Okay, I think we'll get started. Welcome everyone in the room and online to Ascendis Pharma's Oncology Program Update. Hopefully, I can get this working. There we go. Here on slide two, I'm lucky enough to take Tim's part today and remind you that we may make forward-looking comments during this presentation, including statements regarding our TransCon technology platform and our oncology product candidates. Actual results may differ materially from those expressed or implied, and you should not place undue reliance on these statements. For information concerning the factors that could cause actual results to differ materially, please see the Risk Factors section of our most recent annual report on Form 20-F. Turning to slide three, we have a great agenda for you this morning. Today, we will focus in particular on presenting the monotherapy data used to declare the TransCon IL-2 β/γ recommended phase II dose. These data are an updated data cut compared to our ASCO abstract, with three months additional enrolling, dosing, and follow-up, showing that TransCon IL-2 β/γ was well-tolerated as monotherapy, generating robust immune responses along with clinical benefit in a dose-dependent manner in a heavily pretreated patient population. During our presentation, Jan will give an overview of Vision 3x3 and how oncology is a key part of that. Kenneth Sprogøe will walk through the biology and design of our immuno-oncology product candidates. Stina will go into detail on the data I previously mentioned and walk through our clinical development strategy and program. We're also very fortunate and pleased to have Dr. Devaraj, here today from UPMC, to provide an investigator's perspective on both of our immuno-oncology product candidates, including his experience treating a patient with TransCon IL-2 β/γ. Finally, Jan will close with some remarks before we take Q&A. With that said, I'll turn it over to Jan. Thank you, Scott. It's such a pleasure to be back in New York. This is my first really exposure to Investor Day since COVID, and I feel really pleasure to meet new people, see people coming here and getting breakfast, it's really, really nice. What I would like to start, where I always start, our Vision 3x3, which is our strategic roadmap from 2020 to 2025, how we want to build a leading global biopharma company. I would just spend three, four minutes to give you an update, how we are progressing to fulfill this vision. You know, TransCon Growth Hormone for pediatric growth hormone deficiency got approved in 2021. Now, in the being commercialized here in the U.S. under the name SKYTROFA, really building up to be the leading brand in value. We do the commercialization of SKYTROFA in Europe, where we will start to do that in Q3. TransCon PTH for adult hyperparathyroidism, we are filing our response related to our Type A meeting with FDA here in June. In Europe, we are progressing with our filing and expect to get our approval later this year. TransCon CNP for achondroplasia, which is our last product in our rare disease endocrinology pipeline, we really are going through all the regulatory interactions, both in U.S. and Europe. We're getting more and more convinced about our strategic plan to ensure that product will be out in the market in 2025. We're really getting the interaction that we need, the sign-on, how we're really doing the latest part of the development. As you know, we are growing the endocrinology rare disease pipeline to our global clinical reach. We are basic, are having global trials everywhere in the world to ensure that we can be where every patients are. We are pursuing nine total indications, one of the important one that come out is our phase three trial for adult growth hormone deficiency later this year. New endocrinology products. Yes, we are focused on endocrinology. We will continue to focus on endocrinology. This is where we started, this is where we will continue to invest in new product opportunities, developing this area where we have in-depth knowledge from. Going over to the oncology today, I will come to a few slides about oncology. Why did we move into oncology? I think Devaraj and everyone else know the huge unmet medical need. We believe, as we did in rare disease endocrinology, by utilizing the TransCon technology and using the same algorithm that we basically have been extremely successful with in our rare disease endocrinology, we basically can do the same thing in oncology. We utilizing two different platform. One, the systemic delivery, which Kenneth will explain how we use that from IL-2, which basically are the same technology platform we have used in endocrinology. The localized delivery platform, where we basic are developing a paradigm shift, where we basic inside a tumor can deliver for weeks and weeks an unmodified compound. We see the opportunity to work with a lot of different opportunities. Why oncology? Is because we believe we can develop this paradigm shift products. It's not the same time that we will have the same business model in oncology as we do in rare disease or endocrinology, where we basically are going from developing an idea to move it out to the patients. One question I often get asked for: What is your passion for IL-2? Why are you so passionate about IL-2? It goes back, potentially, as Scott said, because I'm so experienced, is a nice way to see it, but I have seen a lot of this product being approved and come to the market. When I look on IL-2, it remind me a little bit about growth hormone. Growth hormone got approved in the '80s. Since the '80s, people have tried to develop an improved version of growth hormone because it has been realized there was a huge unmet medical need in the daily treatment with growth hormone. First, when we got our approval with SKYTROFA in 2021, it was the first once-weekly product that came out to the market in the US with an approved outcome. When I look on IL-2, I actually see the same pattern. It's a product nearly from the same age as daily growth hormone. It got approved in 92 as the first immunological compound in oncology or cancer. It has been through multiple pathways. When people, for 10 years ago, started to make it non-alpha, we thought we have solved it. No, we didn't solve it. We built more knowledge about it, that was why it was a perfect compound for Ascendis to go back, because where do we have our strengths? We have our strengths by utilizing the TransCon technology, really to develop product in a complete unique manner. At the same time, we also believe in the three fundamental pillars of drug development, scientific understanding. We really can spend 20 years utilizing the last 20- 30 years' knowledge about IL-2 failed program, building up on the science, understand it as a pillar one, number one. The second part was really building up a really, really strong preclinical package. We will not show that today because we have presented that before, now we start to see the clinical data coming in. I believe any product opportunity that need to be successful into the market, it need to be successful both on the strong scientific fundament, strong preclinical data, and have the right clinical data. We're starting to emerging the clinical data now. We're starting to have the first in-human data in the dose escalation. The purpose of that is really to prove the safety, finding the recommended phase II data. That is the purpose of this data. We're going into patient group that is different from the patient group we will treat later on. It's heavily pre-treated, diverse tumor type. That is the patient group we will get data from today. Why was my conviction that IL-2 was really the product to focus on and use our effort was? When we solve the treatment regime, just go back it to aldesleukin. It functioned when you really could get the patient to tolerate it. It meant that you need to be sure you can give the highest dose for longest time, meaning taken to intensive care unit, give it as many days as possible, try to stabilize the patient, because you know, if you really provided long enough treatment with high enough dose, you could be successful. There was basically a target profile we wanted to improve on. How could we basic make this as a safe, well-tolerated treatment, and at least see the same benefit with aldesleukin? That was our success. Think about two things: duration of treatment, the potency of the treatment, how you really go out and improve the immunological system. I'm really happy that Kenneth now will take over, move to the next part of the presentation, going in and explain how we designed. I can also advance the slide. Thanks, Kenneth. Technical. There. All right, thanks, Jan. I'm looking forward to taking you through our thinking from when we started designing our immunity, immuno-oncology pipeline with TransCon TLR7/8 Agonist and TransCon IL-2 β/γ. Many of you know our technology very well. It combines the benefits of prodrug technology and predictable release technology. For the purpose of our immuno-oncology pipeline, I would also like to add sustained release, because for example, if you want to inject tumors, you need to. If it's not a superficial tumor, you also need that long duration of action in order to broaden out what types of tumors you can treat. When we look at our IL-2 β/γ, our non-alpha IL-2, we're using the same technology as Jan mentioned, that we're also using in SKYTROFA, and that you know very well from our endocrinology pipeline. If we wanted to make an intratumoral treatment using that technology, we don't believe it would have worked because tumors also clear molecules, soluble compounds flush out quite rapidly. We needed to come up with a different way of making sure that we could keep the compounds that we wanted to treat the tumor with for a long time within the tumor. We had to develop our TransCon hydrogel technology, which I'll go into a little more detail later, but it's an insoluble carrier. When you inject it stays exactly within the tumor, releasing the drug locally. Now we have shown that it works for a TLR7/8 agonist, but it also works with small molecule peptides, antibody fragments, and antibodies. We have experience in coupling all of these types of compounds into the hydrogel. Conceptually, this is the same technology that we're using in our ophthalmology portfolio. When we go into the details of how we designed TransCon IL-2 β/γ, Jan mentioned we had a lot of data to go off by going all the way back to aldesleukin and then other compounds that didn't work as intended. What we realized is you can't solve it all with one technology. You need to have both sustained release as one technology and then also a very potent non-alpha IL-2, and I'll show some data on that