Corporate Presentation - March 2022 March 2022 - March 2022 vF
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Corporate Presentation
March 2022
1
March 2022
DISCLAIMER
This presentation includes express and implied “forward-looking statements. Forward looking statements include all statements that are
not historical facts, and in some cases, can be identified by terms such as “may,” “might,” “will,” “could,” “would,” “should,” “expect,”
“intend,” “plan,” “objective,” “anticipate,” “believe,” “estimate,” “predict,” “potential,” “continue,” “ongoing,” or the negative of these terms, or
other comparable terminology intended to identify statements about the future. Forward-looking statements contained in this presentation
include, but are not limited to, statements about our product development activities and clinical trials, our regulatory filings and approvals,
our ability to develop and advance our current and future product candidates and discovery programs, our ability to establish and
maintain collaborations or strategic relationships or obtain additional funding, the rate and degree of market acceptance and clinical utility
of our product candidates, the ability and willingness of our third-party collaborators to continue research and development activities
relating to our product candidates, our and our collaborators’ ability to protect our intellectual property for our products. By their nature,
these statements are subject to numerous risks and uncertainties, including factors beyond our control, that could cause actual results,
performance or achievement to differ materially and adversely from those anticipated or implied in the statements. You should not rely
upon forward-looking statements as predictions of future events. Although our management believes that the expectations reflected in our
statements are reasonable, we cannot guarantee that the future results, performance or events and circumstances described in the
forward-looking statements will be achieved or occur. Recipients are cautioned not to place undue reliance on these forward-looking
statements, which speak only as of the date such statements are made and should not be construed as statements of fact.
Certain information contained in this presentation and statements made orally during this presentation relate to or are based on studies,
publications, surveys and other data obtained from third-party sources and our own internal estimates and research. While we believe
these third-party studies, publications, surveys and other data to be reliable as of the date of this presentation, it has not independently
verified, and makes no representations as to the adequacy, fairness, accuracy or completeness of, any information obtained from third-
party sources. In addition, no independent source has evaluated the reasonableness or accuracy of our internal estimates or research
and no reliance should be made on any information or statements made in this presentation relating to or based on such internal
estimates and research.
2
March 2022
ENTRADA’S MISSION
Treating Devastating Diseases With
Intracellular Therapeutics
3
March 2022
THE ENTRADA STORY
We are driven to transform the lives of patients by establishing Endosomal Escape Vehicle* therapeutics
as a new class of medicines and become the world’s foremost intracellular therapeutics company
Platform Portfolio People
Diverse set of oligonucleotide
A proprietary, modular and Led by a team of experts
applications and an
broadly applicable with extensive experience
expanding pipeline, including
