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The RNA Oncology Company
NASDAQ Symbol: RNAZ
Michael Dudley, CEO, Co-Founder
Forward Looking Statements
2
Disclaimer
Statements in this presentation contain “forward-looking statements” that are subject to substantial risks and uncertainties.
Forward-looking statements contained in this presentation may be identified by the use of words such as “anticipate,”
“expect,” “believe,” “will,” “may,” “should,” “estimate,” “project,” “outlook,” “forecast” or other similar words, and
include, without limitation, statements regarding TransCode Therapeutics, Inc.’s expectations regarding projected timelines
of clinical trials, and expectations regarding current or future clinical trials. Forward-looking statements are based on
TransCode Therapeutics, Inc.’s current expectations and are subject to inherent uncertainties, risks and assumptions that
are difficult to predict. Further, certain forward-looking statements are based on assumptions as to future events that may
not prove to be accurate, including that clinical trials may be delayed; that the data reported may be interim data,
conclusions as to which may be superseded by subsequent data we receive in connection with other and/or subsequent
clinical trials; and that any anticipated meeting with or presentation to the FDA may be delayed. These and other risks and
uncertainties are described more fully in the section titled “Risk Factors” in TransCode Therapeutics, Inc.’s Annual Report
on Form 10-K and other reports filed with the U.S. Securities and Exchange Commission. Forward-looking statements
contained in this presentation are made as of this date, and TransCode Therapeutics, Inc. undertakes no duty to update
such information except as required under applicable law.
Capitalization
Corporate
Source of Capital Amount
Seed Capital (Angel investors) 2,240,000
SBIR Grant 2,300,000
IPO* 25,400,000
Total $29,940,000
*Net Proceeds
NASDAQ Symbol: RNAZ
Common Shares 12,977,234
Options (WAEP $0.77) 2,094,033
Underwriter Warrants (WAEP $5.00) 312,500
Total 15,383,767
3
Huge Unmet Need in Metastatic Cancer Treatment
Problem
90%
of Cancer
Deaths Due to
Metastasis
$111B
Global Metastatic
Cancer Treatment
Market by 2027
Metastatic Cancer Reduces 5-year Survival
Critical Need for Therapy Targeting Metastasis*
*Source: 2019 American Cancer Society, Inc., Surveillance Research 4
5
RNA Therapy Power and Potential of RNA-based Therapies
RNA-based therapy holds the potential to target a
vast number of genes and cellular pathways with
high specificity*
Advantages of RNA treatments include:
• Access previously “undruggable” targets
• Rapid and cost-effective development
• Relatively easy to modify to address newly
identified targets
Cancer
N
e
u
r
o
l
o
g
i
c
a
l
d
i
s
e
a
s
e
Metabolic disorders
Infectious disease
G
e
n
e
t
i
c
d
i
s
e
a
s
e
Aptamer
ASO: antisense oligonucleotides
mRNA: messenger RNA
miRNA: microRNA
siRNA: short interfering RNA
*Liang X, et al. Biomed Pharmacother. 2020;125:109997.; Damase TR, et al. Frontiers in Bioengineering and Biotechnology. 2021;9.; Dowdy SF. Nat Biotechnol.
2017;35(3):222-229.
Oligonucleotide Therapeutics Efficiently Delivered to Genetic Targets
6
Challenge
“A major obstacle preventing widespread usage of
oligonucleotide therapeutics has been the difficultly in achieving
efficient delivery to target organs & tissues other than the liver.”
Source: Advances in oligonucleotide drug delivery. Nature Reviews Drug Discovery volume 19, pages 673–694(2020)
Robert S. Langer, ScD Institute Professor
David H. Koch Institute for Integrative Cancer Research
Massachusetts Institute of Technology
TransCode Therapeutics - The RNA Oncology Company
RNAi
PRR
CRISPR
mRNA
•Developing multiple RNA approaches in oncology
•Lead therapeutic candidate targeting principal driver of metastasis
Defeating cancer requires many approaches
•Optimized delivery of RNA therapeutics to genetic targets in cancer
•Modular toolbox enabling rational drug design
Resolving delivery challenge of RNA therapeutics
•Early programs targeting biomarkers in numerous solid tumor types
•Access to genetic targets previously undruggable without RNA delivery
R&D: Broad and diverse oncology pipeline
Summary
RNA
Strategy
PRR- Pattern recognition receptors; CRISPR - Clustered Regularly Interspaced Short Palindromic Repeats 7
TransCode
Therapeutics
Approach
8
Develop RNA Therapeutics
for Efficient Delivery to
