
PART I Item 1. Business TransCode Therapeutics is an RNA oncology company developing RNA therapeutics and diagnostics for metastatic disease using its proprietary TTX platform for targeted delivery of oligonucleotides Overview TransCode Therapeutics focuses on RNA oncology, utilizing its TTX platform with iron oxide nanoparticles for safe, effective, and targeted delivery of synthetic RNAs to tumors - The TTX platform uses an iron oxide nanoparticle, already approved as a clinical cancer imaging agent and for iron deficiency anemia, as a physical carrier for RNA therapeutics28 - The TTX delivery system minimizes kidney and liver clearance, resulting in a long circulation half-life and efficient accumulation in tumor cells and metastatic sites, with low toxicity and immunogenicity29 - The nanoparticles' small hydrodynamic size, positive charge, and dextran coating facilitate infiltration into tumor microvasculature and rapid uptake by cancer cells, enhancing access to genetic targets3031 Advancing New RNA Therapeutic Candidates Through a Modular Approach TransCode's modular TTX platform enables customization of nanoparticles and therapeutic loads for diverse RNA therapeutic approaches, overcoming stability and efficiency challenges - The TTX platform is modular, allowing tuning of nanoparticle size, charge, and surface chemistry, and adaptation of therapeutic loads (siRNAs, antisense oligonucleotides, mRNA vaccines, CRISPR, RIG-I agonists) for specific targets32 - The platform aims to overcome stability, efficiency, and immunogenicity issues common with existing lipid and liposomal nanoparticle platforms, while optimizing tumor targeting and accumulation32 - This approach is expected to enable targeting of previously 'undruggable' genes crucial for cancer treatment33 Our Lead Product Candidate TTX-MC138, TransCode's lead candidate, targets microRNA-10b for metastatic disease, demonstrating successful delivery and complete regression in preclinical breast cancer models - TTX-MC138 targets microRNA-10b, a well-validated biomarker for metastatic cancer, which has been historically 'undruggable' due to delivery challenges3637 - Preclinical animal studies showed TTX-MC138 successfully delivered to metastatic lesions in lymph nodes, lungs, and bones, with non-invasive imaging confirming delivery38 - In a Stage II/III breast cancer model, TTX-MC138 combined with low-dose doxorubicin achieved complete regression of lymph node metastases without recurrence in 100% of treated subjects over 12 weeks4041 - In an aggressive Stage IV breast cancer model, TTX-MC138 led to regression of distant metastases and complete regression without recurrence in 65% of treated subjects42 Modular Design Toolbox TransCode's modular drug design integrates a tunable nanocarrier, flexible oligonucleotide therapeutics, genetic code knowledge, and image-guided monitoring for optimized delivery - The nanocarrier delivery mechanism uses a nanoparticle similar to approved imaging agents, tunable for specific RNA targets in tumors and metastases, offering advantages over liver-targeting competitive approaches44 - Modular design allows for diverse therapeutic oligonucleotides (antagomirs, mimics, siRNAs, etc.) and tunable nanocarrier properties (size, coating, charge, antigen-targeting) to create tailored agents4547 - The approach utilizes genetic code knowledge to design specific oligonucleotides corresponding to disease-causing RNA targets, aiming to 'rewrite the story on cancer'48 - Image-guided capabilities via MRI allow non-invasive monitoring of drug delivery, bioavailability, and optimization of drug design, schedule, route, and dose49 Our Team TransCode is led by an experienced team of scientists and executives with expertise in RNA, drug development, imaging, and corporate strategy - The management team includes co-founder and CEO Michael Dudley (40+ years executive leadership), co-founder and CTO Dr. Zdravka Medarova (geneticist, cancer biologist, TTX inventor), and co-founder Dr. Anna Moore (imaging expert)50 - The team also comprises Tom Fitzgerald (CFO), Dr. Peter Liu (VP of R&D and Chief Scientist), Susan Duggan (VP of Clinical Operations), Dustan Bonnin (VP of Corporate Strategy), and Alan Freidman (VP of Investor Relations), bringing diverse expertise5052 Our Pipeline TransCode's pipeline features lead candidate TTX-MC138 for metastatic cancers, alongside preclinical programs like TTX-siPDL1, TTX-siLIN28B, TTX-RIGA, TTX-CRISPR, and TTX-mRNA TransCode Therapeutics Development Pipeline Summary | Drug Candidate | Target | RNA Type | Disease Indication | Discovery | Preclinical | Phase O | Phase | Phose 2 | Phase 3 | Key Anticipated Milestones | | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | | TTX-MC138 (Metastasis focus) | miR-10b | RNAi | Metastatic Breast Cancer, Pancreatic Cancer, Glioblastoma (GBM), SCLC, & Osteosarcoma | | ☒ | ☒ | | | | Rat Tox 1H '22; FIH Clinical 2H '22; Complete Preclinical Study 1H '22; Completed In vitro Study 2H '21; Complete In vivo Studies 2H '22 | | TTX-siPDL1 | PD-L1 | RNAi | PDAC | | ☒ | | | | | Complete Preclinical Study 1Q '22 | | TTX-siLIN28B | Lin28b | RNAi | PDAC | | ☒ | | | | | Complete Preclinical Study 1H '22 | | TTX-RIGA | Multiple | RIGI | Cancer Agnostic | | ☒ | | | | | Complete Preclinical Study 1Q '22 | | TTX-CRISPR | Multiple | CRISPR | Cancer Agnostic | | | | | | | Initiate Preclinical Studies 2H '22 | | TTX-mRNA | Cancer Vaccine | mRNA | Cancer Agnostic | | | | | | | Initiate Preclinical Studies 2H '22 | - The company intends to seek various FDA designations, including Breakthrough Therapy, Accelerated Approval, Priority Review, and Orphan Drug Designation, for its product candidates53 - TransCode has an exclusive license for TTX-siPDL1 and an exclusive option to license TTX-siLIN28B from MGH, expanding its solid tumor programs53 Our Strategy TransCode aims to be a leading RNA oncology company by advancing lead programs, expanding its TTX platform, building a diverse pipeline, protecting IP, and seeking strategic partnerships - The company aims to advance TTX-MC138 and TTX-siPD-L1 programs to deliver transformative therapies and diagnostics, focusing on previously inaccessible, clinically and genetically validated targets5556 - Key strategic components include expanding the TTX delivery platform to additional RNA targets, building a broad pipeline of novel oncology candidates with a precision medicine approach, and protecting intellectual property575859 - TransCode plans to pursue strategic partnerships for complementary capabilities in clinical