TransCode Therapeutics, Inc. (RNAZ) Earnings Call Transcript & Summary

Good morning, everyone, and thank you very much for joining us for this first ever to cover our company research and corporate strategy. I'm Philippe Calais, the Chief Executive Officer and Chairman of the Board of Directors. Having an extensive experience in pharma and biotech, I joined as the first independent Board member right after the company inception in 2018, then became the Chairman of the Board in 2021 as we completed our first public offering and more recently became the Chief Executive Officer last October. It has been quite a ride since 2018, and we hope that this webcast will give you a better idea of what we have achieved so far of our strategy and our plans going forward. First of all, our use word disclaimer. And then who really are we? Our company was founded by two of our faculty members, Professor Anna Moore; and Dr. Zdravka Medarova from the Massachusetts General Hospital and the Harvard Medical School. The goal was to identify and develop new therapeutics to target advanced tumors. Since our first public offering in 2021, approximately $100 million were invested through financing, but also through government-funded non-dilutive grants. We aim at redefining the boundaries of advanced cancer care by pioneering different but complementary approaches that we describe as our 3 sort of goal, [indiscernible] strategy. First of all, RNA-targeted therapeutics that precisely reach tumors with TTX-M138 being our prioritized and lead program. Then we pursue vaccine immunotherapies mobilizing the immune distant to recognize and destroy cancer cells. Thirdly and more recently, immune oncolytic agents directly targeting tumors while at the same time, stimulating systemic immune responses. It is well established that over 90% of cancer deaths are due to advanced forms of the disease. There are numerous challenges to successful treatments in advanced cancer. The most important ones being the dissemination to distant sites, the immune lesion and the resistance. On the right-hand side, you can see the dramatic reduction in relative survival rates in different forms of cancer when comparing to the advance -- when comparing the advanced forms represented by the green line against the earlier forms on the orange line. The market opportunity is enormous and untapped. The American Cancer Society estimates the global market to be in the $120 billion to $250 billion range by 2032, and this is only just 6 years away. Here is a snapshot of the management team that is driving this innovation. We have 12 full-time employees and 4 fractional consultants. You will get to know several of our managers that will be presenting today. However, [indiscernible] our Senior VP, Clinical Operations and Manufacturing as well as Tanya Montgomery, our VP, Business Development and IR will not be presenting today, but they both play a critical role in our organization. Our Board is comprised of four independent members with extensive biotech experience. All funders or currently leading biotech companies, Tom, our CFO, and myself, complete the Board. Our Scientific Advisory Board is headed by our co-founder, Dr. Anna Moore from Michigan State University, where we have recently started an R&D collaboration that was announced last April. The collaboration gives us access to state-of-the-art facilities and the equipment that allow us to timely execute on our preclinical projects. Other members are all board world members all world leaders in their field, as is Keith Flaherty who will speak in a minute. To finish this introduction, let's have a look at our well stage truly innovative and differentiated pipeline. TTX-MC138 is our lead and priority has come on part. TTX-MC138 is an antagomiR, targeting microRNA-10b that is currently in Phase II for colorectal cancer in ctDNA-positive patients. Seviprotimut-L, a Phase III-ready compound was acquired from Polynoma last October. Seviprotimut-L is a cancer vaccine for stages 2B and 2C melanoma. Our versatile proprietary TTX drug design engine has yielded two new programs, TTX-siPD-L1 and TTX-RIGA. Finally, last March, we license a full pipeline from unleash immuno-oncolytic thus adding a new generation oncolytic immunotherapy platform. As you can see, in the last 6 months, we have diversified our pipeline with two new treatment modalities. However, we remain laser focused on our core priority with TTX-MC138 and we will pursue other programs of our pipeline as funding is made available. So now that the scene is set, please allow me to introduce Professor Keith Flaherty, our long-standing adviser who has provided his highly valuable guidance since the company was formed. Keith, the floor is yours.

Thanks, Phil. It's a pleasure to join you and the rest of the team members today. As you said, I've been around the company since inception, but in fact, a little longer than that. So I've been at Massachusetts General Hospital now for 16 years and Doctors Moore and Medarova came to my office sometime in the mid-2010 having worked on sort of the core technology behind MC138 For years at that point, really dialing in the particle characteristics and demonstrating the delivery of the particle chemically in animal models to tumors at various sites and had also deliberated on what might be the most impactful cargo, specifically thinking about microRNA directed therapeutics as really great unmet need scientifically and where we thought clinical impact also could be quite significant. And so it's been an absolute pleasure to, first, watch the company come into inception, translate this science to medicine, and to watch, how this program has matured. Later in the discussion, I'm going to revisit the topic of the very large unmet need that you alluded to in your opening comments. That MC138 is ultimately mean to address. How we've really deliberated on a very broad opportunity with this agent and narrowed down to what we think would be the most impactful demonstration of proof of concept with this agent in patients with cancer. And I'll highlight the rationale for that again a little bit later. And lastly, touch on both the Phase Ia results from my perspective in terms of how it is that corroborates this agent credentials this agent really for further development and touch again upon the Phase IIa design that we've landed on. So quite excited about where 138 stands. And as you said, a whole pipeline now that has elaborated behind it. So looking forward to participating in the discussion.