later. For our innate immune stimulator, a TLR7/8 agonist, this is, per definition, a very toxic, unspecific compound. As we can target it, if you give it systemically, you need to target it else in a different manner. This is what we're doing with the technology of the Hydrogel technology. We make sure that the activity stays within the tumor with minimal systemic exposure. This combination to us of having the systemic and the localized platform is really uniquely suited for harvesting all of the benefits of innate and adaptive immunity to provide amplified and durable immune activation. We hope that this will be able to broaden immuno-oncology out, and also raising the tail, as Stina will go into details on later on. This figure is well known to us all. The only thing I want to mention here is typically when we talk about it, we say we take one parent drug, one carrier, one linker. In order to build the immuno-oncology pipeline, we're also thinking about where do we apply the soluble carrier and where do we apply the insoluble carrier? You can see on the left-hand side in the blue lady there, that for the insoluble carriers, we are putting that in the tumor, and the systemic IL-2 is releasing a native IL-2 with a size that is in the bloodstream, but also small enough to distribute into tumor tissue. If we take a step back and then start thinking about immunity. First line of defense, if there's an invading pathogen or a tumor starts forming, would be your innate immune system as the first defender. That would be macrophages, dendritic cells, antigen-presenting cells, would try to take out the pathogen or the tumor. As we're sitting here and standing talking, our immune system is already clearing malignant cells that are forming, but sometimes immune evasion happens, and tumor starts building out and overwhelming the innate immunity. Through a fairly complex process, the antigen-presenting cells can then call upon help from the adaptive immunity by engulfing new antigens from the tumor, presenting them on the surface of the antigen-presenting cell, and locally activate immune cells already present in tumors, because immune cells survey all our tissues already, but they need a signal, a stimulant, to start clearing the invading pathogen. The ADCs can turn your tumor resident or your tissue resident T cells into cytotoxic T cells that can help the innate immunity. They can also drain to the draining lymph nodes and start educating and activating and expanding your cytotoxic T cell repertoire and also expanding your NK cells, which then, through the bloodstream, can come back into the tissue and further help local resident cells. In order for circulating cells to find their way back into the tumor, they need a homing signal, and that's why the production of chemokines are also extremely important because that gradient is what pulls the cells back into the tissue. This is where we have designed our two candidates, first candidates to work both in monotherapy, but also rationally designed to work in combination. What the TLR7/8 program is intended to do is to turn the tumor hot by increasing the pro-inflammatory microenvironment, which helps educate T cells, both locally and in the draining lymph nodes, and also to recruit in cytotoxic immune cells from circulation. IL-2 alone expands and activates your CD8s and your, and natural killer, your killer cells, and also, due to the size, can act in the autocrine and paracrine fashion that evolutionarily or locally produced IL-2 is able to. If we look in normal tissue, you have immune cells present already. They're not really doing much because there's not a threat. They are, however, still producing cytokines. Locally, you can see IL-2 as an example here being produced. Given that this is a alpha binding IL-2, this is predominantly mopped up by all of the Tregs there because they have the trimeric receptor conformation that contains the alpha subunit. This is very high affinity for IL-2, for native IL-2. Slowly secreted IL-2 acts as a anti-inflammatory component or cytokine in the homeostatic environment of normal tissue. In contrast, when you have an infection, for example, then there's danger molecules being released that activates TLR receptors. This causes your antigen-presenting cells to be activated and start releasing cytokines and chemokines. As mentioned before, that brings in immunity from circulation and also starts activating immune cells already present in the tissue. One of the cytokines being released under these conditions is IL-2, but at much higher levels compared to under normal tissue homeostasis. you saturate the TReg receptors, there's excess IL-2 available to bind to your tissue resident T cells and activate them into cytotoxic T cells. This is how you also get the pro-inflammatory immune response activated in the inflamed tissue. If we take that knowledge and then apply it to the status of cold versus hot tumors, in cold tumors, you can also have lots of immune cells present, but they're not doing anything because they're lacking the signal. In certain instances, even you have the tumor producing anti-inflammatory cytokines, further putting a lid on your immunity. Our goal and our thinking was, if we can turn that tumor type into a much hotter tumor type by pushing on those TLR receptors, we would be able to then leverage not only the local innate immunity, but also the adaptive immune system. That was conceptually the goal of designing a TransCon TLR7/8 Agonist. When we then thought about developing the two compounds in parallel, how do we design the optimal innate immune activator? We want sustained high local concentration because these are non-specific, so they would activate innate immunity throughout the body if present. We wanted a high local concentration, and then we also wanted the most potent TLR agonist to produce cytokines and chemokines. That's how we ended up selecting TLR7/8 agonism. Turning to adaptive immunity, Jan already touched on this. You want a long half-life, so you have a big AUC of your potent non-alpha IL-2 molecule, but also you need the Cmax to be low because Cmax is what drives your dose-limiting toxicity. This is why we had to use the prodrug technology. Also you need full bias, high potency, and a size that is similar to native IL-2. Turning to how we used our TransCon hydrogel technology to design TransCon TLR7/8 Agonist. The TransCon hydrogel itself, we pre-form it using the same type of linkers you know from our endocrine portfolio. We load in our active TLR7/8 Agonist and then inject it into the tumor. Slowly, over the course of weeks, resiquimod is being released into the tumor microenvironment and pushing on the TLR receptors, mimicking inflammation on infection. After a couple of months, the Hydrogel bead itself disintegrate into small polymer-bound fragments that are then flushed out of the tumor and cleared by the kidney. I mentioned it takes a couple of months for the Hydrogel to degrade, keep that in mind when Stina is also showing data later on, because the Hydrogel is, in fact, space-occupying when you inject it into the tumor. Given that we administer every three weeks, you have accumulation of Hydrogel material within the tumor. If you were to image it or caliber measure it, you're measuring both tumor tissue, but also the Hydrogel space-occupying material. If we then look on what does this mean on a PK parameter, on the left, we have a mice experiment, tumor-bearing mice, where we injected the Hydrogel into the tumor, and you can see we have a 1,000-fold higher resiquimod concentration in the tumor compared to in circulation. This is really what allows us to have a high pro-inflammatory cytokine release within the tumor. We are producing that CXCL10 gradient that allows NKS and T effector cells to home in from circulation, and then the antigen-presenting cells are activated, so they can present antigen both locally in the tissue but also in the draining lymph nodes. This latter part is also what we believe is driving the abscopal responses that we're seeing, because when you have education in the draining lymph nodes, you are also mounting a systemic antitumor response. With this approach, we believe we can make not only cold tumors hot, but also hotter tumors or hot tumors hotter, so driving efficacy across the board. When it comes to IL-2 β/γ, we had our soluble technology already validated in the endocrine pipeline, but we never believed it would be enough just to make a reversible conjugate of IL-2, because what you in the end would be releasing would be fully active, non-biased IL-2. We analyzed all of the information that was available in the public domain, and that was quite a bit after 30 years of experience with IL-2. We realized there's no one technology that can address all of the drawbacks of the IL-2 molecule. We started out thinking, how do we make the ideal non-alpha IL-2 molecule? We realized if we made a site-specific mutation in the domain of the protein that binds the alpha receptor subunit, we could site-specifically attach a small PEG there. If we were to inject this molecule into circulation, we would still need to put people in the hospital and give them long infusions because this would clear very rapidly. It's small, it would be renally cleared quickly. We also added on top of this molecule, our TransCon technology, the soluble platform, using exactly the same that we're applying in the endocrine pipeline. This is what gives us that long half-life exceeding 35 hours. Importantly, also, the molecule that we're releasing is that not that different from aldesleukin, only that it has a bias away from the Tregs. This is what you're seeing in the table here in the chart. We actually made multiple different variants to explore and interrogate. What does it mean when you're increasing the size of the PEG that you're putting onto your IL-2 molecule? Because other companies have tried increasing the size of the PEG, so you could have both longer half-life and full bias. We replicated, and in our hands, what we saw was with a small PEG, we retained the most activity, which is not surprising because the larger the PEG, the more steric hindrance, the less ability to interact also with the beta gamma receptor conformation. Also, if you then look at the far side of the table, you're also seeing the sizes going up. Using a 5 kiloDalton PEG also allows you to have native-like size, whereas if you go up in size, it starts having the size of an antibody, and that we know doesn't penetrate well into tumors. We can selectively expand the reservoir of cytotoxic T cells and natural killer cells over Tregs because of the bias. We have a size that allows us to penetrate into tissue and act in the same autocrine and