chromosome 9p21 deletion
MTA accumulation
PRMT5inhibition
PRMT5 and MTAP are a synthetic lethal pair
Confidential | 19
Normal
cells
MTAP-null
cells
CELL DEATH
Existing PRMT5 inhibitors
CELL DEATH
TNG908
NO EFFECT CELL DEATH
PRMT5
MTAPMTAP
SAM
Substrate-Me
Degradation Degradation
MTA
MTA
MTA MTA
MTAMTA
MTA
MTA MTA
MTA
MTA
MTA
MTA
MTA
MTA
Multiple key
cellular functions
Substrate
PRMT5
SAM and MTA bind to the same pocket in PRMT5
X
X
• Work with MTA in the
active pocket
• Take advantage of
the high MTA levels
in MTAP-null tumor
cells
• Inhibit PRMT5 to
lethal threshold in
tumors at much
lower concentrations
than in normal cells
MTA-cooperative
PRMT5 inhibitors
Known PRMT5 inhibitors are not synthetic lethal with MTAP deletion
Confidential | 20
Known PRMT5 inhibitors are not synthetic lethal with MTAP deletion because of their mechanism of action
Cancer cells with no MTAP deletion
and normal cellsMTAP-deleted cancer cells MTAP-deleted cancer cells + TNG908
• PRMT5 catalyzes methyl group transfer from SAM to proteins
• GSK3326595 is substrate competitive
• Prelude, Pfizer and JNJ inhibitors are SAM competitive
• MTAP degrades MTA, which inhibits PRMT5
• MTAP deletion causes high intracellular MTA levels
• High MTA levels partially inhibit PRMT5 creating a vulnerability
• MTA-cooperative PRMT5 inhibitors require MTA in the pocket for PRMT5 binding
• TNG908 is an MTA-cooperative PRMT5 inhibitor
Cytotoxic epigenetic modifiers TNG908 is an MTA-cooperative PRMT5 inhibitor that is synthetic lethal with MTAP deletion
SAM Protein
substrate
PRMT5
MTA
PRMT5
Protein
substrate MTA
PRMT5
MeGSK
Prelude
JNJPfizer
Confidential | 21
Am
ax
at
1 µ
M
200 cancer cell lines representing multiple lineages
TNG908IC50 = 110 nM
15X selectivity for MTAP deletion
MTA-cooperative PRMT5 inhibitors are highly selective for MTAP-null cancer cell lines
MTAP WT
MTAP-null
7-day viability assay
All cell lines represented in both panelsA
max
at
1 µ
M
MTAP WT
MTAP-null
GSK3326595IC50 = 120 nM
No selectivity for MTAP deletion
Confidential | 22
TNG908IC50 = 110 nM
15X MTAP selectivity
GSK3326595IC50 = 120 nM
1X MTAP selectivity
Prelude*IC50 = 90 nM
1X MTAP selectivity
MTAP selectivity of TNG908 makes MTAP-deleted tumors 15X more sensitive than normal cells
Isogenic HAP1 cells (parental WT line)
TNG908 is 15X selective for MTAP-null cells
* Compound I from Patent WO2020168125, chemical structure of Prelude clinical molecules not disclosed
Confidential | 23
TNG908 IC50 110 nM, 15X selectivity for MTAP deletion
LN18(glioblastoma cancer cell line)
HAP1(haploid cell line)
Restoring MTAP in MTAP-null cells reverses TNG908 sensitivity
Confidential | 24
TNG908
MTA-cooperative PRMT5 inhibition is dose-dependent and MTAP-null selective
• SDMA measures PRMT5-specific methylation
• SDMA suppression in MTAP-null and WT cells
cannot be uncoupled by non-selective PRMT5
inhibitors
HCT116 colon cancer xenografts
IC90
IC90
IC90
IC90
HAP1 MTAP isogenic cell lines
150nM 550nM
Confidential | 25
TNG908 IC50 110 nM, 15X selectivity for MTAP deletion
HCT116 (colon)
TNG908 anti-tumor activity is dose and MTAP-deletion dependent
MTAP-null MTAP-WT
Confidential | 26
TNG908 drives tumor regression in MTAP-null xenograft models across lineages
NSCLC (adeno)
PDX
Bladder (TCC)
PDX
• Stasis or
regression in ~55%
of models (n=41)
• No obvious
histology restriction
• Stasis or regression
in ~60% of models
(n=52)
• No obvious histology
restriction
TNG908 IC50 110 nM, 15X selectivity for MTAP deletion
Cholangiocarcinoma
PDX
OCI-Ly19
DLBCL CDXU87MG
GBM CDX
Continuous treatment
Confidential | 27
2021 2022 2023
ADVANCED DRUG DISCOVERY PROGRAM
• Excellent drug-like properties
• Good pharmacokinetics in all pre-clinical species