Genetic Targets in Cancer
9
TTX Platform and
Solution Targeted RNA Therapeutics Using Proprietary Iron-Oxide Nanoparticle Delivery
We believe that demonstrating our ability to overcome the challenge of RNA
therapeutic delivery to genetic targets would represent a major step forward in
unlocking therapeutic access to a variety of genetic targets involved in a range of
cancers and beyond
Our therapeutic strategy employs a nanoparticle
extensively used in imaging that has been repurposed to:
• Deliver oligonucleotides to tumors and metastases
• Achieve robust target engagement inside tumor cells
10
TTX Delivery
Platform One Platform– Multiple RNA Approaches*
TTX
Platform
PRR
Radiolabeled
Therapeutics
RNAi
mRNA
Text
Here
Diagnostics
• Cancer Vaccines
• Small Interfering RNA
• Antisense
• Non-coding RNA Mimics
• Biomarker Screening Assay
• Biomarker Diagnostic Assay
• Gene Repair
• Gene Replacement
• Pattern Recognition Receptors
• Targeting Innate Immune
System
• Theranostic Applications
• Targeted Radiotherapy
CRISPR
*In Oncology and beyond
TTX Platform TTX Delivery System: 16+ Years of R&D Optimization
11
NH2
Iron Oxide Nanoparticle Platform:
• Long circulation half-life
• Unique capability to accumulate in
tumor cells and metastatic sites
• Image capable via MRI
• Highly stable, low toxicity potential;
low immunogenicity
Glucose Polymer (Dextran) coating:
• Stabilizes nanoparticles
• Protects oligos from degradation
• Promotes uptake and entrapment inside
tumor cells
Disulfide bond:
• Allows oligo to disconnect from
nanoparticle in order to bind to
RNA/DNA target
RNA-targeted nucleic acid:
• Strong binding affinity, specificity &
stability while minimizing
immunogenicity
Amino functional groups:
• Provide stabilization
Our delivery system is specifically designed to access targets inside tumor cells:
TTX Platform is Highly Differentiated
TTX Platform
Source: J Nano Res 2014, J Drug Targeting 2012, Alnylam presentation, Molecular Therapy-Nucleic Acids 2016, Nature Communications 2018, Molecular Therapy 2018, Int J Pharmaceut 2014,
Analytical Chem 2013, Large Molecular Therapeutics 2017, Current Pharma Design 2015, Radiology 2018
Particle Size (nm)
Optimized to minimize clearance &
maximize tumor uptake
siRNA lipid nanoparticles
siRNA lipid nanoparticles
siRNA lipid nanoparticles
miR liposomal nanoparticles
miR lipid nanoparticles
Kidney
Clearance
0 120
100
80
60
40
20 >120
miR minicells
siRNA angiplex particles
TTX-XXX
Liver Clearance
12
TTX-MC138
13
Lead Therapeutic Candidate:
Targeted Therapy for
Metastatic Disease
microRNA-10b (miR-10b) is a Unique, Well Documented Biomarker of Metastasis
Validated
Biomarker In A
Metastatic Setting
Clinical Evidence Demonstrated in >200 peer-reviewed publications over the last ten years
14
Linked to Higher Cancer Risk
Poor Survival Outcomes
Linked to Metastatic Progression
in Multiple Cancer Types
Biomarker of Metastasis
TTX-MC138 - Designed to Inhibit miR-10b and Eliminate Metastasis
TTX-MC138
MOA
15
Cancer Res 75, 4407-4415 (2015); Sci Rep 7, 45060 (2017)
TTX-MC138
microRNA-10b
TTX-MC138 Binds to miR-10b Target Inside Tumor Cell
TTX-MC138
Metastatic Lesion
Survival Benefit Observed Preclinically in Multiple TNBC* Models
TTX-MC138
Sources: Can Res 2015, Sci Report 2017 / Figure 11 in S-1 Preclinical results of TTX-MC138 in models of metastatic breast cancer TNBC: Triple Negative Breast Cancer 16
Path Forward
17
First In Human (FIH)
Phase 0 Study
Microdosing Study in Breast Cancer Patients Using Radiolabeled TTX-MC138
18
64Cu-TTX-MC138
Written guidance by FDA informing proposed FIH (Phase 0) trial
Rethinking FIH trials :
‘Methods used to develop patient therapies should be redesigned and clinical trials modified to rapidly identify biomarkers
of response and toxicity, including use of co-clinical trials and phase 0 trials’*
David A. Tuveson, MD, PhD, FAACR (past president of AACR)
*https://leadingdiscoveries.aacr.org/dr-david-a-tuveson-decoding-a-complex-disease/
TTX’s FIH Phase 0 study has the potential to:
• Demonstrate quantifiable evidence of delivery of TTX-MC138 to metastatic lesions in cancer patients
with advanced solid tumors
• Inform Ph I/II clinical trials by measuring pharmacokinetics & biodistribution in vital organs & other
tissues
• Extrapolate therapeutic dose level from microdose results for Phase I/II dose
• Validate delivery for the TTX pipeline and open-up additional previously undruggable RNA targets