studies, tumor indications outside its core interest, and assistance in manufacturing, distribution, and commercialization60 Background of RNA RNA holds therapeutic potential for 'undruggable' targets, but delivery challenges have limited clinical success, though recent drug approvals indicate accelerating advancements - RNA is an attractive therapeutic modality due to rational drug design, high target selectivity, and ability to engage 'undruggable' targets61 - Historical clinical success for RNA therapeutics has been limited by three delivery-related challenges: protecting oligonucleotides from the immune system, maintaining stability, and penetrating target organs and cells61 - Recent FDA approvals of RNA-targeting drugs (e.g., nusinersen in 2016, patisiran in 2018) validate the clinical utility and accelerate advancements in the field62 TTX Design The TTX delivery system uses tunable iron-oxide nanoparticles for optimized, image-guided delivery to primary and metastatic tumors, ensuring long circulation and efficient cellular uptake - The TTX delivery system uses iron-oxide nanoparticles, similar to clinically approved products like Feraheme, designed for optimized delivery to primary and metastatic tumors6567 - Key advantages include small size (20nm+/-) for tumor access and long circulation half-life (17-24 hours), low immunogenicity risk, and quantitative non-invasive imaging via MRI for monitoring drug bioavailability6771 - The dextran coating protects oligonucleotides from degradation, improves stability and cell uptake, and facilitates accumulation in tumors based on the Warburg effect656771 Our Programs TransCode's programs identify and engage microRNA targets in cancer, with TTX-MC138 advancing to Phase 0/I clinical trials and other preclinical candidates like TTX-siPDL1 and TTX-RIGA Target Identification TransCode identifies therapeutic microRNA targets in cancer by analyzing differential expression in models and validating clinical actionability via genomic databases - miRNAs are important post-transcriptional regulators of gene expression, critically involved in cancer emergence, progression, and therapy response, making them attractive therapeutic targets73 - Target identification involves differential expression analysis in cancer cell lines and animal models, followed by validation using genomic databases like The Cancer Genome Atlas (TCGA) to correlate expression with patient outcomes74 Target Engagement Preclinical studies confirmed TTX-MC138 delivery and microRNA-10b elimination in metastatic lesions, supported by clinical data showing Ferumoxytol accumulation in brain metastases - Preclinical studies with fluorescently labeled TTX-MC138 showed uptake by metastatic lesions in lymph nodes, lungs, and bone in murine breast cancer models, confirming delivery and target engagement (miRNA-10b elimination)7576 - Clinical proof of delivery is supported by studies using the approved agent Ferumoxytol, which demonstrated accumulation in brain metastases in patients, suggesting robust target engagement at clinically acceptable doses of TTX77 TTX-MC138 TTX-MC138, TransCode's lead candidate for metastatic cancer, targets microRNA-10b, demonstrating complete regression in preclinical Stage II/III and Stage IV models - The global metastatic cancer treatment market size was $63.03 billion in 2019 and is expected to reach $111.16 billion in 2027, with a CAGR of 7.3%79 - TTX-MC138 targets microRNA-10b, a validated critical driver of metastatic progression, with the potential to improve outcomes over current treatments focused on primary cancer79 - Preclinical studies demonstrated TTX-MC138's ability to eliminate metastasis and achieve complete regression without recurrence in 100% of subjects in a Stage II/III cancer model and 65% in an aggressive Stage IV model79 MicroRNA-10b (miR-10b) MicroRNA-10b is a validated metastasis-promoting factor across 18 cancer types, critical for metastatic cell survival, and TTX-MC138 targets it with a hormone receptor-independent mechanism - MiR-10b is a well-validated metastasis-promoting factor, with over 200 peer-reviewed publications across 18 cancer types, and is considered critical for the survival of metastatic cells8183 - Targeting miR-10b is believed to achieve persistent therapeutic responses by altering fundamental molecular pathways of oncogenesis, making evasion by mutation less likely due to its central role in tumor cell phenotypes81 - TTX-MC138's mechanism of action is hormone receptor independent and has shown efficacy in treating metastatic breast cancer in rodents regardless of hormone receptor type85 Mechanism of Action of TTX-MC138 TTX-MC138 inhibits microRNA-10b to arrest tumor dissemination and induce persistent regression of metastatic lesions, potentially without co-treatment in humans - TTX-MC138 inhibits microRNA-10b, leading to the arrest of tumor cell dissemination and potentially complete and persistent regression of existing metastatic lesions89 - In preclinical studies with aggressive metastatic tumor models, low-dose doxorubicin was used to slow cell division, allowing TTX-MC138 to fully inhibit microRNA-10b; this may be unnecessary in humans due to slower metastatic growth89 - Mechanistic studies suggest TTX-MC138 affects HOXD10 and c-JUN pathways, which are involved in tumor cell migration, invasion, and proliferation89 Results Preclinical studies of TTX-MC138 showed complete and persistent regression of metastatic cancer with no recurrence or systemic toxicity, achieving high survival rates in breast cancer models - In preclinical studies, TTX-MC138 combined with low-dose doxorubicin achieved complete and persistent regression of pre-existing metastatic cancer, with no recurrence and no systemic toxicity91 - A Stage II/III breast cancer model showed 100% survival with eliminated metastatic burden after four weekly treatments, with no recurrence observed over 12 weeks92 - In a Stage IV breast cancer model, 65% survival was achieved with regression of distant metastases by week six, and no elevation in serum biochemistry markers or gross tissue abnormalities were observed9394 Clinical Development Plan TransCode plans a Phase 0 FIH trial for TTX-MC138 to confirm delivery and pharmacokinetics in metastatic lesions, followed by a Phase I/II trial to assess safety and efficacy Phase 0 - First-in-Human Clinical Study (Exploratory IND) The Phase 0 FIH trial for TTX-MC138 aims to quantify delivery to metastatic lesions, measure pharmacokinetics, inform dosing, and validate the TTX pipeline - The Phase 0 trial