paracrine fashion, endogenous IL-2 works in. This is because we have the prodrug approach, and then we have a low Cmax that improves tolerability and allows us to dose up and really provide high exposure over the course of the dosing interval. Stina will show you some comparative data later on, showing how we can push the dose compared to other programs. My final slide is just one showing how we're also thinking about the synergy between the two molecule, because IL-2 can bring that impressive adaptive immunity response, expanding the cell population, but ALC alone doesn't do it. You also need a signal for your circulating cells to find and home into the tumor. That will work in certain cancers that have that. If you have a cold tumor with no homing signal being produced, then there's a high degree of synergy with the TLR7/8 agonist, because that would provide that gradient that will then also allow to expand the number of indications that you can apply an IL-2 type molecule. The two have been rationally designed to work both as monotherapy but also in combination. I think I showed the design, then we're moving over to Stina's presentation, and you'll see something about the pharmacology, how we have sustained inflammation in the tumor with high cytokine and chemokine release, and convenient dosing for the TLR, allowing you to go also for deep-seated tumors. Then for IL-2, we'll show data on expansion on the relevant cell populations and also with the convenient dosing. Thank you. Good morning. Our oncology pipeline is an immunotherapy, although work in immunotherapy for cancer has been ongoing for more than three decades, it hasn't been until the last decade when checkpoint inhibitors came into treatment landscape, that we actually see clinical activity of immunotherapy across various different tumor types. On the left-hand side, you can see the response rates of many different solid tumor types, they really range from the teens to as high as 80%. However, you can see a lot of patients do not respond. Even those patients who do respond, on the right-hand side, you can see that many of those patients have acquired resistance that develop. Let's take the poster child for immunotherapy for better illustration. You're looking at here, overall survival for first-line melanoma. Over the recent years, you have seen incremental benefit of various targeted agents and checkpoint inhibitors. Just to make this a little bit more simplistic to look at, here you're looking at anti-CTLA-4, anti-PD-1, and even combination of checkpoint inhibitors. You see highlighted here the unmet need, even in melanoma. Checkpoint inhibition is not sufficient, even for melanoma. Removing immune breaks, that's what the checkpoint inhibitors do, is just not sufficient for majority of patients with cancer. The Ascendis pipeline is trying to look at and develop product candidates with different modes of action. Our first product candidate, as Kenneth has mentioned, is resiquimod, which is a very potent TLR7/8 agonist. It is a small molecule agonist of both TLR7 and eight. I won't go into too much detail because. Dr. Davar is actually an expert in innate immune activators. He will talk more about them later. Our phase I/II first-in-human trial is called transcendIT-101. In fact, Dr. Davar gave an oral presentation of our monotherapy recommended phase II dose data package at SITC last year in the fall. We declare recommended phase II dose at 0.5 milligram per lesion to be injected. I would just like to highlight some key observations that provide clinical validation of our technology. We have seen that the drug is generally safe. We had seen one dose-limiting toxicity of a grade three local injection site reaction. We dosed 23 patients treated in dose escalation cohorts as monotherapy or in combination with pembrolizumab. Our PK data showed that the drug behaves as expected. There was very low systemic exposure, sustained release of resiquimod over weeks after a single injection. We had biomarker data. You'll see more of them today from Dr. Davar. There is target engagement in not just the injected tumor, but also in the non-injected tumors, along with sustained systemic immune response. We had seen some preliminary clinical activity, anti-tumor effect, not only in the injected, but also in non-injected tumors, and we have somewhat more updated clinical data for you today. This slide just highlights what you saw at SITC of the clinical activity, swim lanes on the left, the blue bars are the patients treated with monotherapy, highlighting there were two patients with responses. one was a confirmed response, 1 was an unconfirmed partial response. On the right-hand side, waterfall, highlighting here a non-injected lesion that reached ACR. We are continuing to enroll patients with monotherapy, and we are continuing to see in additional patients abscopal effect. The highlight of today is really to provide you our first clinical data on our second drug product, which is IL-2 beta gamma. People sometimes forget that Aldesleukin or Proleukin was approved some 30 years ago, starting renal cell and then for melanoma. What people, particularly clinicians who have had to give it is hard to forget how hard it was to give it. Patients had to be hospitalized, oftentimes in the ICU. Aldesleukin is given every eight hours, have to be monitored. We try to give as many doses as tolerated, but oftentimes patients cannot tolerate half of the doses that were prescribed. The clinical experience with Aldesleukin actually suggests that the more drug you are able to give to the patients, you would see higher lymphocyte counts, perhaps more sustained lymphocyte exposure, and that leads to better efficacy. This is some very old data that you can see on the left-hand side. The general sense is, if you can push more drug into patients to allow for sustained immune activation, you may get better efficacy. The challenge has been toxicity. We have seen vascular leak syndrome, severe cytokine release syndrome, requiring vasopressors, oxygen support due to the IL-2 receptor alpha binding to eosinophils and endothelial cells. As Kenneth has described, we are trying to overcome those challenges with both how we are designing, how we're altering IL-2, and also putting it in the TransCon carrier. Maximizing IL-2 therapy has so far been limited by toxicity or insufficient lymphocyte expansion. You can see here, aldesleukin actually does pretty well for those patients who can tolerate it. Recent clinical programs, and there has been 20-plus, I think many of you have been following, they demonstrate generally improved tolerability, somewhat improved PK properties, with the aim to have better efficacy. If you look closely at the scientific data, the actual extent, the both magnitude and duration of lymphocyte expansion has not clearly surpassed that of aldesleukin. On the left-hand side here is some simulation of aldesleukin. You can see over five days, there is wide range of drug exposure, and it is the Cmax that's giving patients a lot of side effects of the alpha activity. On the right-hand side, as Kenneth has described, with the TransCon technology, we're hoping to be able to provide a drug product that will allow IV outpatient once every three weeks until patient has progressive disease. Our phase I/II first-in-human trial is called IL-Believe. It is a fairly standard phase I/II trial. We have a dose escalation portion and also a dose expansion at the recommended phase II dose, identified from dose escalation. Today, it's really our first clinical data. We have reached a milestone, which is declaring recommended phase II dose out of monotherapy dose escalation. You can see we have evaluated five different dose levels. It's not showing you the sequence, we went from 20 microgram per kilogram to 40 to 80 to 160. Based on tolerability, I'm going to show you in a bit, we stepped down a little bit to 120, which ultimately became our recommended phase II dose. Our combination with pembrolizumab is ongoing. We'll show you data towards end of this year. We won't talk about our dose expansions until much later today on next steps. Focusing on our monotherapy dose escalation, you can see generally 3+ 3 design. Very few patients in each dose level. How many DLTs that we have observed here, you can already see we saw one DLT at the 160 microgram per kilogram dose. On the right-hand side is really top-line demographics. Remember, phase I dose escalation patients, they tend to be your very late line, diverse tumor types, very hard to treat patients who have no other standard of care treatment options. Prior lines of systemic therapies out of our 25 patients in monotherapy dose escalation was four. We have a range from one- 15. Many of these patients actually had also participated in other clinical trials and have progressed. About a third of our patients in monotherapy dose escalation had prior checkpoint inhibitor. Of the most common tumor types we saw, head and neck cancer, colorectal, ovarian, and pancreas. This table provides you with very top-line safety information out of monotherapy dose escalation. Across different dose levels, we saw one dose-limiting toxicity at 160. Can see that majority of the grade three or higher treatment-related adverse events happened at the 160 dose. Tell you what those are in the next slide. Can see a few patients with treatment-related adverse events that led to treatment discontinuation. Again, I'll show you what those are in the next slide. No patient died due to treatment-emergent adverse events on study treatment. Here, describing a little bit more detail about what those numbers mean in patients. Our dose-limiting toxicity at 160 was a patient with grade three cytokine release syndrome. At the 160 dose, we had patients that had grade three hypoxia, the same patient worsening CRS was our DLT, and we had a couple patients with significant cytopenias. At the 160 dose, we had a grade four lung infection not related to study drug. At the 120 dose, now, this is our recommended phase II dose. Out of eight patients dosed, we did not see any DLT. We had no grade three or higher adverse events related to study drug. We had two patients that discontinued because of treatment-emergent adverse events. One was a patient with grade one CRS, who also had worsening cancer pain, and we had a second patient with grade four septic shock, not related to study drug. You can see at the lower dose levels, the drug was generally very well tolerated. Moving on to pharmacodynamic effects, we're going to start out with absolute lymphocyte count. You can see that on the left-hand side and eosinophil count on the right-hand side. Looking at absolute lymphocyte count across from different dose