Well, hello. My name is Daniel Vlock. I am an consultant and oncology clinician for TransCode, and I want to take you through the clinical event of our lead compound TTX MC138. So as Keith mentioned, this is an iron oxide nanoparticle platform, which allows the delivery of RNA therapeutics to tumors. And this all outlines the key components of that, it is specifically designed to promote tumor uptake, and we -- and the initial lead is to focus on inhibiting and our miR-10b, which as you can see from the figure over there on the right is a key component that is a regulator of metastatic cancer and has an impact downstream not only on immune evasion but tumor cell motility, apoptosis and also proliferation. And so it is a key target to go after that way. And by inhibiting that, we're hoping to have an impact not only in relapsed/refractory disease, but also in microscopic disease as well, too. So let me show you where we are with the program, and how we are planning to developing it. This is the clinical [indiscernible] above plan for where the first is a Phase 0 in a Phase Ia, which have been completed already, and we are now beginning the dose expansion of micrometastases, and that will hopefully be our first indication. Let me show you the data that we have with those beginning with the Phase 0 program -- study, I mean. This was the Phase was basically to demonstrate the underlying mechanism of action that these nanoparticles can truly target the target metastatic disease. So this was in a patient with metastatic breast cancer with bone liver lung metastases. And in this case, a radiolabel microdose of MC138 was given to this patient on day 1. And then pet scanning was done to look at where it basically track to in the tumor. And what you can see here is that with those arrows that you can see on the right figure, that Pet MRI showed an accumulation of the drug in the metastatic lesions. At the small dose, it was well tolerated as well too, but what it documented is what we have seen in animal models that these nanoparticles were actually able to track to the areas of interest and therefore, at least have a therapeutic impact in those areas. Based on those studies, we began a Phase I trial. And this is a phase trial looking at safety of therapeutic doses of MC138 and the main end point on that is to basically see whether there is any toxicities that we need to worry about. And then to look at it in terms of secondary endpoints, which we response rates as well, too. A total of 16 patients have been treated around 86 doses to date. The duration has gone up to 5 months with patients being out a lot longer than that, and we believe that is significant, and there are still three patients that are on study with this trial as well, too. We ended the toxicity portion of this at the end of last year, but are continuing to fall patients because patients do still remain on study. This is the tumor types that were treated. This is typical for a Phase I study, where you get patients that have exhausted other therapies and are therefore available to be treated for these kinds of tumors, and it is a wide range, certainly with breast cancer, sarcomas and then a variety of unusual tumors as well, too, which is typical for this kind of an initial study. This is the safety endpoints that we looked at this way. So you can see over there that we began with the dose escalation study where we began with 0.8-milligram per kilogram and then gradually escalate it up to 4.8 milligrams per kilogram, which is the top dose that we gave here. This was extremely well tolerated. There was one, would be technically determined to be a serious [indiscernible], which was an infusion reaction. The reason that it was looked at that way, even though it was a low rate, is that because out of an abundance of caution, when this patient presented several hours later with a rash, it was felt to be safer to admit the patient to the hospital, which is why it then got graded that way. But frankly, this was well tolerated. The patient did well and was discharged the next morning. So we have been able to escalate up through 4.8 milligram per kilogram without any dose-limiting toxicities, and it was extremely well tolerated. This gives an overview of the toxicity that we saw. And again, the vast majority of these were really Grade 1. The 1 area where we saw something that was at least initially deemed as higher was in iron overload. This is an iron nanoparticle. We were certainly focused on that. But really on review of this, although it says this was a Grade 3, which would be considered to be a more serious toxicity. That was only based on elevated serum ferritin toxicity with iron ore is based on evidence of organ toxicity, we saw none of that here. And so although we are seeing increased iron levels in these patients there really has not been any organ toxicity based on that. And so we believe that this is still extremely well tolerated. And any kind of significant events were really rare and did not raise the question of any kind of safety concerns. This is the pharmacokinetics that we saw with the study this way. And as you can see over there on the left, is that cohort by cohort, basically, we saw dose levels that would behave in a dose depend fashion with higher levels being achieved at the higher doses. What's important to point out here as well, too, is that the pharmacokinetics really matched quite nicely what has been seen in the animal studies here shown in rats and dogs. So it basically is consistent with what we have seen in preclinical data. So the animal models appear to be consistent with what we're seeing in human models and that gives us greater comfort in terms of what we're going to see in terms of pharmacokinetics and hopefully, with efficacy [indiscernible]. This