aims to demonstrate quantifiable delivery of TTX-MC138 to metastatic lesions in advanced solid tumors100 - It will measure pharmacokinetics and biodistribution in vital organs and other tissues to inform Phase I/II clinical trials and therapeutic dose levels100 - The study is also intended to validate delivery for the TTX pipeline more broadly, potentially opening up additional previously undruggable RNA targets100 Anticipated Phase I Clinical Trial The Phase I trial for TTX-MC138 will assess safety, determine MED/MTD, evaluate preliminary anti-tumor activity, and confirm tumor delivery and microRNA-10b inhibition - The Phase I trial will assess safety, determine Minimum Effective Dose (MED) and Maximum Tolerated Dose (MTD) of TTX-MC138 in metastatic cancer patients expressing microRNA-10b98 - Primary objectives include assessing anti-tumor activity and preliminary efficacy using Objective Response Rate (ORR) and clinical benefit rate (CR, PR, SD)101 - Secondary objectives involve confirming tumor delivery with MRI, measuring pharmacokinetics, and confirming target engagement via microRNA-10b inhibition using PCR101 Accelerated Regulatory Programs The FDA offers various programs to expedite drug development and review for serious conditions, which TransCode anticipates seeking for its candidates - The FDA offers Fast Track, Breakthrough Therapy, Priority Review, Accelerated Approval, and Orphan Drug Designations to expedite drug development and review for serious or life-threatening diseases with unmet medical needs103 - TransCode anticipates seeking one or more of these qualifications for its product candidates, though there is no assurance of obtaining them103 Orphan Drug Designation Status The Orphan Drug Act provides incentives for rare disease drugs, and TransCode plans to seek designation for TTX-MC138 and TTX-siPDL1 in specific cancer indications - The Orphan Drug Act offers benefits such as seven-year marketing exclusivity, 25% tax benefits for R&D, and PDUFA fee waivers for drugs treating rare diseases (affecting <200,000 individuals in the U.S.)104 - TransCode plans in vivo studies to support Orphan Drug Designation for TTX-MC138 in pancreatic cancer, osteosarcoma, and SCLC, and has submitted a request for TTX-siPDL1 in pancreatic cancer105106 TTX-siPDL1 TTX-siPDL1 targets PD-L1 for pancreatic cancer, demonstrating significant tumor growth inhibition and improved survival in preclinical studies, potentially more efficiently than antibodies - Pancreatic cancer is the fourth-leading cause of cancer-related death in the U.S., with a 5-year survival rate of 8%, and is resistant to conventional drugs and initial immunotherapy approaches108 - TTX-siPDL1 uses an siRNA to inhibit PD-L1 expression at the post-transcriptional level, aiming for greater efficiency in T-cell recognition and killing of tumor cells compared to antibody-based checkpoint inhibitors111 - Preclinical studies combining TTX-siPDL1 with gemcitabine in a murine pancreatic cancer model showed a 90% reduction in tumor volume, significantly lower morbidity, and improved survival (67% survival at 12 weeks for high dose)112115 TTX-RIGA TTX-RIGA is an early-stage candidate designed to activate the RIG-I signaling pathway, triggering an immune response and tumor cell death across multiple cancer types - TTX-RIGA aims to activate the RIG-I signaling pathway, a Pattern Recognition Receptor of the innate immune system, to trigger an immune response targeting cancer119121 - RIG-I activation has been reported to induce tumor cell death and activate innate/adaptive immune systems in various cancers, including pancreatic, prostate, head and neck, gastric, breast, and glioblastoma120 TTX-siLIN28B TTX-siLIN28B is an siRNA technology inhibiting LIN28B, a critical oncogene in various cancers, with preclinical studies initiated under an MGH license option - TTX-siLIN28B is a siRNA technology targeting LIN28B, an RNA-binding protein and critical oncogene implicated in various cancers (pancreatic, hepatocellular, breast, colon, gastric)122123 - TransCode has an exclusive option from MGH to license this technology and initiated preclinical studies in 2022, with plans to consider adding it to its MGH license agreement based on test results123124 TRANSCODE DIAGNOSTIC PROGRAM (TCDx) TransCode's TCDx diagnostic program applies its technology for early cancer detection and personalized therapy, including a microRNA nanosensor and TCD-miR10b assay CDx Mechanism of Action TransCode is developing a microRNA nanosensor (CDx) to measure microRNA expression in single cells, tissues, and serum for optimal therapy identification and early cancer detection - TransCode is developing diagnostic product candidates to identify the right therapy for particular patients and reduce cancer mortality through early detection125 - The microRNA nanosensor (CDx) is designed to measure microRNA expression in single intact live cells, tissues, and serum, allowing for the capture of heterogeneity and observation of rare cells like cancer stem cells127128 TCD-MiRNA Screening and Diagnostic Assays The microRNA nanosensor assay offers inexpensive, rapid, highly specific, and sensitive microRNA measurement in various samples, enabling tumor cell phenotype monitoring - The nanosensor assay is inexpensive, rapid, highly specific, and has nanomolar sensitivity, allowing microRNA expression measurement in biopsies, serum, and circulating tumor cells129 - It permits measurement in single, intact, live cells, enabling longitudinal studies to monitor tumor cell phenotype evolution128161 TCD-miR10b TCD-miR10b is an assay using microRNA-10b as a biomarker for diagnosing metastases, predicting survival, informing treatment, and monitoring TTX-MC138 therapy response - TCD-miR10b assay is designed to use microRNA-10b expression as a biomarker for diagnosing metastases and predicting overall/disease-free survival in cancer130 - It aims to stratify tumors by aggressiveness, inform therapeutic decisions (e.g., correlation with 5-FU sensitivity and tamoxifen resistance), and monitor response to TTX-MC138 therapy in clinical trials130132 - Preclinical studies and a small pilot study using human serum have validated TCD-miR10b's performance in detecting miR-10b, showing specificity, reproducibility, dynamic range, and detection limit comparable to qRT-PCR131133 INTELLECTUAL PROPERTY TransCode's IP portfolio covers therapeutic and diagnostic candidates, including issued patents and pending applications for TTX-MC138 and biomarker tests, with active expansion efforts - TransCode's