levels, you can see at the 120 and 160 dose, we are really reaching on treatment, a lymphocyte level that is above normal range one week after dosing. On the right-hand side, in the eosinophils, and also based on the Y-axis here, within the normal range on treatment, there's really no dose effect across dose levels or on study treatment. This is an indication that we have a non-alpha drug. Looking at the specific lymphocyte subtypes, in particular, cytotoxic immune cells, CD8 positive T cells, and NK cells, those are the first two graphs that you see, and then the Tregs. Looking initially at the CD8 positive T cells and the NK cells, you see, again, a dose effect and also on treatment effect. Actually, although sample size is small, at the 120 microgram per kilogram dose, our recommended phase II dose, there is a clear on treatment effect of expansion of CD8 positive T cells. If you look at NK cells, our on treatment number goes up to 2,000 cells per microliter on treatment at the 120 dose. On the other hand, Tregs, again, I would like to point out the Y-axis here is in hundreds, whereas the cytotoxic immune cells, the Y-axes are in the thousands, right? If you look at Tregs, within the normal range, even though there is a small treatment effect, even on treatment, your number of Tregs stay within the normal range. Put this a little bit more in context together in the same graph, so you get a better idea of the magnitude of difference of expansion. In blue, we have your cytotoxic immune cells, your NK cells, and your CD8s, and the Tregs are the black bars. You can see the different dose levels, the available samples for flow, and the pre-dose and cycle one, day eight values. I think even with small sample size across the different dose levels, one thing that is clear is that there is a clear on treatment effect of expansion of cytotoxic immune cells from generally less than 50% pretreatment to more than 50% when you're on treatment. You look at our recommended phase II dose, pre-dose, you're looking at about 300 cells pre-dose of your cytotoxic immune cells. On treatment, you're looking at about 3,000 cells per microliter. There's about a 10-fold increase in amount of cytotoxic immune cells that you can get on study treatment at our recommended phase II dose. How may those immune correlates translate to potential clinical benefit for patients? We have very short follow-up, very early data. This was our first milestone, declaring recommended phase II dose. You can see here in the swimmer's plot, the different dose levels. The patients who are, as of April 28th data cut, efficacy evaluable. Efficacy evaluable are patients whose had reached the first tumor assessment at nine weeks, or they have died. You have seen a few patients here who have died, but not yet had a tumor assessment. That's how we define our efficacy evaluable population. At our recommended phase II dose, currently, we only have three patients who are efficacy evaluable. We have three patients ongoing who have not yet reached the assessment time point, and we have two patients, as I described to you earlier, who discontinued due to an adverse event. There are two patients we would like to provide a little bit more detail on to illustrate. Again, small sample size, we're gonna have to look at this a little bit more detail at patients who might have derived some clinical benefit from study treatment, monotherapy study treatment. What's highlighted here, patient one is a patient with MSI high colorectal cancer, who's had five prior lines of systemic treatment, who's progressed on prior anti-PD-1. We'll describe this patient in detail. Patient three is actually Dr. Davar's patient, so he's going to talk more in detail about that patient. It's a pancreatic cancer patient, three prior lines of treatment, who has been on stable disease for a year on monotherapy, TransCon IL-2 β/γ. The details on patient one. This was a heavily pretreated patient with metastatic colorectal cancer. This patient had microsatellite instability, high MSI-H, also a BRAF mutation. Previously, you can see from the timeline we put on the right-hand side, along with the five prior lines of systemic treatment, many of these are combination chemotherapy agents, targeted treatments. We've highlighted when the patient received nivolumab back in 2020. Patient progressed on each of these treatment lines. Also, best overall response for each of this was stable disease. The patient came on to our study in February this year. Patient at the first tumor assessment at nine weeks, actually, just before our data cut, had a tumor assessment that showed a partial response. This patient had target lesions, peritoneal deposits next to the spleen, omental soft tissue nodule. Non-target lesions were all in the omentum and peritoneum that are hard to measure. Patient is tolerating treatment fairly well with Grade one and Grade two side effects from study drug. The second patient, again, Dr. Davar will go into more detail about this patient, who's received, as of earlier this month, 13 cycles of study treatment. I think that is something we'd like to highlight, which is the fact that we would like to develop IL-2 therapy that can be given chronically as an outpatient. This looks like an index card for you, kind of take-home messages on our recommended phase II dose for TransCon IL-2 β/γ, which was declared earlier this month at 120 microgram per kilogram IV every three weeks as an outpatient. We've seen from the safety profile, it is generally well tolerated at the recommended phase II dose, no DLT out of eight patients dosed, no vascular leak syndrome, no Grade three or four cytokine release syndrome. We have a long effective half-life, more than 35 hours. We have seen low Cmax. We have seen evidence that our drug expands local and systemic cytotoxic immune effector cells, specifically the CD8 positive T cells and NK cells, without clear effects on Tregs and eosinophils, really providing evidence that we have a non-alpha drug. We have seen very early clinical benefit observed with monotherapy in heavily pretreated patients. What are our next steps now that we have the recommended phase II dose? We are going to phase II, indication-specific cohorts. We've picked some, what we call the first wave or our first indications, are selected for speed to meaningful endpoint readouts and the current treatment landscape. You can see here the different dose expansion cohorts we have in protocols right now in seven different tumor types. Just like a standard dose expansion, about 40 patients per cohort. These are in melanoma, cutaneous, squam, head and neck, cervical, other HPV-associated tumor types, non-small cell lung cancer in the neoadjuvant setting, and platinum-resistant ovarian cancer. We are also planning a randomized phase II trial in neoadjuvant head and neck to start this year. We expect to have top line or interim analyses from these phase II dose expansion cohorts in 2024. Aside from current ongoing trials, what do we want to do with our drug that we believe may become backbone treatment in oncology? We believe in the power of combinations for patients to achieve the best benefit, so we are looking around at the different potential combinations, and we believe that TransCon IL-2 β/γ, by amplifying the immune signal, can truly add to benefit of many other treatments or treatment modalities out there. We can see the IO combinations, cytotoxics, antibodies, or even use it as adjuvant, such as for cancer vaccines or cellular therapies. These are all avenues we're exploring currently. I think to sum up, I would like to say across both our programs, we have now declared recommended phase II dose. We have shown what we needed to show out of a phase I dose escalation, which is that our products are safe at the recommended phase II dose, and that we have seen preliminary evidence of clinical activity as a monotherapy. We have a broad clinical development plan that is already in place, and we look to further expand it. We believe that the TransCon platform really gives a potential best-in-class platform to differentiate our product candidates from what is out there today. With that, I would like to turn the podium over to Dr. Diwakar Davar, who has been an investigator with us for both of our first in-human trials. He is our Clinical Director of Melanoma and Skin Cancer Program at the University of Pittsburgh Medical Center, Hillman Cancer Center. Dr. Davar? Thank you, Stina. Thank you all for having me. These are my disclosures. Stina briefly mentioned a patient of ours that we treated on the IL-2 beta gamma product. I'll give you guys a brief outlook of this patient and where he is right now. This is a older Caucasian male with advanced metastatic pancreatic cancer. Much like, almost everybody else with this disease, this patient has got microsatellite stable disease, non-targetable KRAS G12V mutation, extensive prior systemic therapies with only really disease progression, being his best overall response to chemotherapy and more chemotherapy. He essentially enrolled in the clinical trial at the 80 microgram per kilogram dose level in June of last year. After about four cycles of therapy, the patient had cytokine release syndrome, as you've seen earlier in Stina's AE table. This was graded as being Grade two. Tocilizumab was added with cycle eight, and that actually was provided a significant amount of benefit, and he's had consistent, stable disease since then. The major treatment-related adverse events included Grade two CRS, clearly related to the drug, infusion reactions, and a transient reduction in his total white cell count. Now, what you can see here is that on treatment, he's had a very remarkable reduction in his tumor markers, which is, in this case, CA 19-9. It's very interesting to see that it goes down on treatment. It goes up when you hold therapy. In this case, this patient had, which is not uncommon for this disease, a Grade three bacteremia and unrelated to the drug. In the context of the treatment being held, the tumor marker goes up. When the treatment gets restarted, the tumor marker comes down. Very interesting kinetics in relation to the use of the drug in this patient. Clear, ongoing, confirmed disease stabilization lasting more than a year, which in the context of heavily pretreated pancreatic cancer, is quite remarkable, right? The median survival for these patients is oftentimes about two years. This guy is therefore one year past his expiration date, and he's doing well, doing his thing, mowing his lawn, not quite going to the gym because people from Western Pennsylvania don't do that, unlike you guys sitting in the audience, and he's deriving continued benefit. What you can see here is a summary