TTX-MC138 Expected Clinical Path for PhI/II
19
Clinical Path
Dose Escalation
Solid tumors (not otherwise specified)
N=18 (3-6 subjects per dose)
Expansion
Solid tumors (not otherwise specified)
N=30-48
Abbreviated Criteria
• miR-10b expression in serum
• Stage IV with primary tumor resected
Screening Phase 1a Phase 1b
Treatment Cycles
Basket trial with adaptive design (N=62)
Abbreviated Criteria
• miR-10b expression in serum
• Stage IV with primary tumor resected
Follow up:
12 months off-therapy
Screening Treatment Follow up
Phase I
Phase II
TTX Pipeline
20
Pipeline Includes
Multiple Therapeutic
Candidates in
Development
Pipeline of First-in-Class RNA Therapeutic Candidates
Programs beyond
TTX-MC138
Drug Candidate Target
RNA
Type
Disease Indication Discovery Preclinical Phase 0 Phase 1 Phase 2 Phase 3
TTX-MC138
(Metastasis focus)
miR-10b RNAi
Metastatic Breast Cancer
**Glioblastoma (GBM);
Pancreatic Cancer
**SCLC, & Osteosarcoma
TTX-siPDL1 PD-L1 RNAi ***Pancreatic Cancer
TTX-MC138Cu64* miR-10b RNAi Metastatic Breast Cancer
TTX-siLin28b* Lin28b RNAi Pancreatic Cancer
TTX-RIGA Multiple RIGI Cancer Agnostic
TTX-CRISPR Multiple CRISPR Cancer Agnostic
TTX-mRNA
Cancer
Vaccine
mRNA Cancer Agnostic
21
* TransCode signed Exclusive Option Agreements with The General Hospital Corporation, d/b/a Massachusetts General Hospital, or MGH, for TTX-siLin28b and 64Cu-TTX-MC138. Under these Options, TransCode
has the right to negotiate a license for these candidates with MGH. TransCode’s decision will depend on the results of preclinical studies it plans to conduct as shown above. PDAC: Pancreatic ductal adenocarcinoma
** Seeking Orphan designation status
***Received Orphan designation status from FDA
Design Engine to Customize Development of RNA Therapeutics*
Platform
22
Annotated genetic code
Based on phenomenon of genetic complementarity
Nanocarrier delivery mechanism
Tunable chemistries (size, charge, surface chemistry)
optimized depending on the tissue that is being
targeted and approach used
Imaging
Provides specific measurement of drug
delivery to target tissue of interest and
pharmacokinetics of the drug during drug
development
Modular design toolbox
Synthesize libraries of therapeutic agents
optimized for molecular targets/desired approach:
Therapeutic oligonucleotides
Genetic code provides a coded blueprint for
drug design optimized for a given cancer
indication
RNAi
PRR
CRISPR
mRNA Vaccine
*In Oncology and Beyond
Expanding on Strong Pre-Clinical Foundation
! Established Pre-Clinical Results
! TTX-MC138 MOA is the inhibition of miR-10b, master regulator of metastatic
disease in variety of tumor types
! Well tolerated in pre-clinical studies
! Pre-clinical POC in aggressive stage II-IV metastatic breast cancer models, solid efficacy results
! Anticipated participation in one or more of FDA’s Expedited Programs
! Significant results also achieved with siPDL1 and RIGA therapeutic candidates
! Robust Design Engine
! Opportunity to customize RNA therapeutics for specific tumor indications
! First-in-Class lead therapeutic candidate and pipeline
Corporate
23
Timing of Key Milestones
Timing
24
* Pre-clinical
Note: Timelines are estimated and subject to change
Complete IND
Enabling studies
PC study
GBM
PC* Studies
RIGA
1H 2022 2H 2022
Ph 0 study
results
PC Study Lin28b
PDAC
PC Study PD-L1
PDAC
PC study
Pancreatic
1H 2023
Dose patients
Ph I/II
PC Studies CRISPR
PC Study
SCLC
PC Study
Osteosarcoma
PC Studies
mRNA vaccine
TTX-MC138
R&D Pipeline
2022 Corporate Milestones
Intellectual Property:
• File patents for new diagnostics
• File patents for new therapeutics
Regulatory:
• File for Orphan designations
Publications:
• Clinical Applications of non-coding RNA-based Therapies
in the Era of Precision Medicine
• Pre-clinical study results for lead candidate in GBM
• Pre-clinical study results for TTX-siPDL1in pancreatic cancer
• Pre-clinical study results for TTX-RIGA therapeutic
Partnerships:
• TBD
Operations:
• Grow company to 18-20 + employees
• Relocate lab and office
Investor meetings:
• CEO to present at Investor conferences
Marketing:
• Corporate branding
• New corporate website
Goals
25
Seeking Partnership Opportunities
Corporate
Seeking partners to expand:
! Potential of TTX-MC138 lead therapeutic candidate in MBC
! Potential of TTX-MC138 in Colorectal, Pancreatic, Lung,
Hepatocellular, Stomach, Ovarian, Glioblastoma, Osteosarcoma,
Gastric, Melanoma, Esophageal, SCLC, Thyroid, Endometrial etc.