intracellular delivery platform across drug discovery,
intracellular
with potential in a wide range development and company
oligonucleotides, antibodies
of therapeutic areas management
and enzymes
We are harnessing our EEV Platform to develop intracellular therapeutics that are designed to engage
previously undruggable targets and revolutionize the treatment of devastating diseases
* Endosomal Escape Vehicles are referred to as EEVs
4
March 2022
LEADERSHIP TEAM AND BOARD OF DIRECTORS
Board of Directors
Kush Parmar, MD, PhD
Managing Partner
5AM Ventures
(Board Chairman)
Peter S. Kim, PhD
Virginia & D.K. Ludwig Prof. of Biochemistry
Stanford University
Dipal Doshi Natarajan Sethuraman, PhD Nerissa Kreher, MD Nathan Dowden Todd Foley
President & CEO Chief Scientific Officer Chief Medical Officer Chief Operating Officer Managing Director
MPM Capital
John Crowley
Chairman & CEO
Amicus Therapeutics
Mary Thistle
Special Advisor
Bill & Melinda Gates Foundation
Carole Nuechterlein, JD
Head
Roche Venture Fund
Kory Wentworth, CPA Kerry Robert Jared Cohen, PhD, JD Karla MacDonald
Chief Financial Officer Vice President, People General Counsel Vice President, Corporate
Communications & IR
5
March 2022
OUR DIFFERENTIATED AND EXPANDING PIPELINE
Entrada’s pipeline includes a diverse array of high potential and high value assets;
We plan to leverage early learnings to advance subsequent programs
Clinical
Disease/Condition Discovery Preclinical
Phase 1 Phase 2 Phase 3
ENTR-601-44 Exon 44 Skipping Oligonucleotide
Neuromuscular Disease: DMD
Exon 45 Skipping Oligonucleotide
Neuromuscular Disease: DM1 CUG Steric Blocker Oligonucleotide
Neuromuscular Disease: Pompe GYS1 Knockdown Oligonucleotide
Neurodegenerative Diseases CD33 Exon 2 Skipping Oligonucleotide
Inflammatory Diseases IRF5 Knockdown Oligonucleotide
Solid Tumors β-catenin Degrader Antibody
MNGIE ENTR-501 Enzyme Replacement
6
March 2022
EEV PLATFORM
7
March 2022
ENDOSOMAL ESCAPE VEHICLE (EEV TM) PLATFORM
The EEV Platform aims to solve a fundamental problem: lack of efficient cellular uptake and escape
from the endosome. Both are critical to intracellular target engagement and therapeutic benefit
• Cyclic structure designed to extend half
life and increase stability
• Phospholipid binding potentially enables
broad biodistribution to all cells
• Unique chemistry results in improved
uptake and endosomal escape
2. Binding to
Endosome Nucleation Budding Post
Membrane Zones Process Collapse
EEVTMR
DextranAlexa
The combined benefits of Entrada’s unique EEV Platform are designed to drive an enhanced therapeutic index
8
1. 90% retention after 24 hours based on mass balance 2. Sahni, Qian, Pei; ACS Chem. Biol. 2020
March 2022
A BROADLY APPLICABLE PLATFORM
Entrada has demonstrated intracellular uptake of unique moieties ranging from 1 kDa to 600 kDa
Antibodies Enzymes Oligonucleotides
550-600 KDa 150 KDa 98 KDa 96 KDa 86 KDa 46 KDa 37 KDa 32 KDa 16 KDa 6 KDa 1-3 KDa
Hybrid frataxin Antibody Thymidine Purine Alanine- Human frataxin PTP1B EGFP Nanobody Oligonucleotide Various
phosphorylase nucleoside glyoxylate Catalytic peptide cargos
phosphorylase aminotransferase domain
9
March 2022
DIFFERENTIATED PHARMACOLOGY
We believe the unique properties of Entrada’s EEVs can potentially endow favorable pharmacologic
properties to therapeutics to enable improved half-life, uptake and expression throughout the body
Long Half-Life in Circulation High Uptake In Tissue Target Engagement in the Cell
Neuromuscular
ENTR-601-44 in NHP Plasma EEV-PMO
10 6
10 5 Immunology
Concentration (nM)