of his total tumor changes. You can see that he's got a very large amount of tumor at baseline, so the average sum of diameters of all his tumors is 60 mm, which is about 6cm of tumor, so this is not exactly low tumor burden. Every one of these target lesions keeps being stable. There are no new lesions, and it's continued SD. Again, in summary, durable response in a durable, stable disease in a heavily pretreated, widely metastatic patient with chemotherapy-refractory pancreatic cancer. Initially at the 80, then dose reduced to the 40 micro per kilogram dose level with lung and liver involvement, all of the target lesions of which are showing disease stabilization at approximately one year. Why are we excited about this, right? Why am I excited about this? You know, I'm a translational scientist. I run a lab. You know, why am I excited about this? The answer is, you heard from Jenny earlier that IL-2 agonists are essentially the first demonstration of immunotherapy, and that's actually true, right? For those of you guys who are not old enough to know this, 'cause some of you look really young, I'm old enough to, unfortunately, have taken care of patients who whilst in the early days of oncology... These are the dark ages, right? In Pittsburgh, for example, where we ran one of the first IL-2 programs, IL-2 is not on formulary in Canada. Patients used to fly down from Manitoba, so if you were in Canada, they have to fly you somewhere else to get treatment. We were seeing patients who were flown down to get IL-2 therapy, all right? The issue with the first generation of IL-2 was that it was undoubtedly effective, all right? This is the very first immunotherapy, cells that were isolated, first actually demonstration of recombinant use of cells, growth of cells ex vivo. IL-2 generated by Steve Rosenberg's group, demonstrating that you could expand cells in vivo in humans. aldesleukin produced durable responses and led to the first approval of immune therapy for the treatment of advanced cancer. Initially, RCC, subsequently melanoma, 1992, 1988 and 1998. These cells, these drugs essentially worked by essentially activating T cells and NK cells. The aim of the second generation of IL-2 agents... You know, if you think about it, the first generation of IL-2 agents were approved before I was in medical school, right, in the 1990s, then it takes, like, almost 2 decades to get to the second version. The reason there is this 2-decade gap is not because people were just sitting down doing nothing. It's because there were other agents that were developed. There was a whole slew of immune checkpoint inhibitors that were developed based on our understanding of immune checkpoints. The key thing to understand about immune checkpoints is that they're transformational drugs, all right. There's no taking away from the fact that they are extraordinarily effective agents, but they come at a cost. That cost is the fact that the PD-1, PD-L1 checkpoint, and similarly with the CTLA's, CD28, B7H1 mechanism, are designed as checkpoints. They're designed to actually restrict immune activation. When you have loss of tolerance, what immune checkpoints do is that they uncouple the balance between immune response and immune tolerance. For every effect, there's an equal and opposite reaction. With immune checkpoint inhibitors, which are undoubtedly effective, the major heel of immune checkpoint inhibition has been the development of immune-related adverse events. This was particularly seen with CTLA-4, right, which is the first drug that was actually FDA-approved to treat this disease, where you have a response rate of, you know, between 12%-15%, but immune-related adverse event rate of about 30%. Now, again, at the time in which you have no other drug available to treat outpatient cancer, this seems like a really good idea. When you start thinking of these drugs in context... If I, you know, right now, you know, one of you guys were a patient, and I said, "You know, I've got an agent that's got a 15% remission rate. But by the way, it's gonna give you really bad diarrhea 30% of the time." That doesn't seem very appealing. The idea right now, the newer generation of these IL-2 agonists are designed to harness the key immune effector cells that we have, T cells and particularly NK cells, which unfortunately, for reasons that I'm not entirely clear on, do not get enough headlines, without the requirement for additional costim or co-inhibition, and therefore abrogating the need to worry about immune-related adverse events. The preclinical data behind this and the early clinical data behind this really suggests that what IL-2 does is that it activates, and now this we know in more detail because of the recent data from Rafi Ahmed's group, that essentially, they're the stem-like CD8 T cells that are essentially not fate-locked. There was this idea that essentially PD-1 represents a pathway that essentially locks the expression of which locks T cells into expression of checkpoint inhibitors, and these checkpoint inhibitors represent a pathway of exhaustion, and exhaustion results in terminally exhausted T cells. What we now know is that the TCF-1 subpopulation of PD-1 expressing T cells are essentially not quite fate-locked. They are stem-like, and they just need the right cues in order to get them to become effector cells. The antigen-specific T cells, they upregulate increasing amounts of high-affinity receptor, the combination therapy with single agent therapy with IL-2, as well as combinations with checkpoint, demonstrates tremendous amounts of synergy in multiple preclinical cancer models, as well as the viral LCMV model. Even though early data suggested that the synergy was dependent upon CD25 co-engagement, it's important to highlight that that data is not quite necessarily seen with all of the drugs, and it's really the important aspect of the functional efficacy of the drugs is dependent on beta-gamma binding. The whole slew of agents that have been developed, and I will highlight that we have not included, I at least, I have not included Bempeg as well as Sanofi THOR-707 data in this list. The reason for that is because Bempeg was a drug that was developed to much fanfare, and if you look at the drug from a structural perspective, you know, it really kind of, sort of looks like IL-2, like meaning, like aldesleukin. If when it was studied in the early phase I, phase II trials in a program that was developed together initially at Nektar and then subsequently co-developed with BMS. The phase I, phase II results were quite promising in multiple diseases, primarily renal cell carcinoma as well as melanoma. The phase II, phase 3 trial was essentially a dead negative, right? The phase 3 trial was nivo benpeg versus nivo. The response rate of benpeg nivo was 28% relative to 36%, and this has already been publicly reported. THOR-707 was essentially a trial that was then subsequently developed by Sanofi. There's a speculative IL-2 mutein. The phase II results of the Q3 combination with checkpoint has been reported. It's now been publicly reported that the program has been deprioritized, and a dose intensification trial has been announced, but there's no further information about this. What you'll see, therefore, if you look at the available data, is that there are multiple agents that are out there, such as nemvaleukin, which is an IL-2 CD25 fusion, and a whole host of IL-2 antibodies. There is a clear trend, which is to try to generate proof of concept data in melanoma and renal cell carcinoma, primarily, given the original indications for aldesleukin, and expansions in certain key tumor types wherein the single agent activity of PD-1 is low, suggesting that you can overcome the response and produce meaningful responses as a single agent. There are a couple of key unexplored indications, which I think are actually quite important, and that include the neoadjuvant setting in both melanoma and non-small cell lung cancer, and also other cutaneous tumor types wherein CTLA-4 has not been added. Cutaneous tumor types are very interesting because the primary reason why they respond to immune therapy is because of a high tumor mutation burden. These are tumor types like cutaneous squamous cell carcinoma, single-agent response to checkpoint inhibitor therapy, 35%-45%. Merkel cell carcinoma, single-agent response to checkpoint inhibitor therapy, 40%-50%. You don't add CTLA-4 to these, right? CTLA-4 is not FDA approved in these agents, and it represents an area where you can potentially supplant PD-1 monotherapy if IL-2 has got an active efficacy in this space. I've highlighted a couple of these programs, and I think what we are very excited about is the willingness of a company like Ascendis to consider these relatively unusual indications where, you know, you clearly need a big team thinking about how to go into this space. They represent potentially transformational areas where a company can make a huge impact. Neoadjuvant melanoma, for example, Checkpoint inhibitor therapy isn't approved in melanoma for since 2015. All right? That's eight years. When's the last time a phase three trial in melanoma was done? Well, it hasn't. The first approval of neoadjuvant immunotherapy to treat cancer has been in non-small cell lung cancer, breast cancer, and the primary reason why that has been the case is because it's been a lack of willingness on the part of mostly investigators, people like myself, to try to push the boundaries of novel agents. Hopefully, now that we have partners in the pharmaceutical space, we can start thinking about doing some of these things. Why are we very excited about this? Well, the key thing is that immune checkpoint inhibitor resistance is actually underspoken. We have this idea that immune therapy is gonna cure all cancer, and that's kind of sort of true, but not completely. The reason it's not completely true is because, as you've seen in the plot from Stina, the best available immune therapy we have produces durable responses about 40% of the time, right? CheckMate 067, Ipi-nivo, with Ipi at 3 milligrams per kilogram, dosed every three weeks for four doses. The five-year, 6.5-year OS data has already been released, but the durable response rate is 39%. All right? The best available stuff we have is 39%. As much as cell therapy gets all these hype about curing patients, we have to keep in mind that the vast majority of patients are not cell therapy eligible, right? Because cell therapy requires chemotherapy to cause essentially a reduction in the amounts of immune system function to allow the cells to take root, and that immune system depletion with lymphodepleting chemotherapy is actually quite hard for anybody above the age of 75 to tolerate. What