is the efficacy analysis that we saw. We have known that this is -- that this drug leads to basically disease stabilization. It is not designed to basically have cytostatic as opposed to basically tumoricidal in this particular case. And so therefore, what was expected to be seen was disease stabilization, which we saw in 60-plus percent of the patients there. And this is a long period of time that have people on that. So 9 out of the 14 the value of patients had disease stabilization, which again is consistent with the mechanism of action of the drug. That is shown over here in what's called the [indiscernible] where we draw a line of 6 months. And as you can see, a considerable number of individuals, we're out much longer than that. 3 patients remain on study. And that's what you also see with the progression-free survival, which is shown at the Kaplan-Meier curve there on the lower right of this as well, too. I wanted to share this one patient with you because it points to what we think is basically the cytostatic nature of what we're observing. This is a patient with metastatic thyroid cancer with lung metastases. This patient has remained on study. Although we have not seen a regression of the tumor nodules, we basically -- they have not progressed as what to. What was also known, although it was not initially -- we're not drawing these levels as part study, but the was done clinically used thyroglobulin levels. And this is associated with increased tumor burden. And what you could see here is that this patient had rising levels of thyroglobulin, which is indicative of increased tumor burden. But after the patient was begun on study. As you can see there, the thyroglobulin levels dropped to 0. Despite the fact that we saw tumor nodules radiographically, the evidence of tumor burden was basically down to that particular point. Because of concerns about iron overload, the drug was held on cycle 7 and 8, at which point we saw the thyroglobulin levels basically go up again. drug, which we started. And as you could see, it began to go back down again as well, too. And so this would be indicative of a drug that is having a cytostatic in terms of holding the tumor in place. although not seeing the same regressions, and it's consistent with the stabilization that we have seen with the vast majority of patients on this study. Let me now move on to where we want to go next with the drug. And that is using MC138 in colorectal cancer and targeting minimal residual disease. And we believe there's an opportunity here to address a major unmet medical disease, which is basically going after patients with microscopic disease. This field has changed quite dramatically in that with liquid biopsies, looking at ctDNA, we are now able to detect microscopic disease far in advance of when it become radiologically evident. And that becomes important in terms of an intervention at that point, which was up until a few years ago, something that could not happen. This gives us an opportunity to have an agent like MC138 in that microscopic disease setting. And so we are going to be treating patients with micro metastases who are at a high risk of returns. And this is individuals who have undergone therapy for their disease in disputations chloride cancer with curative intent when they have had their surgery, followed by adjuvant therapy, but then it appears that the disease has come back. At present, there is no therapeutic option available for these patients. And we know that if they are ctDNA positive that they are going to have almost a near certainty that the disease is going to come back. And so they have a therapy such as what we have that is well tolerated and that can be given that is specifically designed for these kind of microscopic diseases is a unique opportunity for MC138, and that is -- what we are doing is they take these individuals after conventional therapy and adjuvant therapy has been given with curative intent and then to basically treat that patient population. To do this study, we have done -- we have developed a collaboration with Quantum League Health Care collaboration. This is a multi-institutional collaboration that has involved the plant sites that you can see on the right, it is a collaboration that involves major clinical cancer sites around the country. And as you can see the Mayo Clinic, University of Minnesota, et cetera, major cancer centers that have basically collaborated together to develop novel therapeutics. So these are leading cancer centers that are collaborating with us to basically help develop new standards of care. So we view this not only as [indiscernible] opportunity, but also as a validation of the science that we are doing. By working with Quantum Leap, we are able to basically use their platform to rapidly have the study up and running with accelerated time lines and cost savings and patient enrollment as well, too. This is the trial designed for this initial Phase IIa trial and that will take individuals who have had curative intended therapy with metastatic -- with colorectal cancer who are then ctDNA positive. We are planned on treating 48 patients at the top dose that we have seen. And we will basically follow them with ctDNA positive and the endpoint will be not only clearance of that, but also the evidence of basically preventing radiologic response. This will happen relatively quickly. We think that this is a unique window of opportunity that we can follow these patients and look for evidence of basically a reduction in relapse-free survival in this high-risk group of individuals. At this particular point, that's where we're going with the studies. Let me now move on and reduce to Louis Brenner, who will be talking about the cancer vaccine program that we're doing. Louis all yours, please.