IP portfolio includes issued patents and pending applications for therapeutic and diagnostic candidates, their targeted use, and development in specific patient populations134 - Patents for TTX-MC138 and the biomarker test have issued in the U.S. and U.K. under the MGH License, with plans to pursue new patents for broader coverage134 - A recent patent application was filed for TTX-RIGA, an invention designed to trigger a targeted immune response against cancer, intended to be cancer agnostic134 Therapeutic Patent Rights Assigned to TransCode TransCode holds assigned patent rights for 'Template Directed Immunomodulation for Cancer Therapy,' originating from a December 2020 provisional application - TransCode has assigned patent rights for 'Template Directed Immunomodulation for Cancer Therapy,' originating from a provisional application filed on December 30, 2020, and converted into an International PCT Application (PCT/US21/65580)135 Therapeutic Patent Rights (Covered under MGH License) TransCode licenses multiple therapeutic patent rights from MGH, covering nanoparticles, immune checkpoint inhibition, pancreatic carcinoma treatment, and radiolabeled nanoparticles - Licensed therapeutic patent rights from MGH include 'Therapeutic Nanoparticles and Methods of Use Thereof' (PCT/US 2020/63635, expires 2039) and 'Compositions and Methods for Immune Checkpoint Inhibition' (PCT/US 2019/050003, expires 2038, with national stage filings pending in multiple countries)136 - Other licensed therapeutic patents cover 'Agents and Methods for Treating Pancreatic Ductal Carcinoma' (US 10,588,920, granted March 2020, expires 2035) and 'Radiolabeled Therapeutic Nanoparticles and Methods of Using the Same' (Provisional 63/109,298, filed November 2020)136 Biomarker Patent Requests (Diagnostic test) (Covered under MGH License) TransCode licenses MGH biomarker patent rights for 'miRNA Profiling Compositions and Methods of Use,' including several granted U.S. and European patents - Licensed biomarker patent rights from MGH for 'miRNA Profiling Compositions and Methods of Use' include U.S. patents US 9,763,891, US 9,629,812, US 10,463,627 (all expiring 2031), and US 10,086,093 (expiring 2033)138139 - A European patent, EP 2961386, for 'miRNA Profiling Compositions and Methods of Use' was granted in July 2019 and expires in 2033139 EXCLUSIVE LICENSE AGREEMENT TransCode holds an exclusive, worldwide, royalty-bearing license agreement with MGH for intellectual property, including tiered royalties, annual fees, and milestone payments - TransCode holds an exclusive, worldwide, royalty-bearing, sub-licensable license from MGH for certain intellectual property (Licensed Patents), established in November 2018137 - The agreement includes tiered royalties (low to middle single-digit percentage) on annual net sales and minimum annual license fees ($25 thousand pre-commercial, $50 thousand post-commercial sale)138 - Milestone payments up to an aggregate of $1.55 million are due upon certain events, none of which had been achieved as of December 31, 2021140 - The license expires upon the latest of patent expiration, regulatory exclusivity, or 10 years after the first commercial sale, with termination clauses for default, bankruptcy, or failure to maintain insurance/payments141142 Amendment to License Agreement The MGH License was amended in November 2020, categorizing IP into two families with increased annual fees, while other terms remained consistent - The MGH License was amended in November 2020, categorizing existing IP as 'Patent Family 1' (with a new nanoparticle provisional patent) and creating 'Patent Family 2' for PD-L1 targeting intellectual property143 - Minimum annual license fees increased to $30,000 for Patent Family 1 and $50,000 for Patent Family 2, with all other terms (milestones, royalties, sublicense income) remaining the same144 - Upon expiration, the licenses granted to TransCode will be considered fully paid and royalty-free145 COMPETITION TransCode operates in a highly competitive pharmaceutical industry, differentiating itself with a unique RNA delivery system and broad RNA technology pipeline for oncology - The pharmaceutical industry is intensely competitive, with TransCode facing larger competitors with greater capital and human resources, established market positions, and expertise in sales, marketing, and regulatory matters146 - Competitors in RNA therapeutics for oncology include Arrowhead Pharmaceuticals, Ionis, Moderna, Alnylam, BioNTech, Dicerna, and Siranomics152 - TransCode believes its competitive advantage lies in its delivery systems' ability to target genes inside tumors and metastases, and its pipeline spanning various RNA technologies (ncRNAs, RNA vaccines, CRISPR, immunostimulatory RNAs) solely for oncology, unlike competitors often limited to single RNA technologies152 Targeted therapy Targeted cancer therapies block specific molecular targets, representing a major focus in drug development, with TransCode focusing on therapies like TTX-MC138 for metastatic progression - Targeted cancer therapies block cancer growth by interfering with specific molecular targets involved in cancer progression, differing from standard chemotherapy by acting on specific molecules, being deliberately designed, and often being cytostatic153154 - Targeted therapies represent 48% of total oncology spending, up from 36% in 2010, indicating rapid growth and intense development focus154 - TransCode focuses on targeted therapies with novel therapeutics like TTX-MC138, which has shown success in animals by targeting microRNA-10b, a master regulator of metastatic progression154 Immunotherapy Immunotherapy, including checkpoint inhibitors and CAR T cells, is a significant cancer treatment pillar, with ongoing research focusing on combination approaches and new tumor entities - Immunotherapy, particularly checkpoint inhibitors (CPIs) and CAR T cells, is a major cancer treatment approach, improving prognosis for hematological and solid malignancies155 - The Nobel Prize in 2018 recognized discoveries of CTLA-4 and PD-1/PD-L1 pathways, which malignant tumors exploit to evade the immune system, leading to durable remissions in various cancer types156 Tyrosine kinase inhibitors Tyrosine kinase inhibitors are targeted cancer therapies, with Lapatinib being the sole FDA-approved option for HER2-positive metastatic breast cancer - Lapatinib (Tykerb) is the only FDA-approved tyrosine kinase inhibitor for HER2-positive metastatic breast cancer157 PARP inhibitors PARP inhibitors, targeting DNA repair