we have here is a novel setting in which checkpoint inhibitor resistance can be overcome by key elements of both the adaptive and innate immune system. Innate is a very interesting target. The reason the innate system is very important is because you, me, and, you know, reptiles have toll-like agonists, and the reason is because we've been fighting predators, in this case, bacteria, for a very, very, very long time, and the innate immune system has been designed to be able to do that. Unfortunately, attempts at targeting, using the innate immune system to target cancer have not worked up until relatively recently. For example, attempts at using STING, RIG-I, NLRP3 have not worked, primarily because the preclinical data did, even though it was excellent, did not quite translate into effective antitumor cancer responses in humans. The exception to this has been the toll receptor pathway. The TLR agonists that have been developed, TLR7/8, resiquimod, TLR9, Checkmate's vidutolimod, these have shown repeatedly demonstrable evidence of antitumor immune responses in cancer patients, and they have now gone on to further development. What we are very excited about is the use of immune checkpoint inhibitor combinations, innate agonists plus certain arms of the adaptive immune system to overcome immune resistance. Toll-like receptor pathways are very well-validated targets for the activation of innate and adaptive immune system. They represent means by which you can expand and produce Type I interferon, which is essentially the fuel that funnels T cells. Resiquimod, which is the active ingredient in the Ascendis TLR 7/8 Agonist program, essentially is a very, very potent TLR 7/8 agonist. It, in combination with by producing the huge amounts of Type I interferon, you're essentially expanding T cells, you're educating T cells. The Type I interferon signal is magnified and cascades downstream, and hopefully, what you have is an anti-tumor immune response. Resiquimod, small molecule agonists of 7 and 8. 7 is expressed on pDCs, 8 DCs, as well as macrophages, and potent activation of the innate immune system. The importance of TLR immune activation cannot possibly be overstated. The classical example that I give people is the Shingrix vaccine, right? Almost everybody in the room hopefully has been vaccinated against hepatitis B. If you did not have a TLR agonist in the hepatitis B vaccine, you'd be vaccinating people repeatedly. On the other hand, your vaccination schedule with Shingrix is three doses: zero, one month, six months. The reason for that is because of memory responses, and the memory responses happen because of the vaccine ingredient, in this case, the TLR agonist. In the transcendIT-101 trial cohort, there were dose optimization and dose expansions. The dose optimization was involved a monotherapy arm, with... That basically enrolled any number of patients, any line of therapy, as long as they had an injectable tumor, combination therapy in tumor types where there was known checkpoint inhibitor benefit in combination with checkpoint. Then there were dose expansions, multiple, dose expansions, as you've seen in Steena's slides. The interesting dose expansions are really the neo-adjuvant melanoma and squam cohorts. In summary, from the PK and PD data that we released at SITC earlier that I presented, it's a well-tolerated agent. There's a low incidence of DLTs. The 1 DLT that was seen was a grade 3 injection site reaction. All the treatment-related adverse events that were considered related were grade 1 or grade 2, except for the 1 injection site reaction. The PK, there's very low resiquimod Cmax systemically, likely due to the fact of the construct. There's no drug interactions with pembro. The mean half-life of the drug is 9 days. It doesn't appear to accumulate. That's actually a very important thing, the lack of accumulation. You will see there was a paper from Novartis. The first author is Filip Janku. The reason for that is because TLR7/8 has got a very narrow therapeutic index. What Novartis did was they actually created this rather interesting agent, which was essentially a HER2-linked TLR7/8 program, and they gave it to patients. There was some very, very nice regressions. The toxicity was quite overwhelming. The fact that we're not seeing a lot of DLTs with a low systemic concentration is actually very valuable because it tells you that the drug is having an effect from a PD perspective, but is not having an undesired effect, and that's very important given the narrow therapeutic index of TLR7/8 from a biological perspective. You can see here that we've got several patients now with durable responses. Several of these patients are patients that I treated. Two out of the 11 had a PR, one confirmed, one unconfirmed, and out of the 11 actually had a CR, meaning, you know, a complete response even in uninjected lesion, and some of these responses are actually ongoing. The most exciting data is actually the translational data. What you see is that the overall idea of this drug is to activate innate and adaptive. How is it doing that? Well, one, it's activating. There's a clear induction and sustain of intratumoral TLR programming, resulting in type I interferon release. I said that, and you're seeing it. Very importantly, that activates macrophages because macrophages have the receptor on it, and the macrophage activation is seen both by immunohistochemistry, as shown in the bottom left panel on the right, but also by plasma MCP-1, which essentially is a macrophage cytokine. Canonical TLR pathway activation results in CXCL10 induction. This is a graph that you've seen in almost every single TLR paper. You've, you know, the 2 papers we published on vidutolimod had the same CXCL10 induction. What you'll see here is that the CXCL10 induction is significantly high. In fact, the Y-axis had to be broken to allow for the upper limit of CXCL10 induction to be illustrated. That is associated with the PD effect, in this case, the T cell influx, and you can see that the T cell influx is quite dramatic, and it's also very early. One week after dosing, you see T cells that are influx. Again, there are several candidates that are in development. The intratumoral candidates, Ascendis, a major highlight, the sustained release. Several systemic candidates, TLR7/8 from Seven and Eight Biopharma, which is a salt form of resiquimod. The intratumoral agent from initially from Checkmate, now since acquired by Regeneron, vidutolimod, currently in development as well. There are a couple of other agents, such as the taxanes or one from Tallac Therapeutics. I will highlight the resiquimod... The NKTR-262 agent has, you know, since been discontinued. There are several agents that are in development, and we're going to hopefully see in the next two months to years how all of these agents will shake out. The major thing to highlight about these compounds is that when you look at the key properties that make for successful drug development, sustained exposure, a schedule that is tolerable, a agent that has got limited systemic exposure, and the limited is key because, as I told you, look at the data from Novartis. When you have high amounts of systemic exposure, you have tox, which you don't want. You have enough drug that you're having early sustained releases of pathway activation, CXCL10 induction being the proximal measure of that. TransCon appears to have all those properties. The indications that are currently under development include head and neck cancer, neo-adjuvant melanoma, and squam, potentially the opportunity to combine with a very exciting partner, in this case, beyond checkpoint, potentially with an IL-2 agent, so that you get synergy without immune-related adverse events, that would be quite exciting. In summary, checkpoint inhibitors have been transformational. There's no getting away from that. They have limitations. One, they don't work in everybody. Two, they uncouple response from tolerance. That is a problem that cannot possibly be overstated. It is transformational. There's no getting away from that. When you start seeing tox, Grade three tox, Grade four tox, without means of addressing it, that becomes a real issue. Keep in mind, that the first drug to treat stem cell transplants were FDA approved, kind of saw it in the 1960s and 1970s to treat patients with hematological malignancies. The first drug to treat GVHD, 2022. That's 50 years of drug development in the hematological malignancy space before the primary dose-limiting toxicity of heme malignancies was addressed. That's the problem with checkpoints. Why we are causing significant Grade three tox, and we don't have a way of treating it, because the understanding of immune-related adverse events, the biology behind it, and means to treat it, have lagged. Cytokines and intratumoral agents that act as innate agonists, represent a means to overcome that. The primary target cells that we are hoping to target with this program are antigen-experienced T-cells, as well as NK cells. The platform offers the ability to transform active drugs into prodrugs with sustained release properties. Both of these agents, therefore, have the potential to be quite transformational. The development strategy that you've heard outlined, I think, is a very promising one, and we are hoping to help partner with Ascendis and the Ascendis team to at least try to get this advanced into human cancer patients with at least some of the indications. With that, I'll thank you, and I'm happy to take any questions either now or later. Thanks so much for a really inspiring presentation, and we come to questions pretty soon. I will make it very, very short. I will just sum up. We saw the competitive landscape here for Deva, and I actually think I will not talk more about it. What we have done and seen in our TransCon TLR7/8 Agonist is we've solved a safety profile, general, well-tolerated with low systemic effect, exactly how it was designed. We solve a long effective half-life over weeks, one single injection inside the tumor, exposure inside the tumor with low systemic effect, exactly how it got designed. Sustained inflation in the tumor, we saw all the biomarker, we see the initial clinical response exactly as we have. We see a abscopal effect in the non-injected, with more patient having a complete response. Going to the IL-2 β/γ. I'm really excited about IL-2 beta gamma because we see the unmet medical need. We heard the story about a checkpoint inhibitor. This is not a free launch. You are removing a national checkpoint system in the body. Not only we see the side effect, we will also see the long-term complication of organ dysfunction and other things like that. We designed TransCon IL-2 because we believe