Thanks, Dan. It's a pleasure to have the chance to talk about the company and its programs. Similar to Dan, I'm an adviser to the company. I've been working with this company for the past couple of years. I'm myself and a clinician and have had the chance in my industry career to work on both iron oxide nanoparticles as therapeutics and diagnostics as well as immunotherapy for cancer. And so the elements of this platform, including the approach to go after significant unmet needs in advanced metastatic cancer is something that is quite attractive to me. I'll focus briefly with some commentary on another aspect of the company's portfolio, the Seviprotimut cancer vaccine. Next slide, please. So this program came about as part of a partnership with CK Life Sciences. It is a vaccine to go after patients who still have unmet needs due to metastatic or advanced cases in melanoma. This is a polybalent vaccine. As many would know that the immunotherapy approach in Metsa melanoma has been quite successful with key important drugs that have really been significant advances in the industry and for the benefit of patients, including KEYTRUDA and OPDIVO. These checkpoint inhibitors are used for the treatment of advanced melanoma. However, they're not universally effective or universally well tolerated in patients, and it does leave an opportunity for additional approaches that leverage some of the scientific understanding that's been developed to provide another technological approach in this case a vaccine rather than a checkpoint inhibitor. The side effects in a vaccine have the potential to moderate some of the immune-related toxicity associated with checkpoint inhibitors. The patient eligibility assumptions are just unable to tolerate or aren't able to be treated with checkpoint inhibitors and the ability to have this administered potentially in the dermatologist or the oncologist office might have an opportunity. In addition, there's a potential for combination or sequential therapy. The drug has gone through -- Seviprotimut has gone through an initial Phase III study called the MAVA study, which I'll cover in a moment. It's had very good and active dialogue with the [indiscernible] at the FDA to try to advance this towards what could be a planned pivotal Phase III study. This would obviously be a larger, more significant study and the company is considering its options in terms of how to pursue manufacturing, and what would objective to be a large study, several hundreds of patients, the kind of which would potentially be transformative, but also would require a significant commitment of resources. It does provide significant optionality for the company as it thinks about carrying forward its platform of advanced cancer therapeutics. Next slide, please. So just briefly cover the study that completed and has been published in the Journal of Immunotherapy for Cancer in 2021. This is the MAVA study. Looking at Seviprotimut versus placebo, an adult population with advanced but resected forms in melanoma. The dosing starts relatively quickly after the first dose, it's done with an intradermal injection. This was a significant study in that had 55 sites in United States and Canada. You see on the right, both the recurrence-free survival and the overall survival and the hazard ratio of 0.65 and 0.37. This puts it in the potential ballpark of some of the other therapies that have been approached. However, acknowledging that this study at 100-something-patient is a little bit smaller than other studies that have been done in the past. So it is definitely a hypothesis generating and it does allow the company to think through what options it might have including potentially looking at patients with advanced disease that haven't been treated before or have not been able to be treated with a traditional checkpoint inhibitor therapy. And so as we think about the portfolio more broadly, having this cancer vaccine for melanoma is something that adds to the MC138 story. In addition, there's additional parts of the portfolio for treatment of bladder cancer. And with that, I'll introduce my colleague, Michelle Janicot to talk about our other platform for immunotherapy in bladder cancer.

My name is Michel Janicot. I'm PhD in molecular and cellar biology. I have about 35 years' experience in oncology R&D. And I'm supporting TransCode as Acting Head of Translational Medicine which, in other words, I'm helping the company to strengthen the two-way bridge between preclinical and clinical development. The following set of slides illustrate an interesting and very complementary addition to TransCode R&D pipeline with the recent acquisition of Unleash Immuno-oncology and consequent integration of an oncolytic virus platform in the company portfolio. Oncology viruses are designed to selectively target and replicate in tumor cells, which induce significant tumor cell lysis or killing, which in turn generates tumor antigen released in the tumor microenvironment, which are then used by the host patient as signaled for broad antitumor immune response. Specifically, our lead candidate, UIO-524a represents a rationally designed next-generation of oncologic virus, which is based on anovirus type 5, which in real life is responsible for mild symptoms of regular code. Among other genetic elements, very important elements. UIO-524 consists of a target recognition motive namely the fiber 5 Sage 3, which targets desmoglobin 2, a receptor known to be expressed in malignant cell, and this [ motive ] is actually sort of piloting the virus to tumor cell. The second important element is a tumor microenvironment, sensitive, hybrid promoter namely KH Spark, which in real life, regulate the expression of key matricellular glycoprotein involved in extracellular metrics remodeling and tumor agenesis and that is highly active in malignant cell and [indiscernible] associated [indiscernible] compartment. This promotor senses at Ipoxia and inflammation in tumor microenvironment and therefore, driving selective virus efficient virus replication. And last but not least, the virus also contains three highly relevant immunostimulatory factors intended to activate dendritic cells, T cells, natural killer cells, and those agents are CD40 ligand, which is also known as CD154, which is a protein primarily found on activated T cells, which act as a critical communication bridge between the immune system. The second immunostimulatory factor is the 4-1BB ligand, also known as CD137, which is a transmembrane cytokine and immune checkpoint molecule that points to 4-1BB receptor found primarily on antigen presenting cells, which are the dendritic cells and provide a crucial custimulary signal to promote T cell activation proliferation and antitumor immunity. The third element is interleukin 21, IL-21, which is a cytokine that coordinate the transition between innate and adaptive immunity. So all these elements concur to the fact that these [indiscernible] will replicate efficiently in selectively in tumors and create an environment very, very adequate for reaction of the post immune system. It is of note that UIO-524 is currently in preclinical development