• Dose-dependent, MTAP-null selective in vivo tumor regression
• In-life portion of rat and dog 28-day GLP tox studies complete, IND filing on track
• Composition of matter patent applications filed to provide meaningful patent protection through at least 2041
Development candidateselection
PHASE 1/2
TNG908 is a potentially first-in-class PRMT5 inhibitor that is synthetic lethal with MTAP deletion
IND-ENABLING
IND
filing1H study
start
1H early
clinical data
Confidential | 28
• Strong preclinical activity
in xenograft and patient-
derived models of
multiple histologies
• Expansion cohorts
provide optionality for
multiple registration
strategies
• Planned study start 1H
2022
Lung(squamous and non-squamous)
Mesothelioma
Cholangiocarcinoma
n ~ 20 each
15-70%
MTAP-null
Malignant peripheral nerve sheath
tumorsn ~ 20
30-50%
MTAP-nullAccelerated
approval option
Histology-agnostic “bucket”
(enriched for bladder,
pancreatic & unknown
primary)
n ~ 20
20-35%
MTAP-nullHistology-agnostic
approval option
Any solid tumor
with MTAP
deletion
DOSE
ESCALATION
Efficient trial design to evaluation efficacy in multiple histologiessupporting several registration strategies
CLINICAL RATIONALE
Confidential | 29
An
MTAP deletions occur in 10-15% of all human cancers
• Planning multiple rational
combination trials based on
strong pre-clinical synergy
data
• Extensive effort to define and
address resistance
mechanisms in a range of
genetic backgrounds
• Aggressive, structurally-
enabled medicinal chemistry
program of nextGen PRMT5
inhibitors with an experienced
team
• One of the largest genetically-defined
patient populations that may benefit
• Potential first-in-class PRMT5 inhibitor
that is 15X more potent in MTAP-null
cells than normal cells
• Multiple synergistic combination
partners in various cancer types
• A homozygous deletion that cannot
revert to wild-type as a resistance
mechanism
A very large and important opportunity A COMPREHENSIVEDEVELOPMENT PLAN
The most common
homozygous deletion
in human cancer
Confidential | 30
Nextgen PRMT5 exemplar compounds drive strong tumor regressions
Add
Exemplar IC50 4 nM, 20-fold selectivity for MTAP deletion
• Increased potency and MTAP-
deletion selectivity may
increase therapeutic index and
anti-tumor efficacy
• Multiple highly potent and
selective MTA-cooperative
PRMT5 inhibitors being profiled
• Next-generation compounds
follow TNG908 by ~ one year
Next-generation
PRMT5 inhibitors
LN18 (glioblastoma)
Confidential | 31
USP1 inhibition in BRCA1 mutant cancers
Confidential | 32
Control
(DMSO)
USP1i
(0.5 µM)
BR
CA
1 m
ut
BR
CA
1 W
T
UWB1.289
MDA-MB-436
HCC1954
AU565
• USP1 is a de-ubiquitinating
enzyme (DUB) that is
synthetic lethal with BRCA1
but not BRCA2
• Loss of USP1 results in
replication fork collapse in
BRCA1 mutant cells
• Some BRCA1 WT lung
cancer cell lines are sensitive
to USP1 inhibition, patient
selection marker being
evaluated
Fals
e d
iscovery
rate
Effect size Resistance markersPotential drug targets
Tango druggable genome CRISPR screen
in 13 cell line panel
USP1
USP1 and BRCA1 are a synthetic lethal pair
Confidential | 33
%
MDA-MB436 (mutant) vs HCC1954 (WT)
TNGXXX IC50 38 nM, > 200-fold selectivity for BRCA1 mutation
Lead series with good physiochemical properties and 200-fold selectivity for BRCA1 mutant cells
• Low nanomolar potency
• Highly selectivity for BRCA1
mutant vs. WT cells
• High oral bioavailability
• Moderate clearance
• Low hERG risk
Lead Series
Confidential | 34
Dose dependent in vivo anti-tumor activity with USP1 lead series exemplar
MDA-MB-436(BRCA1mut breast)
• Strong anti-tumor activity
in BRCA1 mutant
xenografts
• Recently solved inhibitor-
bound crystal structure