in the vision of cytokine therapy. Think about a car. It's easier to get speed on by pressing a speeder than removing a brake. We designed it. We saw the safety profile, general, well-tolerated, no DLT at the recommended phase II. We saw the long effective half-life with low Cmax. We see exactly all the pillars. We have studied the 20, 30 years literature, trying to understand all the biology, how to decide it, how to build up the optimal compound. Then we saw it in the preclinical data, and now we start to see it in the clinical data. I would like to compare it some way to perhaps the benchmark that is out in the industry was TOR 7/7. When we look on the compounds, they are built in some way in the same manner. Both of them have a pegylation directly into the alpha. One have a 30 kilodalton peg, one have, like us, have a 5 kilodalton peg. We saw Kenneth's presentation, how you really are decreasing the potency when we go for a 5 kilodalton up to a 30 kilodalton. When we look on the key element, we have about 120 microgram on recommended phase II. TOR went down to 24 microgram per kilo, more than 5-fold difference. When you look on the potency, we believe the potency is so much higher with the IL-2 for TransCon IL-2. Half-life, huge difference. This is really important because as we heard about it from the stories today, you need to have long-term exposure, really have a potent immune system for a long time. 35 hours compared to 9-12 hours. Non-alpha, both of them. When we look on just the fold expansion, and it's not really taking into the consideration the duration of the response, but just the fold expansion, you can also see the difference. When we look on expansion of CD8 cells, 5.6 or six-four, expansion of NK cell for 20- 84. Why CD8 is a little bit different? Because CD8 is not like NK cells. As we heard, the important of NK cells. CD8 is really much more difficult to quantify it in the blood compartment because they also have a strong migration when they get activated into the tissues. When you look on the NK cell, which don't have this, you really see the real proliferation of our system. We not seeing any meaningful change in either eosinophils or Tregs. When we three available patients, and we saw already one partial response. TOR 7/7 is actually being repositioned now, as we said and heard before. It's basically going down to really trying to compensate for where we see this optimal treatment need to be. It's going in as a once weekly treatment now. It's being repositioned, start up again in phase I trial, where it's been repositioned as a once weekly for the first six weeks, and then moving over to a twice weekly or bi-weekly treatment regime. Where are we with Ascendis immunotherapy program? We see the diversity, we hear how we really want to make paradigm shift treatment regimes. We see the initial data coming in now. We see how we have now recommended phase II for both program. We saw the expected safety profile. We also saw the expected single clinical activity. This is exactly what we had hoped for in our initial clinical trial. We're now going into what we call cohort expansion, as Stina said, and we heard about how we're going into more well-defined clinical indication, early-stage patient, so we really can see the clear effect. What we believe, we have started enrolling this patient, and in 2024, it will be the year where we really come out with all the clinical data that really proving how we really are moving into oncology with these two paradigms shift compound. I think we open now for the questions. Scott, you are directing. I'm not sure if you can hear me, but I think, Patty, you'll have a microphone, and we'll come around, and we just ask that maybe, Tazeen, if you start, you can say your name as a... Show everybody how you can, identify yourself and then say the question out loud. Okay, great. Good morning, everybody. Tazeen Ahmad from Bank of America. Thanks for the presentation. Just wanted to get some clarification about your chosen dose of 120. How are you thinking about durability of response and how long patients can stay on therapy? If you go back to some of your earlier slides, you did see, again, the ends are very small, but discontinuation at 80 from one case of cytokine release syndrome, as well as at the 120. I'm just trying to get a better sense of how you chose the 120 over the 80. Also perhaps for the doctor on pancreatic, I think you started the patient on 80 and then down dosed to 40. How are you thinking about the 120 in respect to that particular type of patient? Thanks. Stina, will you start? Yeah, sure. Thanks for the great question. In choosing between 80 and 120, we see that 120 has better pharmacodynamic effect than at 80. The question is really, is that tolerable, right? What we see in clinic is that if you start a patient at a certain dose, and there is so much variability in how patients tolerate study treatment, if they need to, if you are at 120, it allows you a couple of dose reductions. We know 80 is effective, so it allows a dose reduction down to 80 if you start at 120. We also know that patients have dose reduced down to 40. It allows a couple of dose reductions as patients tolerate study treatment, where we think that starting out at a more optimal pharmacodynamic effect may be beneficial for patients. To your point, we have very short follow-up so far, so I think with longer data, we'll be able to let you know how long are patients able to stay at 120 before they require a dose reduction. Diwa? Just to answer your question about the pancreatic cancer patient. This patient started at 80, was dose reduced to 40 because of a grade two cytokine release. I think Stina's point has to be really well taken, right? Like, in a development program, you do not want to start low and go lower. You want to start at what you think is the right dose, and then if you have the opportunity to develop over time, and you see that there's stops, that is cumulative, you can always go down. You can't do things the other way around. You can't declare your dose at 20 and then say, "Oh, you know what? I kinda wish I'd gone to 80." That's what happened with tremelimumab, all right? Not going too well. I think the key thing here is Stina's observation that you pick the dose based on clinical activity and PK and PD parameters, and the best PK and PD appears to be at the 120 dose. If you start there, you can always dose reduce. You can give patients the options to go down. I think, Stina, there's also one additional point. When we look on day zero in the different cycles, we actually see an increase in baseline of the different lymphocytes. When we add in, we actually see a dose staggering effect, and this is potentially also why you later on will see potentially a demand for lower doses. Maybe across the other side of the room, I saw Jess back there first, so. Oh. Lee. Hey. Hey, good morning. Thanks for that presentation. I guess my first question is, have you seen any correlation between the lymphocyte count and the clinical benefit, and just how sustained this lymphocyte elevation that you've shown is after dosing? Also, do you have any, you know, infiltration data that you can show for these T cells and NK cells? My second question is, you know, looks like at the 160-microgram dose, the activation of the lymphocyte is not as high as the 120. Just wondering if that's just some variability here or there could be some other reasons. Thanks. I think I heard three questions in there. Let me see if I can remember them all. First question is, I think it follows from what Jan said. There appears in the few patients. Again, in a phase I dose escalation, you have heavily pre-treated patients, right? Not many patients actually stay on study treatment for a long time. We have sparse data on repeat dosing, and what is that level of lymphocyte count as patients stay on treatment. Of a few patients who are able to have repeat dosing, what we are seeing is that the baseline pre-dose, every three weeks, the lymphocyte count seems to climb up. I don't have long enough data or enough data to really show you, but we hope that by enrolling more patients, we'll be able to have that information for you. The second question on tumor infiltration of lymphocytes. We have sparse data of available biopsy data. We do see infiltration of lymphocytes on study treatment, as correlating to study treatment, infiltration of T lymphocytes into tissue. Again, sparse data. We hope to, with additional patients, provide you more information. The third question- Variability of lymphocytes? Variability of lymphocytes at the 160 dose. If you remember, we dosed five patients at the 160 dose. Two of those patients had significant cytopenias. I think the absolute lymphocyte count is actually confounded by the fact that these patients had cytopenias. One patient had pancytopenia of all the different cell types. Even in that patient, his absolute lymphocyte count has increased, but the magnitude of increase by fold change does not look very impressive. I think it is at the 160 dose, you are seeing an exaggerated IL-2 effect, and it has the absolute lymphocyte count is confounded somewhat if you're trying to interpret the amount of lymphocyte expansion. Okay. actually, just a reminder for those online, you can send questions to ir@ascendispharma.com, and Tim's ready to ask them for you. maybe next... Okay, we'll stay on this side of the room. Great. Jessica Fye, J.P. Morgan. It looks like you're taking the IL-2 into a number of tumor-specific expansion cohorts. Depending on what you see from those cohorts, how would you characterize Ascendis' appetite to continue advancing that agent into what could potentially be a broad late-stage development program in the context of your other pipeline priorities? A question that is reflecting what I would call our success in oncology. What do we do with success in oncology? I believe we, as a company, can never be a leader, as we want to be a leader in endocrinology. We can be leader in endocrinology. We cannot be leader in oncology. This is why we feel that if we really want, which, our mission is to come out with as many patients as possible, to really benefit them in the treatment, we need to have strategic partnerships. We need to work with other company, really to expand our vision to develop IL-two beta gamma to be a backbone in oncology treatment. You're 100% right. We will really be looking at about how we really can do the best for the patients. How can we really get this treatment out to as many as possible, different trials and different indication. We need partnerships for that. Maybe on the other side of the room. Dave, over here. Thank you. This is David Lebowitz from Citi. You