enzymes, show promise for metastatic breast cancer patients with BRCA1/2 mutations and are currently in clinical trials - PARP inhibitors, which target DNA repair enzymes, are under study for many cancer types, including metastatic breast cancer158 - These inhibitors show the most promise for metastatic breast cancer patients with BRCA1 or BRCA2 gene mutations and are currently offered in clinical trials158 Cyclin dependent kinase 4 and 6 (CDK4/6) inhibitors CDK4/6 inhibitors interrupt cancer cell growth by targeting cell division enzymes, with Palbociclib approved for hormone receptor-positive, HER2-negative metastatic breast cancers - CDK4/6 inhibitors are a new class of drugs that interrupt cancer cell growth by targeting enzymes crucial for cell division159 - Palbociclib (Ibrance), a CDK4/6 inhibitor, is FDA-approved in combination with hormone therapy for hormone receptor-positive, HER2-negative metastatic breast cancers159 PI3 kinase inhibitors PI3 kinase inhibitors are a new class of drugs under study for metastatic breast cancer, designed to interrupt PI3 kinase signals and halt tumor growth - PI3 kinase inhibitors are a new class of drugs under study for metastatic breast cancer, designed to interrupt PI3 kinase signals and stop cancer cell growth160 - These inhibitors target the PI3 kinase enzyme, whose activity can be affected by mutations in the PIK3CA gene, which drives tumor growth160 Diagnostics TransCode's diagnostic approach aims to overcome limitations of existing microRNA detection by enabling sensitive, rapid, and inexpensive single-cell and serum analysis in live cells - TransCode's diagnostics aim to permit microRNA measurement in single cells (e.g., from biopsy or circulating tumor cells) and serum samples, allowing for accurate capture of heterogeneity and observation of rare cells161 - The diagnostics are designed to be applicable in intact, live cells for longitudinal studies, highly sensitive (uptake of over 1x10^6 nanoparticles per cell), inexpensive, and rapid, using fluorescence readouts161 - This approach contrasts with existing methods like PCR and northern blotting, which analyze tissue in bulk, or high-affinity hybridization probes with cumbersome protocols161 MANUFACTURING TransCode relies on third-party CMOs in Germany and the Netherlands for cGMP-compliant manufacturing of its nanodrugs, including TTX-MC138, addressing extensive CMC requirements Manufacturing: Chemistry, Manufacturing and Controls (CMC) TransCode's nanodrugs, like TTX-MC138, undergo extensive R&D optimization and are manufactured by CMOs in Germany and the Netherlands, adhering to GxP requirements - TransCode's nanodrugs, such as TTX-MC138, are based on dextran-coated iron oxide nanoparticles conjugated to LNA-modified antisense oligonucleotides163 - The oligonucleotide drug substance is manufactured by a CMO in Germany, and the final drug product is produced by a second CMO in the Netherlands, both expected to meet GxP (GMP/GLP) requirements163164 - The dextran-coated iron oxide particles are analogous in structure and size to those used in the FDA-approved iron replacement therapy, Ferraheme®164 COMMERCIALIZATION TransCode retains worldwide commercialization rights but plans to pursue partnerships or out-licensing for sales, marketing, and distribution of its therapeutic and diagnostic candidates - TransCode retains worldwide commercialization rights for its key therapeutic and diagnostic candidates but currently lacks internal sales, marketing, or product distribution capabilities165 - The company plans to explore partnerships with larger pharmaceutical organizations or out-license drug candidates as they get closer to FDA approval165 - TransCode also intends to license certain technologies to other oncology-focused companies, with commercial plans subject to change based on program advancement, market conditions, and clinical data166 GOVERNMENT REGULATION TransCode's drug development and commercialization are extensively regulated by global authorities, involving rigorous testing, submissions, and compliance with healthcare laws, with potential for expedited programs - Drug products are extensively regulated by the FDA and other authorities across research, development, testing, manufacturing, approval, marketing, and post-approval monitoring167 - The U.S. regulatory process involves preclinical studies (GLP), IND application, IRB approval, multi-phase clinical trials (GCP), NDA submission, FDA review, manufacturing facility inspections (cGMP), and user fees170171186 - TransCode anticipates seeking expedited regulatory programs such as Fast Track, Breakthrough Therapy, Priority Review, Accelerated Approval, and Orphan Drug Designations to facilitate development and review103199 - Post-approval, products are subject to ongoing requirements including recordkeeping, adverse event reporting, promotion/advertising compliance, and potential Phase 4 studies or REMS plans208209 - The company's operations are also subject to various healthcare laws (Anti-Kickback, False Claims, HIPAA, Sunshine Act) and evolving global data protection regulations (GDPR, CCPA), with potential for significant penalties for non-compliance215221222227263 Preclinical and clinical trials for drugs Drug development involves rigorous preclinical testing and multi-phase clinical trials (including Phase 0 exploratory studies) under IND, GCP, and IRB requirements, with adaptive designs expediting oncology development - Preclinical studies, including laboratory evaluations and animal studies (GLP), are required before human testing, with results submitted to the FDA as part of an Investigational New Drug (IND) application171 - Clinical trials are conducted in phases: Phase 1 (safety, dosage, pharmacokinetics), Phase 2 (preliminary efficacy, optimal dosages), and Phase 3 (statistically significant efficacy, overall risk/benefit)175176177178 - Exploratory IND (Phase 0) studies involve limited human exposure to determine mechanism of action, pharmacokinetics, or biodistribution, without therapeutic intent179 - The FDA's 'Expansion Cohorts' guidance allows adaptive trial designs in early oncology development to compress traditional phases into continuous trials, potentially reducing costs and time180182 U.S. marketing approval for drugs U.S. marketing approval requires an NDA submission to the FDA, demonstrating safety and efficacy, followed by review, facility inspection, and potential post-approval requirements like REMS - U.S. marketing approval requires submitting an NDA to the FDA, containing preclinical