! Pipeline of therapeutic candidates beyond TTX-MC138
! RNA therapeutic potential outside of oncology
26
Addendum
27
Additional Therapeutic
Candidates in
Development
TTX-siPDL1 Targets PD-1/PD-L1 with RNAi
R&D Pipeline
Checkpoint Inhibitors may not be effective in many cancers,
including pancreatic cancer:
*TTX-siPDL1 – (RNAi) advantages:
We employ an RNAi approach which is intended
to prevent the synthesis of PD-L1 altogether
Traditional checkpoint inhibitors simply block
PD-1/PD-L1 from binding each other
© 2015 Terese Winslow LLC
U.S. GOVT has certain rights
28
* Received Orphan Designation Status from FDA for Pancreatic Cancer
TTX-siPDL1 Generated Robust Preclinical Response in Mice
R&D Pipeline
90% tumor regression in the first two weeks of treatment
Source: Scientific Reports, 9 (1), 4712 2019
Results:
• High-dose TTX-siPDL1 + gemcitabine regressed pancreatic tumors
by 90% within the first two weeks of treatment and delayed tumor
growth. (Figure A above)
• Treatment increased survival - 67% of the experimental animals
survived for 12 weeks. (Figure B above)
29
gem = gemcitabine
TTX-siLin28b: Lin28b is a Therapeutic Target for Multiple Solid Tumors
R&D Pipeline
Lin28b is a biomarker of tumor survival and an actionable therapeutic target for solid tumors:
• RNA-binding protein that regulates mRNA translation and miRNA let-7 maturation in embryonic stem cells and developing tissues
• Evolutionarily constrained but aberrantly reactivated with overexpression of oncofetal proteins
• Increasing evidence, it serves as a critical oncogene for SIRT6 deficiency associated with tumor cells
• Believed to have broad applicability in aggressive solid tumors
• Increased expression of Lin28b correlated with poor survival in Pancreatic
Ductal Adenocarcinoma (PDAC) patients (Figure A)
o Lin28b is required for the growth and survival of SIRTlow PDAC
o Knocking down Lin28b with both small hairpin RNA (shRNA) and small
interfering RNA (siRNA) resulted in potent suppression of cell
proliferation and tumor sphere formation
o Knocking down Lin28b inhibited in vivo xenograft growth (Figure B)
o Knockdown of Lin28b led to both G1 cell-cycle arrest and induction of
apoptosis
Sources: Cell 2016 30
TransCode executed an exclusive option agreement with Massachusetts General Hospital (MGH),
for TTX-siLin28b, under which TransCode has the right to negotiate an exclusive license for this asset.
Key Preclinical Observations
Novel Targeting of Cancer Via RIG-I Signaling Pathway
TTX-RIGA
TTX-RIGA
(5’ppp-antisense tsRNA)
Tumor-specific
RNA (tsRNA)
RNA Sensing &
Activation of RIG-I
tsRNA-antisense tsRNA
hybridization
5’ppp-dsRNA/RIG-I Agonist
(retinoic acid-inducible gene I)
RIG-I Signaling & Cell Death
Release of immunological factors (IF) including type I interferons (IFN), pro-
inflammatory cytokines, DAMPs (damage-associated molecular pattern) and
tumor antigens that trigger the innate and adaptive immune responses in the
tumor microenvironment (TME)
RIG-I
Immunological
factors (IF)
PRR/Tum
or Antigen
(pattern
recognition
receptor)
Naïve T-cells
Clonal Expansion
& Activation
C
r
o
s
s
P
r
i
m
i
n
g
Maturation of DCs
Antigen Processing &
Presentation
Activated CTLs
(cytotoxic T lymphcytes)
Activation of
Macrophages, NK & DCs
Memory T Cells
(cancer prevention)
Tregs
(immune cell suppression)
K
i
l
l
i
n
g
o
f
C
a
n
c
e
r
C
e
l
l
s
Primary Tumor (Cells)
A
c
ti
v
a
ti
o
n
Inhibition
M
ature
APCs
(antigen-presenting
cell)
Lymph Nodes
Killing of
Cancer Cells
• Novel delivery of TTX-RIGA inside tumor cells to produce a potent agonist
of the RIG-I signaling pathway.
• Activation of RIG-I signaling leads to type I IFN-driven immune response
and preferential activation of programmed tumor cell death.
• Tumor cell death through RIG-I has been shown to build immunological
memory and would reject tumors as “foreign”.
31
CRISPR/Cas9 Cancer Therapy
32
TTX-CRISPR
TTX can be designed to deliver CRISPR/Cas9
therapy inside tumor cells to:
• Delete cancer-causing gene sequences
• Repair cancer-causing gene sequences
Important when a gene that protects against cancer
is disrupted by mutation and needs to be repaired to
function properly
©TransCode Therapeutics, Inc.
Created with BioRender.com
mRNA Cancer Vaccine
33
TTX-mRNA
Delivery of TTX-mRNA inside tumor cells to produce an
immune response specific to that tumor’s immune profile
Activation of cytotoxic immunity against the tumor
resulting in tumor cell death
Mechanism behind TTX-mRNA vaccine:
• TTX-mRNA delivers the code for immunogenic tumor
antigens
• Once injected into the muscle, TTX-mRNA is taken up
by muscle cells (2a) or antigen presenting cells (2b),
which synthesize the tumor antigens
• This leads to either direct priming of cytotoxic T cells
by the muscle cells (3a) or activation of T helper cells
by the APCs (3b)
• Both pathways result in activation of cytotoxic T cells
(4), followed by tumor infiltration by the immune cells
(5), and tumor cell death (6)
The result of this process is the immune destruction of
tumors throughout the body
©TransCode Therapeutics, Inc.