30 mg/kg IV in NHP
10 4
and Oncology
10 3
10 2
10 1 Skeletal and
10 0
cardiac muscle Monocytes and
10 -1
0 10 20 30 40 50 macrophages
Time (hr)
ENTR-501 in NHP Plasma EEV-Enzyme
10 6
5 mg/kg IV
15 mg/kg IV
10 5 5 mg/kg SC
15 mg/kg SC
Serum ENTR-501
Cerebellum
10 4
Neurodegenerative
(ng/mL)
10 3 and Pain
10 2 DRG
10 1
0 24 48 72 96 120 144 168 192 216 240
Hours
10
March 2022TRANSLATION FROM UPTAKE TO OUTCOMES
EEV-therapeutic candidates observed to significantly improve reaching intracellular targets and
can potentially enable high tissue concentration across a range of therapeutic applications
Long Half-Life Upregulation via Exon Skipping Splice Correction via CUG Repeat Block
10 6 Cardiac Dystrophin Expression Splicing of Mbnl1
30 mg/kg IV in NHP
10 5 40 15
Concentration (nM)
Exon 5 Inclusion (%)
10 4
% of WT Dystrophin
10 3 30 EEV-PMO corrected
10
DM1 associated splicing
10 2
20 defects with a single
10 1 dose
5
10 0
10
10 -1
**
**
0 10 20 30 40 50 0
0
Time (hr) WT Vehicle DM1 Vehicle 30 mg/kg 15 mg/kg 30 mg/kg
1W 2W 4W PMO-DM1 EEV-PMO-DM1
High Concentration and Downregulation via Exon Skipping and Downregulation via Exon Skipping and
Concomitant Gene Expression Nonsense Mediated Degradation Nonsense Mediated Degradation
Enables 1.5
10000 100
Tissue Concentration Near complete 1.5
Knockdown of target protein
Tissue Concentration (ng/g)
knockdown of gene
Proportion of GYS1
mRNA Expression
80
expression relevant to multiple
Relative IRF5 expression
1000 expression relevant to
Exon Skipping (%)
1.0
Exon Skipping immune mediated diseases
60 Pompe disease with a 1.0
100 DMD example single dose
40 0.5 ✱
10 0.5
20
0.0
** ** ✱✱
✱✱✱
1 0
e
O
O
O
cl
PM
PM
PM
hi
0.0
Ve
10 20 30 40
V-
V-
kg
EE
EE
g/
m
g
g
Dose (mg/kg)
k
k
μM
μM
e
M
27
g/
g/
cl
3μ
m
m
hi
30
10
3.
27
.5
Ve
13
11
March 2022DUCHENNE MUSCULAR DYSTROPHY (DMD)
12
March 2022DMD DISEASE OVERVIEW
A significant therapeutic need exists within a validated DMD market;
A safe and effective approach is necessary to treat patients over the long term
• Disease caused by mutations in the DMD gene and altered levels of 7.6%
normal dystrophin
8.1%
• Lack of functional dystrophin leads to muscle cell membrane damage
and progressive loss of function
9.0%
• Progressive muscle degeneration, wasting and paralysis generally lead
to death via respiratory and/or cardiac failure in the third or fourth
decade
• ~30,000 patients in the US and Europe 14.0%
• Corticosteroids are the current standard of care
• Exon skipping therapeutics have been approved based on a very
modest improvement in dystrophin levels ranging from ~1 to ~6% ~40% (~12,000 US and Europe total) of
patients with DMD have mutations
• Continued FDA approval of existing exon skipping drugs may amenable to exon skipping of exons 44,
require verification of clinical benefit in confirmatory clinical trials 45, 51 and 53
13
March 2022REPEAT EEV-PMO TREATMENT RESTORES
MUSCLE INTEGRITY IN RIGOROUS D2-mdx MICE
Robust exon 23 skipping after four monthly IV doses of Broad dystrophin expression and restoration of muscle integrity after
EEV-PMO-23 in D2-mdx mice four monthly IV doses of EEV-PMO-23 in D2-mdx mice
Representative Immunofluorescence of Gastrocnemius Muscle (Dystrophin Staining in Green)
Heart Diaphragm
100 **** 100 ****
**** ****
80
Exon skipping (%)
80
Exon skipping (%)
60 60
40 40
20 n.s. 20 n.s.
0 0
Vehicle PMO EEV-PMO Vehicle PMO EEV-PMO
Tibialis Anterior Triceps
**** Representative Histopathology of Gastrocnemius Muscle (H&E Staining)
**** ****
120 **** 100
100 80
Exon skipping (%)
Exon skipping (%)
80
60
60
40
40
n.s.