stage, pathways to IND but we have also additional alternative in discovery phase. With this virus, an initial clinical proof of concept has been achieved in human tumor-bearing immunodeficient mice. Those mines are used to allow your mature growth in development. As you can see on the top left of the slide, briefly, the human cells were injected under the skin of the animal to form subcutaneous tumors, and when those tumors were established, either vehicle control, in gray or UIO-524 in green was injected intravenously three times during the first week. And then the tumor size was measured over time and is what you see on the top left. Clearly, results demonstrated that a well-tolerated dose, systemic administration of UIO-524 were then to induce promising significant inhibition of growth which in this case is essentially due to oncolytic activity as this experimental model were performed in immune-deficient mice leaving the immune system component of the reaction to the virus majorly out. And this was compared to the vehicle control arm. And you see clearly a good efficacy of that particular virus. On the top right, the company initial focus for clinical evaluation is proposed to treat adult patients with low-grade muscle invasive bladder cancer, which represents an unmet medical need. Muscle invasive bladder cancer account for about 25% of all bladder cancer diagnosed and carries a higher risk of spreading to other parts of the body. As you can see in the very, very naive scheme in the insert, that you see that the tumor starts at a low grade in the wall -- in the interval of the bladder. And then progressively, the tumor is developing start to invade muscles, and it's where you start to have the metastatic property with a dreadful outcome. Talking about bladder cancer and muscle-invasive bladder cancer, from a health economic perspective, bladder cancer represents the 9th most common cancer globally with over 600,000 new cases worldwide diagnosed annually. The market size for muscle invasive bladder cancer alone is currently about $2 billion. And according to the expert analyst is projected to progress to more than $3 billion by 2035 million with an expected compound annual growth rate of about 5% over the next decade. Using intravesical administration of the virus, which if eventually necessary, further increased the safety profile of this drug class. We strongly believe that UIO-524 represent a valuable additional option to the therapeutic armamentarium to treat patients with bladder cancer and certainly beyond bladder cancer in solid tumor indication. And for the following section of this presentation, I leave the floor to my colleague, Zdravka Medarova, who's going to lead you to the next section.

Hello. My name is Zdravka Medarova. I'm Chief Scientific Officer of TransCode, I also cofounded TransCode, along with Anna Moore and Michael Dudley back in January of 2016, based on technology that we developed at Harvard Medical School. I'm also Associate Professor of Radiology at Havard Medical School and one of the investigators at the Massachusetts General Hospital. When we first started TransCode, we envisioned the company as a platform company. And it's a platform company based on two properties. The first one is the fact that we develop nucleic acid-based drugs for cancer. And because of the modularity of the genetic code, one can develop drugs that are purely modular. The advantage of that is that currently, only 20% of cancer causing genes are druggable using traditional approaches such as small molecules or monoclonal antibodies, whereas using the genetic code as a target, essentially any cancer causing gene will be druggable, which will then open up the remaining 80% of cancer causing genes for the design and development of drugs. And as you can imagine, this is going to open a huge pipeline of of cancer drugs if it winds up being successful. The second property of TransCode's technology that makes it platform-based, is the use of the TTX drug design engine. And TTX is essentially a nanoparticle as mentioned earlier, which is modular in terms of its synthesis. And because of that modularity, we can use this particle to develop a wide variety of drugs, specifically towards cancer but also towards macrophage-related diseases. And the chemistry behind this particle allows us to tune the delivery of these drugs to various tissues and cell types such as we can, for example, achieve controlled release in terms of time, in terms of the macro environment, we can achieve the delivery, not only of nucleic acids, but also peptides, small proteins, which will then allow us to develop targeted versions of these drugs. So these are all potential directions that we could take using this platform-based technology. So as part of TransCode's pipeline, we have developed a couple of therapeutics for cancer. First one is a novel immune checkpoint inhibitor, which we call TTX-siPD-L1. That inhibitor is essentially the TTX platform conjugated to a small interfering RNA against PD-L1. PD-1 is a target for immune checkpoint inhibitors. And in this table, we're outlining some of the advantages of TTX-siPD-L1 to the traditional checkpoint inhibitors, which are monoclonal antibodies. And I'd like to draw your attention to the safety and potency advantages that TXX-siPD-L1 holds because TTX-siPD-L1 uses an RNA-based approach that silence is the gene for PD-L1. It is potentially a much more powerful inhibitor of PD-L1. The analogy that could be used these traditional checkpoint inhibitors mop up the floor in the case of a flood, whereas the RNA-based approach would effectively turn off the faster. So you can imagine based on this analogy, how much more powerful siRNA-based approach would be the traditional monoclonal antibody. So that's in terms of potency. A second element related to potency is the potential of the siRNA component to convert cold tumors into hot which is unnecessary signal that needs to be present in addition to the immune checkpoint inhibitor in order to have an effective response against cancer. So with the TTX-siPD-L1 platform, we could actually achieve both inhibiting the checkpoints, but also converting a cold tumor into a hot tumor. So again, increased potency compared to traditional checkpoint inhibitors. In terms of safety, because of the tunable release that could be achieved using the TTX platform, we could lower the systemic exposure or we can tune the systemic exposure to the checkpoint include, in effect, then lowering systemic immune activation in minimizing the potential for undesired side effects. So these are some of the advantages of TTX-siPD-L1. And here, we're showing some preliminary results in a mouse model of pancreatic cancer, in which we treated these mice either with TXX-siPD-L1 or an inactive drug called TTX scrambled. We used two doses of TTX-siPD-L1, a low dose and a high dose. And what you can see from the graph on the left is that with the high-dose TTX-siPD-L1, we can achieve a profound delay in tumor progression relative to the control treatments, which translates into quite significant enhancement in survival, as you can see from the graph