and clinical data to establish drug safety and efficacy for one or more indications186 - The FDA conducts an in-depth review, may refer the application to an advisory committee, and inspects manufacturing facilities for cGMP compliance190191 - Approval may be subject to limitations on indications, warnings, post-approval studies (Phase 4), or a Risk Evaluation and Mitigation Strategy (REMS) to ensure benefits outweigh risks189193 Orphan drug designation and exclusivity Orphan drug designation provides incentives and seven years of marketing exclusivity for drugs treating rare diseases, with specific conditions for maintaining or losing exclusivity - Orphan drug designation is for drugs treating rare diseases (<200,000 U.S. patients or unrecoverable development costs), offering incentives like tax credits and application fee waivers194 - The first FDA-approved orphan-designated product receives seven years of marketing exclusivity for that indication, generally precluding approval of similar products195 - Exclusivity can be lost if designation was defective, the manufacturer cannot assure sufficient supply, or a subsequent product demonstrates clinical superiority195197 Rare pediatric disease designation and priority review vouchers The FDA incentivizes drugs for rare pediatric diseases with Priority Review Vouchers, which can be used or transferred for expedited review of subsequent drug applications - The FDA incentivizes drugs for rare pediatric diseases (serious/life-threatening, primarily affecting 0-18 years, <200,000 U.S. patients or unrecoverable costs) with Priority Review Vouchers (PRVs)198 - A PRV can be used to obtain priority review for a subsequent human drug application and is transferable. The program is extended through September 30, 2026198 Expedited development and review programs for drugs The FDA offers Fast Track, Breakthrough Therapy, Priority Review, and Accelerated Approval programs to expedite drug development and review for serious conditions, without altering scientific standards - FDA programs like Fast Track, Breakthrough Therapy, Priority Review, and Accelerated Approval expedite development and review for drugs addressing serious conditions or unmet medical needs199 - Fast Track and Breakthrough Therapy designations offer increased FDA interaction and potential for rolling review, with Breakthrough Therapy providing intensive guidance and expedited development commitment200 - Priority Review shortens FDA review to six months, and Accelerated Approval allows approval based on surrogate endpoints, contingent on post-approval confirmatory trials201202 Pediatric information and pediatric exclusivity PREA requires pediatric safety and efficacy data in NDAs, with sponsors submitting a Pediatric Study Plan, and voluntary pediatric studies may grant six months of exclusivity - PREA requires NDAs to include pediatric safety and efficacy data for relevant subpopulations, with sponsors submitting an initial Pediatric Study Plan (PSP) early in development206 - Pediatric exclusivity, granted for voluntary pediatric studies in response to an FDA 'Written Request,' adds six months to existing exclusivity periods and patent terms207 U.S. post-approval requirements for drugs Post-FDA approval, drugs face ongoing regulation, including surveillance, adverse event reporting, and cGMP/cGCP compliance, with non-compliance leading to severe penalties - Approved drugs are subject to pervasive and continuing FDA regulation, including post-marketing surveillance, adverse event reporting, and compliance with cGMPs and cGCPs for clinical trials208209372374 - Manufacturers must register with the FDA and state agencies, undergoing periodic unannounced inspections for cGMP compliance and product tracking/tracing requirements210 - Later discovery of problems or non-compliance can result in product recalls, marketing restrictions, withdrawal of approval, fines, injunctions, or criminal prosecution213378 Other healthcare laws Commercialization activities are subject to federal and state healthcare laws like Anti-Kickback, False Claims, HIPAA, and Sunshine Act, with non-compliance leading to significant penalties - The federal Anti-Kickback Statute prohibits knowingly offering or receiving remuneration to induce referrals or purchases under federal healthcare programs, with violations leading to civil/criminal fines and exclusion216217 - The federal civil and criminal False Claims Act (FCA) prohibits presenting false claims to the government, with manufacturers liable for 'causing' such claims, leading to treble damages and penalties218 - HIPAA and HITECH impose criminal/civil liability for healthcare fraud and strict requirements on privacy and security of individually identifiable health information, with new tiers of penalties220221 - The Physician Payments Sunshine Act (ACA) requires annual reporting of payments and 'transfers of value' to physicians and teaching hospitals, expanding to non-physician providers from January 1, 2022222 Insurance Coverage and Reimbursement Product sales depend on adequate third-party payor coverage and reimbursement, a costly and uncertain process, with insufficient rates materially impacting sales and profitability - Sales of approved products depend on coverage and adequate reimbursement from third-party payors, including government programs (Medicare, Medicaid) and commercial insurers229406 - CMS decisions on Medicare coverage and reimbursement significantly influence private payors. Obtaining coverage requires demonstrating medical necessity and cost-effectiveness through expensive studies229230 - Lack of coverage or insufficient reimbursement rates can materially and adversely affect sales, operations, and financial condition, as payors increasingly challenge prices and impose cost controls230232408 Current and future healthcare reform legislation Healthcare reform, including the ACA and drug pricing proposals, creates uncertainty and downward pressure on pharmaceutical pricing and reimbursement, impacting the U.S. healthcare system - The Affordable Care Act (ACA) introduced changes including annual fees on branded drugs, expanded Medicaid eligibility, revised Medicaid rebate calculations, and established the Medicare Part D coverage gap discount program234235 - Ongoing judicial, administrative, and legislative challenges to the ACA, along with other legislative changes like the Budget Control Act of 2011 (Medicare payment reductions) and various drug pricing proposals, create significant uncertainty235236237238 - These reforms and initiatives