Created with BioRender.com
34
Our goal is to rapidly advance
new scientific discoveries to
revolutionize the way cancer is
treated to significantly improve
patient outcomes

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TransCode Therapeutics Investor Presentation June 2022

  • 1. The RNA Oncology Company NASDAQ Symbol: RNAZ Michael Dudley, CEO, Co-Founder
  • 2. Forward Looking Statements 2 Disclaimer Statements in this presentation contain “forward-looking statements” that are subject to substantial risks and uncertainties. Forward-looking statements contained in this presentation may be identified by the use of words such as “anticipate,” “expect,” “believe,” “will,” “may,” “should,” “estimate,” “project,” “outlook,” “forecast” or other similar words, and include, without limitation, statements regarding TransCode Therapeutics, Inc.’s expectations regarding projected timelines of clinical trials, and expectations regarding current or future clinical trials. Forward-looking statements are based on TransCode Therapeutics, Inc.’s current expectations and are subject to inherent uncertainties, risks and assumptions that are difficult to predict. Further, certain forward-looking statements are based on assumptions as to future events that may not prove to be accurate, including that clinical trials may be delayed; that the data reported may be interim data, conclusions as to which may be superseded by subsequent data we receive in connection with other and/or subsequent clinical trials; and that any anticipated meeting with or presentation to the FDA may be delayed. These and other risks and uncertainties are described more fully in the section titled “Risk Factors” in TransCode Therapeutics, Inc.’s Annual Report on Form 10-K and other reports filed with the U.S. Securities and Exchange Commission. Forward-looking statements contained in this presentation are made as of this date, and TransCode Therapeutics, Inc. undertakes no duty to update such information except as required under applicable law.
  • 3. Capitalization Corporate Source of Capital Amount Seed Capital (Angel investors) 2,240,000 SBIR Grant 2,300,000 IPO* 25,400,000 Total $29,940,000 *Net Proceeds NASDAQ Symbol: RNAZ Common Shares 12,977,234 Options (WAEP $0.77) 2,094,033 Underwriter Warrants (WAEP $5.00) 312,500 Total 15,383,767 3
  • 4. Huge Unmet Need in Metastatic Cancer Treatment Problem 90% of Cancer Deaths Due to Metastasis $111B Global Metastatic Cancer Treatment Market by 2027 Metastatic Cancer Reduces 5-year Survival Critical Need for Therapy Targeting Metastasis* *Source: 2019 American Cancer Society, Inc., Surveillance Research 4
  • 5. 5 RNA Therapy Power and Potential of RNA-based Therapies RNA-based therapy holds the potential to target a vast number of genes and cellular pathways with high specificity* Advantages of RNA treatments include: • Access previously “undruggable” targets • Rapid and cost-effective development • Relatively easy to modify to address newly identified targets Cancer N e u r o l o g i c a l d i s e a s e Metabolic disorders Infectious disease G e n e t i c d i s e a s e Aptamer ASO: antisense oligonucleotides mRNA: messenger RNA miRNA: microRNA siRNA: short interfering RNA *Liang X, et al. Biomed Pharmacother. 2020;125:109997.; Damase TR, et al. Frontiers in Bioengineering and Biotechnology. 2021;9.; Dowdy SF. Nat Biotechnol. 2017;35(3):222-229.
  • 6. Oligonucleotide Therapeutics Efficiently Delivered to Genetic Targets 6 Challenge “A major obstacle preventing widespread usage of oligonucleotide therapeutics has been the difficultly in achieving efficient delivery to target organs & tissues other than the liver.” Source: Advances in oligonucleotide drug delivery. Nature Reviews Drug Discovery volume 19, pages 673–694(2020) Robert S. Langer, ScD Institute Professor David H. Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology
  • 7. TransCode Therapeutics - The RNA Oncology Company RNAi PRR CRISPR mRNA •Developing multiple RNA approaches in oncology •Lead therapeutic candidate targeting principal driver of metastasis Defeating cancer requires many approaches •Optimized delivery of RNA therapeutics to genetic targets in cancer •Modular toolbox enabling rational drug design Resolving delivery challenge of RNA therapeutics •Early programs targeting biomarkers in numerous solid tumor types •Access to genetic targets previously undruggable without RNA delivery R&D: Broad and diverse oncology pipeline Summary RNA Strategy PRR- Pattern recognition receptors; CRISPR - Clustered Regularly Interspaced Short Palindromic Repeats 7
  • 8. TransCode Therapeutics Approach 8 Develop RNA Therapeutics for Efficient Delivery to Genetic Targets in Cancer