on the right. So in effect, what happened was that in this animal model, we increased survival very dramatically compared to the controls to 67% at 12 weeks, which in this animal model is quite a dramatic improvement. A second drug that we are developing as part of our pipeline is TTX-RIGA, and that's a pattern recognition that our agonist. Pattern recognition receptor agonist have been of interest for a while not only because they can lead to regression of pre-existing tumors, but also because they can help build lifelong immunity against rechallenge with these tumors. So in patient terms or in human terms, what that would mean is if a patient response to therapy with a pattern recognition receptor agonist, they would effectively be assured the absence of recurrence because of immune activation against the tumor antigens. So here is a table outlining some of the advantages of our approach relative to traditional pattern recognition receptor agonist. And it relates a lot to safety. Traditional pattern recognition receptor agonist hold potential for cytokine-related toxicity, because the target is present not only in tumor cells, but also in multi cells. For that reason, typically, pattern recognition receptor agonists are injected intratumorally to avoid systemic exposure. The way the TTX-RIGA is designed, it would permit systemic administration of the drug and targeted activation only in the tumor microenvironment. And the reason why that's important is because as we know, cancer is a systemic disease. It's not a local disease, therefore, systemic delivery of the drug in the context of tumor-targeted activation will then increase the potency while also increasing the safety of this drug compared to traditional pattern recognition receptor agonists. And here is an example of a study that we did in mice with melanoma. I'd like to draw your attention to the graph in the middle. That graph depicts the growth of the tumors over time for up to 22 days after treatment. These tumors are secondary tumors. So essentially, what was done is mice were implanted with melanoma tumors. They were treated at that point. They were rechallenged at the end of treatment with secondary tumors to mimic cancer recurrence. And what you can see in the red line is that the animals treated with TTX-RIGA in this case, failed to progress their secondary tumors where the control groups did progress their tumors grew. And what that indicates is that we have successfully built systemic immunity against the tumor antigens and are preventing the growth of secondary tumors. So that's an interesting result that remains to be replicated in additional animal models, but potentially illustrates the value of this technology in this particular drug. So to summarize, we believe that TransCode holds the key to really broad pipeline of cancer therapeutics because of the modularity of the design of the drugs that we're developing. We have the unique advantage of being able to deliver nucleic acids to cancer, which has so far slowed down the development of these technologies or the translation into clinical practice and believe -- therefore, we believe that with the illustrated examples of TTX-siPD-L1 and TTX-RIGA, we are just at the beginning of a kind of an exponential growth curve in terms of drug development. And with that, I'd like to introduce Tom Fitzgerald, our CFO, who will talk about our corporate finance.

Thanks very much, Z. And thank you, everybody, for joining this morning. We're thrilled to have you here and thrilled to share the story. As you can see and you've heard, we've -- since the IPO in just about 5 years ago, we've made substantial progress on a number of fronts. Clinically, as you've heard a lot of the details about from prior speakers, organizationally, the team that we've assembled here over the past few years is just extraordinary, some of the best people that one could ever hope to have in the oncology area. And then most recently, strategically, which is just summarized here. So in addition to moving forward in the clinic with the TTX program. We've gotten added two additional shots on goal as Philippe had described earlier, one of those being the Seviprotumit program for cancer vaccines and the immuno-oncolytic program for immunotherapy. In Q4 of '25, it was October '25, we did the acquisition of Polynoma, and that involved issuing to CK Life Sciences, which was the ultimate owner of Polynoma, Series A convertible preferred shares. So when you see those on our balance sheet, that's what that went to and at the same time, concurrent with the acquisition of Polynoma, we also received a $25 million investment in common in stock from CK Life Sciences, and that was represented with Series B preferred shares. They were also issued 83,000 common shares to CK in connection with the Polynoma acquisition. So you'll see that on our cap table as well. And then in March of this year was when we did the exclusive worldwide licensing of the oncolytic portfolio from unleashed immuno-oncolytics. And that involved us issuing Series C convertible preferred shares to the unleash entity. And then in April of '26 of this year, just a couple of months ago, we entered into a financing arrangement with Yorkville Advisors, a standby equity purchase agreement or [ CEPA ] that provides for up to $20 million of financing under a variety of conditions, fairly common to those kind of programs. Uncommon to those programs that involve the issuance of up to $6 million of convertible notes. And we've taken down $1 million of the face amount of those convertible notes and are on track to receive the additional $5 million of face value of convertible notes shortly after our shareholder meeting, which is coming up on July 2 of this year, once shareholders approve the convertibility of the Series A, B and C shares and all the shares that are potentially issuable to Yorkville Advisors, all of those will become part of our cap table on an as-converted basis. So here's a summary of our capital position right now. This is using the share price a few days ago, [ $5.69 ] a share. Prior to any of the convertibility that I described with the Series A, B and C shares and the Yorkville shares. We've got about 950,000 shares outstanding, giving us a market cap of $5 million -- just over $5 million, which we think is -- doesn't fully reflect the company's potential or accomplishments to this point. On a pro forma basis, assuming conversion of all the shares that I've talked about, we'll have about 18.6 million shares outstanding, and that would give us a pro forma market cap of a little bit over $100 million. We have no long-term debt, the only short-term debt that we have or the convertible notes to Yorkville that I mentioned. And as of March 31, the date of our latest Q filing, we had just under $13 million of cash, and we anticipate receipt of additional cash over the course of the next 30 to 45 days. So that we'll have -- we'll be in a good position to go into 2027 and hopefully beyond that. So with that, I'll turn it over -- turn it back to Philippe Calais, who will provide some concluding remarks. And again, thank you all for being here.