20 n.s. 20
0 0
Vehicle PMO EEV-PMO Vehicle PMO EEV-PMO
• D2-mdx is a DMD mouse model on DBA/2J background and better recapitulate disease pathology (Fukada et al. Am. J. Path. 2010)
• D2-mdx mice (male, n=6-7) were treated with 4 monthly doses of either vehicle, 20 mg/kg PMO or 20 mg/kg PMO equivalent of EEV-PMO, and the data were
collected ~4 weeks after the last dose
14
n.s. not significant, *pREPEAT EEV-PMO TREATMENT RESULTS IN CK
CORRECTION AND FUNCTIONAL IMPROVEMENT
Repeat EEV-PMO-23 treatment normalized serum CK levels and showed significant improvements in
muscle function when compared to PMO alone after four monthly IV doses in D2-mdx mice
Serum Creatine Kinase (CK) Levels Wire Hang Time Grip Strength
n.s.
**** ****
Normalized grip strength: Fgm/gm
250 400 ** 5
*
Creatinine Kinase U/L
Wire Hang Time (Sec)
200 4 n.s.
300
150 3
200
100 n.s. 2
100
50 1
0 0 0
Wild Type Veh PMO EEV-PMO Wild Type Veh PMO EEV-PMO Wild Type Veh PMO EEV-PMO
• D2-mdx is a DMD mouse model on DBA/2J background and better recapitulate disease pathology (Fukada et al. Am. J. Path. 2010)
• D2-mdx mice (male, n=6-7) were treated with 4 monthly doses of either vehicle, 20 mg/kg PMO or 20 mg/kg PMO equivalent of EEV-PMO, and the data were
collected ~2 weeks after the last dose
15
n.s. not significant, *pSIGNIFICANT PROMISE OF ENTR-601-44 IN PATIENT
CELLS AND TRANSGENIC MOUSE MODELS
Robust dose-dependent exon 44 skipping and
Dose-dependent tissue exposure and exon skipping in cardiac and skeletal
dystrophin protein restoration were observed in DMD
muscles in a transgenic mouse carrying the full-length human DMD gene
patient-derived muscle cells treated with ENTR-601-44
Exon Skipping
Heart Tibialis Anterior (TiA) Diaphragm
120
**** ****
**** 100000
% DMD Exon 44 Skipping
100.0 98.7
100 93.0 10000 10000 100
Tissue Concentration (ng/g)
100 100
Tissue Concentration (ng/g)
Tissue Concentration (ng/g)
10000
Exon Skipping (%)
80 80
1000
Exon Skipping (%)
80 1000
Exon Skipping (%)
80
1000 60
60 60
100 60
100 100 40
40 40
40
10 10 20
20 20 10
10.9 20
0
0 0 1
0 1 0
1 0 20 40 60 80 100
Healthy DMDΔ45 10 µM 3 µM 1 µM 0 20 40 60 80 100
Dose (mg/kg)
0 20 40 60 80 100 Dose (mg/kg)
Dose (mg/kg) Tissue Concentration
(ng/g) Exon Skipping (%)
Dystrophin Restoration
120
• hDMD transgenic mice express full-length human dystrophin gene which
% Dystrophin Restoration
100.0
100
80
allows for preclinical testing (target engagement) of human sequence-
60
**** specific PMO for DMD transcript correction
43.7
****
40 33.8 ****
24.7 • Exon skipping and tissue concentrations in various muscles groups
assessed 5-day post 10, 20, 40 and 80 mg/kg IV dosage
20
4.2
0
Healthy DMDΔ45 10 µM 3 µM 1 µM
****pENTR-601-44 IN NHP CONFIRMS LEAD CANDIDATE
A single 30 mg/kg IV dose of ENTR-601-44 resulted in meaningful
An extended circulating half-life for ENTR-601-44
levels of exon skipping in both skeletal muscles and the heart of the
was observed in the NHP