  • 9. 9 TTX Platform and Solution Targeted RNA Therapeutics Using Proprietary Iron-Oxide Nanoparticle Delivery We believe that demonstrating our ability to overcome the challenge of RNA therapeutic delivery to genetic targets would represent a major step forward in unlocking therapeutic access to a variety of genetic targets involved in a range of cancers and beyond Our therapeutic strategy employs a nanoparticle extensively used in imaging that has been repurposed to: • Deliver oligonucleotides to tumors and metastases • Achieve robust target engagement inside tumor cells
  • 10. 10 TTX Delivery Platform One Platform– Multiple RNA Approaches* TTX Platform PRR Radiolabeled Therapeutics RNAi mRNA Text Here Diagnostics • Cancer Vaccines • Small Interfering RNA • Antisense • Non-coding RNA Mimics • Biomarker Screening Assay • Biomarker Diagnostic Assay • Gene Repair • Gene Replacement • Pattern Recognition Receptors • Targeting Innate Immune System • Theranostic Applications • Targeted Radiotherapy CRISPR *In Oncology and beyond
  • 11. TTX Platform TTX Delivery System: 16+ Years of R&D Optimization 11 NH2 Iron Oxide Nanoparticle Platform: • Long circulation half-life • Unique capability to accumulate in tumor cells and metastatic sites • Image capable via MRI • Highly stable, low toxicity potential; low immunogenicity Glucose Polymer (Dextran) coating: • Stabilizes nanoparticles • Protects oligos from degradation • Promotes uptake and entrapment inside tumor cells Disulfide bond: • Allows oligo to disconnect from nanoparticle in order to bind to RNA/DNA target RNA-targeted nucleic acid: • Strong binding affinity, specificity & stability while minimizing immunogenicity Amino functional groups: • Provide stabilization Our delivery system is specifically designed to access targets inside tumor cells:
  • 12. TTX Platform is Highly Differentiated TTX Platform Source: J Nano Res 2014, J Drug Targeting 2012, Alnylam presentation, Molecular Therapy-Nucleic Acids 2016, Nature Communications 2018, Molecular Therapy 2018, Int J Pharmaceut 2014, Analytical Chem 2013, Large Molecular Therapeutics 2017, Current Pharma Design 2015, Radiology 2018 Particle Size (nm) Optimized to minimize clearance & maximize tumor uptake siRNA lipid nanoparticles siRNA lipid nanoparticles siRNA lipid nanoparticles miR liposomal nanoparticles miR lipid nanoparticles Kidney Clearance 0 120 100 80 60 40 20 >120 miR minicells siRNA angiplex particles TTX-XXX Liver Clearance 12
  • 13. TTX-MC138 13 Lead Therapeutic Candidate: Targeted Therapy for Metastatic Disease
  • 14. microRNA-10b (miR-10b) is a Unique, Well Documented Biomarker of Metastasis Validated Biomarker In A Metastatic Setting Clinical Evidence Demonstrated in >200 peer-reviewed publications over the last ten years 14 Linked to Higher Cancer Risk Poor Survival Outcomes Linked to Metastatic Progression in Multiple Cancer Types Biomarker of Metastasis
  • 15. TTX-MC138 - Designed to Inhibit miR-10b and Eliminate Metastasis TTX-MC138 MOA 15 Cancer Res 75, 4407-4415 (2015); Sci Rep 7, 45060 (2017) TTX-MC138 microRNA-10b TTX-MC138 Binds to miR-10b Target Inside Tumor Cell TTX-MC138 Metastatic Lesion
  • 16. Survival Benefit Observed Preclinically in Multiple TNBC* Models TTX-MC138 Sources: Can Res 2015, Sci Report 2017 / Figure 11 in S-1 Preclinical results of TTX-MC138 in models of metastatic breast cancer TNBC: Triple Negative Breast Cancer 16
  • 17. Path Forward 17 First In Human (FIH) Phase 0 Study
  • 18. Microdosing Study in Breast Cancer Patients Using Radiolabeled TTX-MC138 18 64Cu-TTX-MC138 Written guidance by FDA informing proposed FIH (Phase 0) trial Rethinking FIH trials : ‘Methods used to develop patient therapies should be redesigned and clinical trials modified to rapidly identify biomarkers of response and toxicity, including use of co-clinical trials and phase 0 trials’* David A. Tuveson, MD, PhD, FAACR (past president of AACR) *https://leadingdiscoveries.aacr.org/dr-david-a-tuveson-decoding-a-complex-disease/ TTX’s FIH Phase 0 study has the potential to: • Demonstrate quantifiable evidence of delivery of TTX-MC138 to metastatic lesions in cancer patients with advanced solid tumors • Inform Ph I/II clinical trials by measuring pharmacokinetics & biodistribution in vital organs & other tissues • Extrapolate therapeutic dose level from microdose results for Phase I/II dose • Validate delivery for the TTX pipeline and open-up additional previously undruggable RNA targets