Thank you very much, Tom. That's so far a very, very interesting and enlightening presentation from everyone. If we look at the investment thesis, our mission is really to build an innovative and differentiated oncology company that will meaningfully improve the treatment of advanced cancer by developing breakthrough treatment modalities that are acting on metastatic cancer and enhancing the power of the immune system. We believe that the power of innovation is at the intersection of three limits; the targeted delivery, the immune activation and the tumor biology, all $ serving to unlock the next wave of innovative cancer drugs with marked clinical impact for the patient. We're building a balanced and scalable portfolio. The Phase III shots on goal that came back a few times today, that combined near-term value creation, platform-driven innovation and long-term pipeline sustainability. This approach allows us to advance promising drug candidate technology platforms today while continuously generating differentiated program for the future. We have prioritized TTX-MC138 as our lead asset and are laser focused on the clinical program execution. We see three potential catalysts in the next 18 months, the Phase IIa enrollment completion, the preliminary data readout and the final data. Our next clinical program is Seviprotimut, is Phase III ready. Both clinical programs serve as fundamental assets for combination strategies. Behind those clinical programs is a deep and expanded preclinical pipeline anchored by three core engines of innovation. We plan to evaluate the combination of TTX-MC138 and Seviprotimut-L in a preclinical program to explore potential strategies between both modalities to address metastatic disease in melanoma and capitalize on the roles of miR-10b in the target. Our proprietary delivery engine, TTX, you've heard about that one from Z has already yield two in-house program with siPD-L1 and RIGA. In addition, the TTX delivery engine enables the use of diverse and flexible payloads, leading to different therapeutic modalities that aim at improving precision and targeting platforms. TTX is available for partnering. Through our newly acquired unleash immuno-oncologic platform, we will be developing agents that directly target tumors while simultaneously stimulating systemic immune response. This platform expands our reach into a novel mode of action and enables the creation of differentiated next-generation cancer therapies. We will initially focus our efforts on model invasive bladder cancer. So together, those programs and platforms provide a scalable framework for project pipeline expansion, allowing us to generate multiple product candidates for either internal development or for partnering. And in order to meet those challenges, as an organization, we focus on execution. It's all about execution, execution and execution. We also operate and a strict capital discipline. This capital discipline applies to all levels of the organization. For example, we optimized our research operations through our R&D collaboration with Michigan State University. We benefit from unique pool researchers and state-of-the-art equipment that will be difficult to acquire by ourselves. We also elected to collaborate with Quantum Leap to manage TTXMC138 Phase IIa clinical trial with significant benefits expected as compared to a traditional CRO model. Finally, both Polynoma and Unleashed Transactions whereby design structured to avoid upfront financial commitment. We also believe that communication with all our stakeholders and investors will promote a better understanding of our mission and ultimately help fill the valuation gap. Today, our first webcast is the best example of how we implement this strategy. So I hope that you appreciated today the extent of the work that has been done by the absolutely amazing team that we have gathered at TransCode Therapeutics, and I thank them really for their contribution and their dedication. This is not small work. It is extensive, and we have gone for such a long way since 2018. So talking about the execution, let me show you a brief slide of the near-term catalyst, much of -- most of which are related to TTX-MC138 and each has a potential to be a significant inflection point. In the second quarter of '26 and we are in that second quarter, we expect to have the enrollment initiation in the Phase IIa. In the third quarter, we will have an update on the enrollment. And in the fourth quarter of this year, we will look at preliminary results. The first half of 2027 will lead to the Phase Ia results being released at the major oncology conference and also Phase IIa enrollment completion. The second half of 2017 will see the Phase IIa completion and the preliminary readout that is associated with the completion. And for the other programs, we will advance those some preclinical assets towards IND as obviously available -- funding is made available, and that includes government grads. So that's non-dilutive grant. Because we are reaching the end of our webcast, please allow me to turn back to our Scientific Adviser, Professor Keith Flaherty for a few concluding remarks.