revealed novel allosteric
binding site
TNGXXX IC50 38 nM, >200 fold selectivity for BRCA1 mut vs. WT
Confidential | 35
SUM149PTBRCA1 mutant
SUM149PTBRCA1 WT (revertant)
• USP1i + PARPi is
synergistic in BRCA1
mutant cells but not in WT
• BRCA1 mutant selective
synergy confirmed in 16
cell line panel (6 BRCA1
mut, 10 WT)
• Synergy not seen in
BRCA2 mutant cell lines 0.001 0.01 0.1 1 10 100
0
50
100
150
SUM149PT(BRCA1m breast)
Olaparib concentration (M)
% c
ell v
iab
ilit
y r
ela
tive t
o D
MS
O
PARPi (olaparib)
PARPi + 0.12M USP1i
0.001 0.01 0.1 1 10 100
0
50
100
150
SUM149PT BRCA1 revertant
Olaparib concentration (M)
% c
ell v
iab
ilit
y r
ela
tive t
o D
MS
O
PARPi (olaparib)
PARPi + 0.12M USP1i
USP1i + PARPi is synergistic in BRCA1 mutant cells
20 fold IC50 shift
Confidential | 36
NOVEL TARGET
• Strong synthetic lethality with BRCA1
mutation
• Single agent activity and strong
PARP1 synergy in preclinical models
ADVANCED DRUG DISCOVERY
• In-licensed and internal chemical
matter provides optimized IP position,
multiple provisional patents submitted
• Lead series with low nanomolar in vivo
activity
• Recently solved inhibitor bound crystal
structure may drive further potency
gains
SIGNIFICANT PATIENT OPPORTUNITY
• ~15% ovarian, 5% breast, and 1%
prostate cancers are BRCA1 mutant,
~ half of PARP inhibitor market
• Selective dependency identified in a
subset of lung cancer cell lines, patient
selection markers being evaluated
USP1 development candidate anticipated 1H 2022
PROGRAMPATIENT
SELECTIONDISCOVERY
IND-ENABLING
CLINICAL TRIALSANTICIPATED MILESTONES
Phase 1/2 Phase 3
USP1BRCA1-mut
cancersIND filing 2022
Confidential | 37
Target 3 inhibition reverses immune evasion in SKT11 mutant cancers
Confidential | 38
The foundation of our collaboration with Gilead
Discovering drug targets that reverse immune evasion is a two-step process
Novel drug targets reverse
immune evasion in cancer cells
and enable immune cell killing
Context-specific
Immune evasion
Immune
destruction
Discover novel drug targets
that disable immune evasion
caused by specific tumor
suppressor gene loss
TARGET DISCOVERY SCREEN
2
Tumor suppressor gene loss is not directly druggable
Immune evasion driven by
tumor suppressor gene loss
CONTEXT DISCOVERY SCREEN
Identify tumor suppressor
genes that drive immune
evasion when deleted or
inactivated
1
X
Confidential | 39
Immuno-competent
+αPD1
Immuno-
competent
Immuno-
compromised
Immune evasion
contextsTumor suppressor
genes driving immune
evasion are enriched
CRISPR
tumor suppressor
gene library
Sequence tumorsgrowing under
increasing
immune pressure
Identifying tumor suppressor gene loss that drives immune evasion
Confidential | 40
Loss promotes
immune evasion
Loss promotes
immune-mediated killing
3-factor-comparison (exclude BL6)
adaptive+T
adaptive_PD1.beta
adaptive
_P
D1.f
dr
-1.00 -0.50 0.00 0.50 1.00 1.50 2.00 2.50 3.00
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
LKB1 KEAP1
Data table:
3LL-mageck4way- exclude_
Color by
Gene_type
Deleted_gene
Essential_gene
IO_positive_control
Other_gene
Tumor_suppressor
Filter settings
trends
- Gene: (Acvr1b)
masterTwoCondUsingNTC
- cond1_treatments: (nude)- cond2_treatments: (PD1_10mg)
False
discovery
rate
STK11AND KEAP1 MUTATIONS
are strongly associated
with clinical immune
evasion manifest as
checkpoint inhibitor
resistance
Nude mice vs. B6 mice + anti-PD1
Multiple tumor suppressor genes being
validated for immune evasion effect
Effect Size
STK11
Multiple tumor suppressor genes drive immune evasion when deleted
Confidential | 41
Control knockout
(MC38)
0 5 1 0 1 5
0
1 0 0 0
2 0 0 0
3 0 0 0
D a y s a f t e r t r e a t m e n t
Tu
mo
r V
olu
me
(m
m3
)
B A L B / c , P B S , I P , B I W x 2 , n = 1 8