NHP which provides confidence in translational potential
ENTR-601-44 in NHP Plasma ENTR-601-44 Exon Skipping in NHP Muscle
120%
100%
Exon Skipping (%)
80%
60%
40%
20%
0%
• At 7 days post 1 hour IV infusion at 30 mg/kg, robust exon 44 skipping observed across different muscle groups isolated from the
ENTR-601-44 treated NHP
17
March 2022ENTRADA DMD DATA SUMMARY
Entrada’s mouse and NHP data are consistent and promising;
These advances represent a robust set of translational data
• Promising exon skipping across mdx, D2-mdx, human dystrophin mouse and NHP studies
• Exon skipping translates to promising dystrophin production in heart and skeletal muscles
• Dystrophin production sufficient to result in functional improvement
• Durable dystrophin production over 4+ weeks from a single injection
• ENTR-601-44 candidate selected on the basis of exon skipping and tolerability with IND planned in 2H 2022
• Accelerating exon 45 candidate expected to enable second DMD candidate selection in quick succession
18
March 2022MYOTONIC DYSTROPHY TYPE 1 (DM1)
19
March 2022DM1 OVERVIEW
DM1 is a debilitating multi-systemic disease with no available treatments; CUG repeats in DMPK
mRNA sequester MBNL1 proteins, resulting in aberrant gene expression and protein expression
• DM1 affects over 40,000 in US and over 50,000 in Europe
Prevalence of at least 1 in 8,000 worldwide
Congenital 15%, childhood 10%, or classical (adult onset) 75%
Multisystemic; including myotonia, muscle weakness and atrophy,
cardiac and pulmonary complications, cataracts and endocrine
dysfunction
Currently no approved therapies
• DM1 is caused by CUG repeats in the mRNA that sequester
MBNL proteins and retain them in the nucleus
Mutant DMPK mRNA and MBNL proteins form aggregates called
foci in the nucleus
• MBNL activity is decreased as a result of sequestration
MBNL proteins are responsible for splicing and expression of many
downstream transcripts, including MBNL1, BIN1, INSR, LDB3 and
SOS1
• PMOs can be used to bind to the CUG repeats in mutant DMPK
mRNA
Decrease the number of foci in the nucleus
Adapted from Todd and Paulson, 2012
Increase MBNL activity and restore splicing and expression
20
March 2022CUG-REPEAT BLOCKING PMO IN DM1 MYOTUBES
Administration of EEV-PMO in a DM1 patient-derived cell line resulted in a dose-dependent correction
in MBNL1 gene splicing associated with muscle tissue development and insulin response
MBNL1 SOS1 BIN1
80 80 100
*
** *** *** 80
***
% Exon 11 Inclusion
% Exon 25 Inclusion
% Exon 5 Inclusion
60 60
60
40
40 40 4
CUG repeat blocking *
3 ***
***
with EEV-PMO Steric 20 20 2
Blocker *** 1 **
0 0
0
µM
1
µM
µM
y
µM
µM
1
µM
µM
M
y
lth
µM
µM
1
µM
µM
y
µM
M
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D
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lth
3
10
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ea
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0.
3
10
3
1
ea
D
3
10
3
1
0.
H
ea
0.