are expected to continue downward pressure on pharmaceutical pricing, increase regulatory burdens, and may adversely affect reimbursement for approved products236238 Compliance with other federal and state laws or requirements; changing legal requirements Pharmaceutical products are subject to extensive federal and state regulations, with non-compliance leading to severe legal actions and changes in regulations impacting business operations - Pharmaceutical product distribution is subject to extensive record-keeping, licensing, storage, and security requirements to prevent unauthorized sales245 - Failure to comply with these laws or regulatory requirements can result in criminal prosecution, fines, injunctions, product recalls, and suspension or withdrawal of product approvals246 - Changes in regulations, statutes, or their interpretation could adversely affect business operations by requiring manufacturing changes, labeling modifications, product recalls, or additional record-keeping247 Other U.S. environmental, health and safety laws and regulations TransCode's R&D activities involving hazardous materials are subject to environmental, health, and safety laws, with compliance being expensive and carrying risks of substantial liabilities - TransCode is subject to environmental, health, and safety laws governing the handling, use, storage, treatment, and disposal of hazardous materials and wastes in its R&D activities248 - The company faces risks of contamination or injury, potentially leading to liability for damages, civil/criminal fines, and operational disruptions, with no environmental liability or toxic tort claims insurance250251 - Compliance with current and future environmental laws is expensive and may impair research, development, or production efforts252 Government regulation of drugs outside of the United States Marketing products outside the U.S. requires compliance with diverse foreign regulations, with the EEA offering data and market exclusivity for new and orphan medicinal products - Marketing products outside the U.S. necessitates compliance with varying foreign regulatory requirements for safety, efficacy, clinical trials, manufacturing, and marketing authorization253 - In the EEA, marketing authorization can be obtained through centralized or national procedures, with new products qualifying for eight years of data exclusivity and ten years of market exclusivity254256 - Orphan medicinal products in the EEA receive financial incentives and ten years of market exclusivity for approved indications, which can be reduced or lost under certain conditions257 Brexit and the Regulatory Framework in the United Kingdom Brexit introduces uncertainty into the U.K.'s medicinal product regulatory framework, with potential divergence from EU legislation despite mutual GMP recognition in the TCA - Brexit has created uncertainty in the U.K.'s regulatory framework for medicinal products, with Great Britain's regime currently aligning with EU legislation but potential for future divergence266 - The EU-United Kingdom Trade and Cooperation Agreement (TCA) includes mutual recognition of GMP but does not foresee wholesale mutual recognition of UK and EU pharmaceutical regulations266 EMPLOYEES AND HUMAN CAPITAL RESOURCES As of December 31, 2021, TransCode had nine employees, supplemented by consultants, with human capital objectives focused on recruiting, retaining, and incentivizing staff for cancer treatment goals - As of December 31, 2021, TransCode had nine employees (one part-time, three with Ph.D.s), with five in R&D/clinical/quality and four in business/finance/management267 - The company supplements employee efforts with consultants and advisors267 - Human capital objectives include identifying, recruiting, retaining, incentivizing, and integrating employees, with equity incentive plans used to motivate staff267 CORPORATE INFORMATION TransCode Therapeutics, incorporated in Delaware in 2016, completed its IPO in July 2021, raising $25.4 million net proceeds, and operates as an 'emerging growth company' - TransCode Therapeutics, Inc. was incorporated in Delaware in January 2016, with its principal executive office in Boston, Massachusetts268 - The company completed its IPO in July 2021, selling 7,187,500 shares of common stock at $4.00 per share, generating approximately $25.4 million in net proceeds269 - TransCode is an 'emerging growth company' (EGC) under the JOBS Act, allowing it to take advantage of reduced reporting requirements for up to five years or until certain financial/market capitalization thresholds are met270 AVAILABLE INFORMATION TransCode Therapeutics provides free access to its SEC filings (10-K, 10-Q, 8-K) on its website and through the SEC's EDGAR system - TransCode's SEC filings (10-K, 10-Q, 8-K, etc.) are available free of charge on its website (www.transcodetherapeutics.com) under 'Media & Investors' and through the SEC's EDGAR system (www.sec.gov)[271](index=271&type=chunk) - Information on the company's website is not incorporated by reference into the 10-K unless specifically stated271 - The company's code of conduct, corporate governance guidelines, and committee charters are available on its website under 'Governance'272 Item 1A. Risk Factors Investing in TransCode's common stock involves significant risks due to early-stage development, financial losses, funding needs, high failure rates, regulatory hurdles, and internal control weaknesses - TransCode has incurred significant losses since inception ($10.3 million accumulated deficit as of Dec 31, 2021) and expects to continue incurring losses, raising substantial doubt about its ability to continue as a going concern without additional funding274276295 - The company's business is highly dependent on the success of its lead candidate, TTX-MC138, which is in early preclinical development and has not yet entered clinical trials, carrying a high risk of failure296301305 - Clinical development is a lengthy, complex, and expensive process with uncertain outcomes; preclinical and early-stage results may not predict later-stage success, and product candidates can fail at any stage308309 - TransCode faces substantial competition from major pharmaceutical and biotechnology companies with greater resources and established market positions, potentially developing more successful products sooner146413414 - The company has no marketing and sales organization and relies heavily on third parties for manufacturing and clinical trials, which introduces risks related to performance, supply, and regulatory