Thanks, Phil. I've been a clinical investigator now for 26 years at mass general for 16 of those now and met the TransCode founding team back in the inception of the company, how -- in the mid-2010s. And I've watched this story evolve in a way that I think is really maintains all of the novelty and potential unique impact that was potential within view based on preclinical data now several years back. I think the unmet need that MC138 potentially addresses, I think, is really quite substantial. A couple of ways to describe that, but I think probably first and foremost, the ability to halt the progression -- the metastatic progression of cancers and further dissemination even once enters have initially met has size, I think, is quite a real value proposition. But the fundamental premise really does start from the preclinical data -- extensive preclinical data suggesting that if you can deliver [indiscernible] 10B to tumors systemically, you can have a sort of diverse mechanistic effect, ultimately, leading to halting the progression of metastatic disease. As we've deliberated on translating the preclinical data into clinical development strategy, we've really focused on kind of these two aspects. One is the ability to halt progression of metastatic disease when it is microscopic. And as this audience is well aware, in recent years, we've been able to develop technologies that allow us to find those patients, with far greater reliability, largely leveraging circulating tumor DNA detection methods, which are becoming timely sensitive. So we now have a very large fraction of the solid tumor population who undergo definitive surgery, followed by radiation as appropriate. And then when tested with the circular tumor DNA detection assays can basically be found at a state where they have microscopic metastatic disease only, so not visible on the radiographic scans and certainly not symptomatic. We think that's a point in disease evolution where this approach can be very impactful, again, based really directly on the preclinical data. And this is an emerging area of clinical investigation in the field where we're deploying established therapies now in this so-called MRD-positive solid tumor setting, but also investigational agents that have a particular mechanistic rationale as this one does. And reflecting on the Phase Ia data, basically, in my experience, is an early phase clinical trial investigator. We're always looking to try to understand the degree to which we can connect the dots from preclinical data and our expectations based on preclinical efficacy studies as well as toxicology, pharmacokinetics and the like. And basically, I would say the Phase Ia data really affirms what had been seen preclinically in terms of ability to deliver doses, achieve exposures that are very, very well tolerated as they were in preclinical species. So absolutely no surprises on that front. And so this product appears to be behaving as expected in terms of ability to administer it systemically. We're going to have an increasing focus, of course, and shift into the Phase IIa study in terms of trying to corroborate the ultimate mechanism of action, as alluded to in the MRD-positive setting, where we think we'll be able to take patients who are detected to have circulating tumor DNA monitor that circulating tumor DNA on therapy and basically aim to suppress the progression of metastatic disease in that setting. We know that patients who are MRD-positive are essentially certain to relapse and generally within a matter of months time. And so we will need not follow this population for very long to have a sense of whether this agent as monotherapy is able to suppress the further progression of disease and true radiographic or clinical relapse. That's ultimately the goal and deliberating on the various tumor types where we have reasonably miR-10b plays a substantial role based on extensive preclinical data generated by the company and by others in the field. Colorectal cancer is one indication that we think really sort of is at the center of this opportunity in terms of taking patients who are MRD positive and demonstrating that we can suppress the progression to metastatic disease over metastatic disease. Ultimately, this platform technology in terms of the delivery strategy, this very unique nanoparticle that had been derisked even before the development of this program as a core that can be used to deliver contrast agents for radiographic studies really represents quite a unique platform for delivering therapeutics beyond miR-10b. This is for the life cycle of the company thus far been the lead program and product, but establishing proof of concept with this agent we'll really open the door to substantially expand the pipeline and use this unique delivery platform to achieve systemic delivery in a way that we've not been able to in prior years when trying to achieve target delivery with RNA therapeutics in particular. So again, I think we're quite pleased with the progress of the program so far. It's the agent's graduation from Phase Ia, just clearly supports its further investigation in Phase IIa. And again, we think our -- the most profound proof of concept would be the ability to suppress progression of metastatic disease in patients who are MRD positive. In future studies, we also expect to follow preclinical data leads in terms of combining this agent with other standard therapies, where we have preclinical evidence of synergy and deploy those standard therapy-based combinations in patients with overt metastatic disease, where we have reason to believe we can achieve a more deep and durable responses with a combination of conventional agents combined with MC138. So a progression of studies to be done and establish essentially two-pronged version of clinical proof of concept. But as I said from the outset, this is an agent that was highly novel at the time that it was first conceived and developed preclinically remains really truly unique in the field in terms of its potential. With that, back over to you, Phil.

Thank you very much, Keith. We hope that we were able to convey our vision and our passion for our company as we are fully anchored on our -- laser focused on TTX-MC138, as you have heard from Keith, the development and the execution in the context of our three shots on goal against advanced cancer. Our team is fully committed on executing on our goal to serve the needs of the patients, also our stakeholders and investors. So thank you very much, and have a great rest of the day.