H
H
EEV-PMO
LDB3 INSR
120 8
*pEEV-PMO-CAG IN DM1 MURINE MODEL
Single administration of EEV-PMO-CAG in DM1 murine model resulted in full correction of disease
relevant splicing biomarkers in various muscle groups and myotonia phenotype
Splicing of Atp2a1 Splicing of Nfix Splicing of Clcn1 Splicing of Mbnl1
100 *** *** 80 25 15
WT Vehicle
Exon 5 Inclusion (%)
Exon 22 Inclusion (%)
Exon 7a Inclusion (%)
Exon 7 Inclusion (%)
80 20 DM1 Vehicle
60
10 30 mg/kg PMO-CAG
60 15
40 15 mg/kg EEV-PMO-CAG
40 10 30 mg/kg EEV-PMO-CAG
5
20 *** *pADDITIONAL PROGRAMS
23
March 2022THERAPEUTIC AREA EXPANSION
We plan to advance beyond rare disease markets into broader therapeutic areas over the next
several years, bringing EEV-therapeutic candidates to more patients with devastating diseases
CNS and Beyond
Beyond
Immunology and Oncology
Neuromuscular
24
March 2022IMMUNOLOGY
IRF5 has been shown to be a master switch implicated in proinflammatory cytokine release and
M1 polarization across high unmet need diseases, making this an attractive “pipeline in a product”
IRF5 Implicated Across a Wide Range of Diseases Significant Knockdown
IRF5 of IRF5
Protein expression 24hrExpression in vitro
post-treatment
1.5
Relative IRF5 expression
CNS/Pain
MS
Neuropathic pain
Rheum 1.0
RA
JRA
OA ✱
Interferon Regulatory Cardiometabolic
Atherosclerosis
Polyarthritis
Factor 5 Obesity
CHF post AMI Multisystem
0.5
✱✱
SLE ✱✱✱
Glycolysis Sjogren’s Syndrome
Scleroderma
HLH Gastro 0.0
Pro-inflammatory cytokines Ulcerative Colitis
Crohn’s
µM
µM
M
e
(IFN, TNFa, IL6,12, 23, etc.)
cl
3µ
PBC
hi
30
10
3.
Pulmonary
Ve
NASH
Asthma ALD *pADDITIONAL PLATFORM OPPORTUNITIES
Entrada continues to invest in and build upon our EEV Platform to extend our efforts in
developing novel EEV-therapeutic candidates
Target Platform Approach Goal
DNA Gene editing Deliver CRISPR enzyme and repair gene function with guide RNA
RNA editing Deliver oligonucleotide therapeutics for RNA editing
RNA splicing Modify RNA via exon/intron splicing to activate protein expression
RNA
RNA blocking Block trinucleotide repeats in RNA to inhibit adverse binding
RNA silencing Silence or knockdown RNA to prevent protein expression
Protein replacement Replace proteins and enzymes
Protein Protein inhibition Inhibit protein signaling pathways
Protein degradation Degrade disease-causing proteins
26
March 2022CORPORATE HIGHLIGHTS AND
MILESTONES
27
March 2022KEY CORPORATE HIGHLIGHTS
With ~$122M cash and cash equivalents as of September 30, 2021, and our recent IPO, Entrada is
well capitalized to deliver initial DMD human data from ENTR-601-44 and progress the pipeline
IPO on October 29, 2021 33 Distinct Patent
(Nasdaq: TRDA) >100 Employees
Families on File
• IPO Price: $20 • Exclusive EEV Platform rights • Seasoned leadership team
across functions
• Shares Issued: 10,436,250 • 5 families with one or more
granted patents covering • Recognized as a Top Place to
• Gross Proceeds: $208.7M composition of matter, Work 2021 by The Boston
• Common Shares Outstanding: manufacturing and use Globe
31,169,207* • ~70% have advanced degrees
and ~50% have PhDs
* pro forma as of 9/30 basic shares outstanding
28
March 2022POTENTIAL VALUE CATALYSTS
We intend to build the leading intracellular therapeutics company with a growing pipeline of
oligonucleotide and protein-based therapeutics; First IND filing expected in 2H 2022
Future
2023
2022
Entrada expands the
Entrada anticipates portfolio
Entrada anticipates delivering clinical data
• ENTR-601-44 MAD/Phase 2b
becoming a clinical stage
company • ENTR-601-44 clinical data • DM1 clinical data
• DM1 IND filing • DMD exon 45 IND filing
• ENTR-601-44 IND filing
• DM1 and DMD exon 45 • Pompe candidate selection • Pompe IND filing
candidate selection • Immunology/oncology • Immunology/oncology/CNS
• Immunology/oncology in vivo candidate selection candidate selection
PoC
29
March 202230 March 2022
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