compliance405422427 - Protecting intellectual property is difficult and costly, with risks of patent challenges, infringement claims, and inadequate protection in foreign jurisdictions, which could prevent or delay commercialization463475477 - The company has identified material weaknesses in its internal control over financial reporting, which could affect accurate financial reporting and investor confidence509510515 Risks Related to Our Financial Position and Need for Additional Capital TransCode's history of losses and negative cash flow, with limited existing funds, necessitates substantial additional capital, risking dilution or relinquishing technology rights - TransCode has incurred significant net losses since inception, with an accumulated deficit of $10.3 million as of December 31, 2021, and expects these losses to increase substantially with ongoing R&D and public company operations276277 - The company has never generated revenue from product sales and may never be profitable, with success dependent on achieving numerous goals including successful clinical development, regulatory approvals, and commercialization278 - Existing cash is only sufficient to fund operations into the first quarter of 2023, requiring substantial additional funding. Failure to raise capital when needed would force delays, scale-backs, or discontinuation of development programs285290295 - Quarterly operating results may fluctuate significantly due to factors like clinical trial outcomes, regulatory approvals, R&D costs, and market conditions, potentially causing stock price volatility294 Risks Related to Research and Development and the Biopharmaceutical Industry As a preclinical-stage company, TransCode faces high risks in product development, particularly for TTX-MC138, with uncertain outcomes in clinical trials, manufacturing, and regulatory approval - As a preclinical-stage company with a limited operating history, TransCode faces a high risk of failure in developing marketable products, with no assurance that any product candidates will be successfully developed, approved, or profitable296301 - The business is highly dependent on TTX-MC138, its lead candidate, which is in early development and requires substantial investment, preclinical and clinical development, and regulatory approval before commercialization305 - Clinical development is a lengthy, complex, and expensive process with uncertain outcomes; preclinical and early-stage results may not predict later-stage success, and product candidates can fail at any stage due to lack of efficacy, unacceptable side effects, or regulatory hurdles308309312 - Difficulties in patient enrollment, undesirable side effects, or changes in manufacturing methods/formulations could delay or halt clinical development, prevent regulatory approval, or limit commercial potential319323335341 Risks Related to Our Business and Industry TransCode faces significant business risks from critical quality control and FDA compliance requirements, alongside new challenges posed by social media in adverse event reporting and reputation management - Quality control is critical for product development and regulatory approval; failure to meet existing or future quality standards (e.g., 21 CFR Part 312, 50, 56, ICH Guidelines) could materially and adversely affect commercialization332333334 - The increasing use of social media platforms presents new risks, including challenges in monitoring and complying with adverse event reporting, potential for litigation related to off-label marketing, and reputational harm from negative or inaccurate posts343 Risks Related to Regulatory Approval, Healthcare Regulations and Ongoing Regulatory Compliance TransCode's early-stage candidates face unpredictable regulatory approval, ongoing compliance burdens, and complex healthcare laws, with reform and economic volatility further complicating the landscape - The regulatory approval process is unpredictable and lengthy, especially for new drug classes like TransCode's, with potential for delays or rejections due to disagreements on trial design, safety/efficacy concerns, or manufacturing deficiencies344345347 - Even if approved, products are subject to ongoing regulatory requirements, post-marketing surveillance, and compliance with cGMPs, cGCPs, and potential REMS plans, incurring significant additional expense372374377 - Relationships with customers and third-party payors are subject to anti-kickback, fraud and abuse, and other healthcare laws (e.g., False Claims Act, HIPAA, Sunshine Act), with violations potentially leading to criminal sanctions, civil penalties, and exclusion from government programs380381382 - Obtaining approval in one jurisdiction does not guarantee approval elsewhere, and foreign regulatory processes vary, potentially causing delays and increased costs383384 - Ongoing healthcare legislative and regulatory reforms (e.g., ACA, drug pricing initiatives) and evolving global data protection laws (e.g., GDPR, CCPA) create uncertainty, increase compliance costs, and may adversely affect pricing and reimbursement385386387388389390391392393394541544545 Risks Related to Commercialization TransCode lacks commercialization capabilities, requiring significant investment or partnerships, with product sales dependent on market acceptance, competition, and uncertain reimbursement policies - TransCode has no sales, marketing, or distribution capabilities and no experience commercializing products, requiring significant resources to build these or reliance on third-party partnerships405 - Failure to establish effective sales and marketing capabilities, either internally or through collaborations, or inability to secure favorable terms with third parties, could prevent the generation of product revenue405420 - Commercial success depends on adequate coverage and reimbursement from third-party payors, which is uncertain and can be limited, making profitable sales difficult406408 - Sales of approved products are expected to involve a lengthy sales cycle, influenced by market conditions, perceived product value, competing technologies, and insurance/prior authorization requirements, potentially affecting market acceptance421 Risks Related to Third Parties and Suppliers TransCode's reliance on third-party manufacturers and CROs for R&D and clinical trials poses risks of supply interruptions, quality issues, regulatory non-compliance, and potential liabilities - TransCode relies on third-party manufacturers for product candidates, facing risks of limited/interrupted supply, unsatisfactor