C 5 7 B L / 6 , a n t i - I g G 2 a , 1 0 m g / k g , I P , B I W x 2 , n = 1 8
C 5 7 B L / 6 , a n t i - P D - 1 , 1 0 m g / k g , I P , B I W x 2 , n = 3 0
Immune deficient
Immune competent
Immune competent + PD1
STK11-DRIVEN IMMUNE EVASION
Unique model
validated for use in
target discovery
STK11 knockout
(MC38)
STK11 deletion drives immune evasion
0 5 10 150
500
1000
1500
Days after the start of treatment
Tum
or
volu
me
(mm
3)
Tum
or
volu
me
(mm
3)
0 5 10 150
500
1000
1500
C57BL/6 anti-PD1
Days post treatment initiation
Tu
mo
r V
olu
me (
mm
3)
NTC_nude
NTC_C57BL/6 + anti-IgG
NTC_C57BL/6 + anti-PD1
NTC+STK11_nude
NTC+STK11_C57BL/6 + anti-IgG
NTC+STK11_C57BL/6 + anti-PD1
0
500
1000
1500
0 5 10 15
Days after the start of treatment
Aggressive growth
in immune
competent mice
-PD1 resistant
0 5 10 150
500
1000
1500
C57BL/6 anti-PD1
Days post treatment initiation
Tu
mo
r V
olu
me (
mm
3)
NTC_nude
NTC_C57BL/6 + anti-IgG
NTC_C57BL/6 + anti-PD1
NTC+STK11_nude
NTC+STK11_C57BL/6 + anti-IgG
NTC+STK11_C57BL/6 + anti-PD1
-PD1 sensitive
Confidential | 42
Days
Lead series molecules with strong in vivo efficacy with anti-PD1
Biochemical IC50 6 nM
Cellular IC50 127 nM
Isoform selectivity 139
CYP3A4 IC50 >10 M
CL
(ml/min/kg)21
%F 27
Lead series exemplar
• CRISPR library of 850
immune response-related
druggable genes
• Target 3 inhibition reverses
immune evasion in STK11
mutant tumors
• Pharmacologic validation in
vivo with tool compound
Target 3 identified with in vivo CRISPR
screening• Good pharmacologic
properties with marked
isoform selectivity
Lead series
Days after treatment start
Tum
or
volu
me (
mm
3)
No detectable tumor in 10/10 mice at day 60
Treatment
stopped
Confidential | 43
STK11 and KEAP1 mutations drive clinical checkpoint inhibitor resistance
45%
33%29%
7%
Overall response rate in first line pembrolizumab + chemotherapy in non-small cell lung cancer
77% OF PATIENTS
with primary refractory
disease had STK11 and/or
KEAP1 mutations % PR/CR
as best
overall
response
ASCO 2019
Confidential | 44
NOVEL TARGET
• Multiple tumor suppressor genes play a
role in immune response to cancer
• In vivo target discovery leveraging
synthetic lethality identifies drug targets
that reverse immune evasion caused by
specific tumor suppressor gene loss
• Target 3 inhibition reverses checkpoint
inhibitor resistance in pre-clinical
STK11-mutant models
ADVANCED DRUG DISCOVERY
SIGNIFICANT PATIENT OPPORTUNITY
Target 3 IND-enabling studies planned for 2H 2022
PROGRAMPATIENT
SELECTIONDISCOVERY
IND-ENABLING
CLINICAL TRIALSANTICIPATED MILESTONES
Phase 1/2 Phase 3
TARGET 3STK11-mut
lung cancerIND filing 2023
• Multiple diverse lead series
• Structurally enabled to drive further lead
optimization
• Strong in vivo PD, in vivo efficacy with
lead series compound
• STK11 mutations occur in ~20% NSCLC
and are associated with checkpoint
inhibitor resistance
• STK11 mutation enables the first genetic
patient selection for an immuno-oncology
clinical trial
Confidential | 45
FINANCIAL HIGHLIGHTS AND MILESTONES
Confidential | 46
Cash balance Shares outstandingCash runway
a
88M common shares outstandingSufficient to fund operations into 2H 2024
$504M cash, cash equivalents and marketable securities
• Including net proceeds of $327M from SPAC/PIPE closing in August 2021
Q3 2021 financial highlights (Nasdaq: TNGX)
Confidential | 47
2021
2H2023
FY
2022
FY
IND filing for Target 3
Preliminary safety and efficacy data on TNG908 in 1H
Initiate TNG908 first-in-human clinical trial in 1H
Development candidate declaration for USP1
File IND for USP1
Development candidate declaration for Target 3
Full GLP toxicology profile for TNG908 (PRMT5)
IND filing for TNG908
Projected key milestones