  • 19. TTX-MC138 Expected Clinical Path for PhI/II 19 Clinical Path Dose Escalation Solid tumors (not otherwise specified) N=18 (3-6 subjects per dose) Expansion Solid tumors (not otherwise specified) N=30-48 Abbreviated Criteria • miR-10b expression in serum • Stage IV with primary tumor resected Screening Phase 1a Phase 1b Treatment Cycles Basket trial with adaptive design (N=62) Abbreviated Criteria • miR-10b expression in serum • Stage IV with primary tumor resected Follow up: 12 months off-therapy Screening Treatment Follow up Phase I Phase II
  • 20. TTX Pipeline 20 Pipeline Includes Multiple Therapeutic Candidates in Development
  • 21. Pipeline of First-in-Class RNA Therapeutic Candidates Programs beyond TTX-MC138 Drug Candidate Target RNA Type Disease Indication Discovery Preclinical Phase 0 Phase 1 Phase 2 Phase 3 TTX-MC138 (Metastasis focus) miR-10b RNAi Metastatic Breast Cancer **Glioblastoma (GBM); Pancreatic Cancer **SCLC, & Osteosarcoma TTX-siPDL1 PD-L1 RNAi ***Pancreatic Cancer TTX-MC138Cu64* miR-10b RNAi Metastatic Breast Cancer TTX-siLin28b* Lin28b RNAi Pancreatic Cancer TTX-RIGA Multiple RIGI Cancer Agnostic TTX-CRISPR Multiple CRISPR Cancer Agnostic TTX-mRNA Cancer Vaccine mRNA Cancer Agnostic 21 * TransCode signed Exclusive Option Agreements with The General Hospital Corporation, d/b/a Massachusetts General Hospital, or MGH, for TTX-siLin28b and 64Cu-TTX-MC138. Under these Options, TransCode has the right to negotiate a license for these candidates with MGH. TransCode’s decision will depend on the results of preclinical studies it plans to conduct as shown above. PDAC: Pancreatic ductal adenocarcinoma ** Seeking Orphan designation status ***Received Orphan designation status from FDA
  • 22. Design Engine to Customize Development of RNA Therapeutics* Platform 22 Annotated genetic code Based on phenomenon of genetic complementarity Nanocarrier delivery mechanism Tunable chemistries (size, charge, surface chemistry) optimized depending on the tissue that is being targeted and approach used Imaging Provides specific measurement of drug delivery to target tissue of interest and pharmacokinetics of the drug during drug development Modular design toolbox Synthesize libraries of therapeutic agents optimized for molecular targets/desired approach: Therapeutic oligonucleotides Genetic code provides a coded blueprint for drug design optimized for a given cancer indication RNAi PRR CRISPR mRNA Vaccine *In Oncology and Beyond
  • 23. Expanding on Strong Pre-Clinical Foundation ! Established Pre-Clinical Results ! TTX-MC138 MOA is the inhibition of miR-10b, master regulator of metastatic disease in variety of tumor types ! Well tolerated in pre-clinical studies ! Pre-clinical POC in aggressive stage II-IV metastatic breast cancer models, solid efficacy results ! Anticipated participation in one or more of FDA’s Expedited Programs ! Significant results also achieved with siPDL1 and RIGA therapeutic candidates ! Robust Design Engine ! Opportunity to customize RNA therapeutics for specific tumor indications ! First-in-Class lead therapeutic candidate and pipeline Corporate 23
  • 24. Timing of Key Milestones Timing 24 * Pre-clinical Note: Timelines are estimated and subject to change Complete IND Enabling studies PC study GBM PC* Studies RIGA 1H 2022 2H 2022 Ph 0 study results PC Study Lin28b PDAC PC Study PD-L1 PDAC PC study Pancreatic 1H 2023 Dose patients Ph I/II PC Studies CRISPR PC Study SCLC PC Study Osteosarcoma PC Studies mRNA vaccine TTX-MC138 R&D Pipeline
  • 25. 2022 Corporate Milestones Intellectual Property: • File patents for new diagnostics • File patents for new therapeutics Regulatory: • File for Orphan designations Publications: • Clinical Applications of non-coding RNA-based Therapies in the Era of Precision Medicine • Pre-clinical study results for lead candidate in GBM • Pre-clinical study results for TTX-siPDL1in pancreatic cancer • Pre-clinical study results for TTX-RIGA therapeutic Partnerships: • TBD Operations: • Grow company to 18-20 + employees • Relocate lab and office Investor meetings: • CEO to present at Investor conferences Marketing: • Corporate branding • New corporate website Goals 25
  • 26. Seeking Partnership Opportunities Corporate Seeking partners to expand: ! Potential of TTX-MC138 lead therapeutic candidate in MBC ! Potential of TTX-MC138 in Colorectal, Pancreatic, Lung, Hepatocellular, Stomach, Ovarian, Glioblastoma, Osteosarcoma, Gastric, Melanoma, Esophageal, SCLC, Thyroid, Endometrial etc. ! Pipeline of therapeutic candidates beyond TTX-MC138 ! RNA therapeutic potential outside of oncology 26
  • 28. TTX-siPDL1 Targets PD-1/PD-L1 with RNAi R&D Pipeline Checkpoint Inhibitors may not be effective in many cancers, including pancreatic cancer: *TTX-siPDL1 – (RNAi) advantages: We employ an RNAi approach which is intended to prevent the synthesis of PD-L1 altogether Traditional checkpoint inhibitors simply block PD-1/PD-L1 from binding each other © 2015 Terese Winslow LLC U.S. GOVT has certain rights 28 * Received Orphan Designation Status from FDA for Pancreatic Cancer
  • 29. TTX-siPDL1 Generated Robust Preclinical Response in Mice R&D Pipeline 90% tumor regression in the first two weeks of treatment Source: Scientific Reports, 9 (1), 4712 2019 Results: • High-dose TTX-siPDL1 + gemcitabine regressed pancreatic tumors by 90% within the first two weeks of treatment and delayed tumor growth. (Figure A above) • Treatment increased survival - 67% of the experimental animals survived for 12 weeks. (Figure B above) 29 gem = gemcitabine
  • 30. TTX-siLin28b: Lin28b is a Therapeutic Target for Multiple Solid Tumors R&D Pipeline Lin28b is a biomarker of tumor survival and an actionable therapeutic target for solid tumors: • RNA-binding protein that regulates mRNA translation and miRNA let-7 maturation in embryonic stem cells and developing tissues • Evolutionarily constrained but aberrantly reactivated with overexpression of oncofetal proteins • Increasing evidence, it serves as a critical oncogene for SIRT6 deficiency associated with tumor cells • Believed to have broad applicability in aggressive solid tumors • Increased expression of Lin28b correlated with poor survival in Pancreatic Ductal Adenocarcinoma (PDAC) patients (Figure A) o Lin28b is required for the growth and survival of SIRTlow PDAC o Knocking down Lin28b with both small hairpin RNA (shRNA) and small interfering RNA (siRNA) resulted in potent suppression of cell proliferation and tumor sphere formation o Knocking down Lin28b inhibited in vivo xenograft growth (Figure B) o Knockdown of Lin28b led to both G1 cell-cycle arrest and induction of apoptosis Sources: Cell 2016 30 TransCode executed an exclusive option agreement with Massachusetts General Hospital (MGH), for TTX-siLin28b, under which TransCode has the right to negotiate an exclusive license for this asset. Key Preclinical Observations
  • 31. Novel Targeting of Cancer Via RIG-I Signaling Pathway TTX-RIGA TTX-RIGA (5’ppp-antisense tsRNA) Tumor-specific RNA (tsRNA) RNA Sensing & Activation of RIG-I tsRNA-antisense tsRNA hybridization 5’ppp-dsRNA/RIG-I Agonist (retinoic acid-inducible gene I) RIG-I Signaling & Cell Death Release of immunological factors (IF) including type I interferons (IFN), pro- inflammatory cytokines, DAMPs (damage-associated molecular pattern) and tumor antigens that trigger the innate and adaptive immune responses in the tumor microenvironment (TME) RIG-I Immunological factors (IF) PRR/Tum or Antigen (pattern recognition receptor) Naïve T-cells Clonal Expansion & Activation C r o s s P r i m i n g Maturation of DCs Antigen Processing & Presentation Activated CTLs (cytotoxic T lymphcytes) Activation of Macrophages, NK & DCs Memory T Cells (cancer prevention) Tregs (immune cell suppression) K i l l i n g o f C a n c e r C e l l s Primary Tumor (Cells) A c ti v a ti o n Inhibition M ature APCs (antigen-presenting cell) Lymph Nodes Killing of Cancer Cells • Novel delivery of TTX-RIGA inside tumor cells to produce a potent agonist of the RIG-I signaling pathway. • Activation of RIG-I signaling leads to type I IFN-driven immune response and preferential activation of programmed tumor cell death. • Tumor cell death through RIG-I has been shown to build immunological memory and would reject tumors as “foreign”. 31
  • 32. CRISPR/Cas9 Cancer Therapy 32 TTX-CRISPR TTX can be designed to deliver CRISPR/Cas9 therapy inside tumor cells to: • Delete cancer-causing gene sequences • Repair cancer-causing gene sequences Important when a gene that protects against cancer is disrupted by mutation and needs to be repaired to function properly ©TransCode Therapeutics, Inc. Created with BioRender.com
  • 33. mRNA Cancer Vaccine 33 TTX-mRNA Delivery of TTX-mRNA inside tumor cells to produce an immune response specific to that tumor’s immune profile Activation of cytotoxic immunity against the tumor resulting in tumor cell death Mechanism behind TTX-mRNA vaccine: • TTX-mRNA delivers the code for immunogenic tumor antigens • Once injected into the muscle, TTX-mRNA is taken up by muscle cells (2a) or antigen presenting cells (2b), which synthesize the tumor antigens • This leads to either direct priming of cytotoxic T cells by the muscle cells (3a) or activation of T helper cells by the APCs (3b) • Both pathways result in activation of cytotoxic T cells (4), followed by tumor infiltration by the immune cells (5), and tumor cell death (6) The result of this process is the immune destruction of tumors throughout the body ©TransCode Therapeutics, Inc. Created with BioRender.com
  • 34. 34 Our goal is to rapidly advance new scientific discoveries to revolutionize the way cancer is treated to significantly improve patient outcomes