referenced the Cmax being a contributor to the tolerability issues with prior generation IL-2. How definitive is that correlation, and how much do you think that the more steady PK of your IL-2 will improve the tolerability? Will you start, Kenneth, or? Yes, sure. It is clear that tox comes from the amount of immune stimulation that you put into the system. What we have then tried to do with making the prodrug is, yes, we have a potent molecule, but it's slowly released. You can give what you want of drug that is supposed to last you in the treatment interval of every three weeks, for example, but you're only gradually releasing it into the system. While you're giving all of the drug on day one, it's not active. It only slowly becomes activated. In contrast, if you have a permanently PEGylated compound, everything that you give on day 1 is active, all of it. The max exposure you get at that time point is multiple times higher, and then it gradually declines over time. There's a kinetic dissonance between the tolerability and the exposure that you can get with the permanent conjugation technology compared to a prodrug technology. This is where we saw and believe that there is a clear benefit of using prodrug technology in order to, kind of, get the exposure you want, the potency you want, but with a low Cmax. Okay. I think Patty gave up. Paul, you have the... Okay. Hi, Paul. There's Patty. Sorry. Paul Choi with Goldman Sachs. Maybe for Stine and Dr. Davar: I think you provided some baseline demographics on patients who were PD-1 experienced, but could you maybe comment on sort of how many patients in your baseline were PD-L1 positive at baseline, and did you see any conversions of patients who are negative to positive status with increased exposure? Dr. Devar, do you think that's particularly important? Yeah. as you see, many of those tumor types actually are not really appropriate for checkpoint inhibitors, right? Checkpoint inhibitor is actually not in many of those tumor types. Which means that a lot of those patients, we collect the local lab information on PD-L1 status, but many of them don't provide it because it is not standard of care to check for PD-L1 status on those tumor types. We have collected of available patient tumor biopsies on treatment. We have collected the information. It's very sparse information right now, and we plan to disclose the information at a medical conference later. Your question for me is, do I think that the conversion from PD-L1 negative to positive, if observed, is important? Is that right? Yes. Okay. what I. To increase your conviction in IL-2 β/γ here. Okay. What I would say is that the problem with PD-L1 as a biomarker is that outside of maybe three diseases, in the front line setting, it's quite uninterpretable. I think if you're looking for a proximal readout of the efficacy of a drug like IL-2 β/γ or any IL-2 program, right, it probably behooves us to focus on the effect of the T cell. Because the issue with PD-L1 is functionally, PD-L1 is a transient protein that is upregulated by IFN-γ. What it means is you need to know when to look, where to look, and you have to be lucky, right? Using that as a biomarker of the PD effect of the drug is not necessarily the best way to gauge the PD effect of the drug, because it doesn't mean if it's not there that you aren't seeing it. It could just mean that you looked at the wrong time, in the wrong place, and did not use the right, in this case, stain. The possible way to solve this problem is to really look for T cells and NK cells, which are the most proximal effect of having a successful immune engagement, right? If you did that, what you would probably do is look early, right? one week, ideally, two weeks, up to, and look for sustained increases in CD8 T cells and NK cells. You'd be looking in the tumor, if you happen to see PD-L1 there, then okay, fine, that's great. If you didn't see it there, you saw T cells there, that's probably more important. It's probably more important to see T cells than it is to see PD-L1 status. You can look at that collectively, probably T cells and NK cells would be what I would focus on. Then just one more. You, you know, showed us some data on the CD8 expansions that you've seen so far. Can you maybe also comment on what you've seen with CD4s, how that looks relative to the data here? Is that an important consideration as you're thinking about your expansion strategy? Thank you. If you remember the bar graph on the slide, you can look at the on-treatment effects on the CD4 positive cells. What we were highlighted on that graph are clearly the cytotoxic immune cells versus the Tregs. The other half are your other different lymphocyte subtypes. I would just add, the deck will be available to download and for a replay on our website as well. Maybe in the back, Andreas? Andreas Argyrides from Wedbush. Could you just expand on the rationale for going after the seven different tumor types in the phase II, and also for the randomized phase II in the neoadjuvant head and neck small cell cancer? Then also for the pancreatic cancer patient, I mean, and then thinking about just kind of maybe identifying patients' responses based on tumor genetics, maybe you can if there's anything that you've seen, and you can expand on that. Thanks. The first question on picking the seven different tumor types, it's really looking to see where immunotherapy hasn't made too great a mark yet, right? These are places where high unmet needs still exist, and also in the setting, it's looking earlier, neoadjuvant setting, where we can get a very clean signal and a very quick readout. Those are indications that are potentially more acceptable to have in the neoadjuvant setting. For the randomized head and neck study, you can imagine for patients with curative stage but locally advanced head and neck cancer, if you're able to shrink the tumor, you can downstage it, or you can make the surgical outcome better by shrinking the tumor, right? It's clinically meaningful for patients, and also it's also a couple of cycles of treatment, so you can actually get your pathologic evaluations quickly. In our clinical development strategy, we are picking these indications because we believe we can get a proof of concept efficacy signal fairly quickly in indications of high unmet need. Davar? Sure. Your question was about the patient with pancreatic cancer and the tumor genetics. This patient, essentially had fairly extensive, you know, sequencing, FoundationOne-type sequencing done. There's nothing in that foundation panel that would suggest that the guy had a high likelihood of responding to checkpoint inhibitor therapy, de novo, right? Microsatellite stable, TMB is low, so not what you would conventionally characterize as a somebody who's highly likely to respond to, you know, immune therapy in general. Was more extensive, you know, sequencing done? Not in the recent trial, right? We're not doing whole exome or whole transcriptome in these patients at this time. I can tell you what we did was the publicly available FoundationOne-type sequencing. It did not show anything exciting. Just one quick follow-up. The size of the studies, do you guys have an idea of how many patients you're going to enroll? I'm sorry, what was the? The size of the patient number. Patient sample size. Patient sample size in dose expansion? we have certain benchmarks. In dose expansion, single-arm dose expansions, is based on benchmarks, is approximately 40 patients per arm, indication-specific cohorts. In the middle here, to Gospel, I think. I have a question. Which, expanded cytotoxic and cytotoxic T cells, have you guys looked at the cytokine profiles to see, you know, if they're producing IFN-γ, TNF-α, and all that? Yes. Yes, we have collected quite a bit of cytokine data, and we are analyzing them, and we expect to have the data available at a medical conference later this year. Awesome. Yes. A second question: How do you balance getting optimal desired T cell activation, effective T cell activation, without driving your T cells towards T cell exhaustion, given that you're dosing this patient with IL-2? That is a great question. Incoming data with more patients staying on study treatment, analyzing their biomarker, is gonna help us answer that question. I think for now, for monotherapy, for any dose escalation, it's really to, a primary objective, identify what is the dose that is tolerable and is safe for patients to start with. Like I said, I think this is our very first milestone, first clinical data out of dose escalation. We've identified a dose so that we can answer some of those questions that you have. Great question. Thank you. I believe what we're seeing out of our data now, what we wanted to see, we wanted to see that we had a compound where we really are addressing the limitation of aldesleukin. We can really see today that we really can stimulate the immune system to a level at least what we see with aldesleukin. We can do it in what we call in a very, very safe outpatient setting. Really meaning is that there was really the target we wanted to show, that you really can remove the limitation that had limited the first oncology treatment compound that came out for nearly 20 years or 30 years ago. I think we have achieved that with the data already now. This is why we are so excited about it. We feel that, as we heard today from Davar and all, that the checkpoint inhibitor is not a free lunch because you're removing basic and normal control mechanism of the body. It make more sense if you can turn the immunological system into a stimulation instead of removing a brake. I think that is have a inspiration, has been the goal for all IL-2 therapy. This is why there have been founded about 20, 30 companies building on the IL-2. We also know that the biology has been a major challenge to do it. It was not just to make it non-alpha. It's not enough, because we did that for 10, 15 years ago. We had the first non-alpha 10, 15 years ago, but we couldn't utilize them in an optimal way before we really got the right exposure into it. That is what we typically see in a lot of major development in drugs. Development is that you start somewhere, you mature it, then you try again, then you mature it because you fail, learning from that, and then suddenly you succeed. I believe we are coming to a place where we're building to getting success in what we dreamed about, really to do in IL-2 therapy, really have what we call a basic immunological stimulation, really to the benefit in oncology. This is how we deliver it. It's basically to make it as a safe outpatient thing and getting the right stimulation. Just one question. Hi, this is Caroline Palomeque with Berenberg Capital Markets. I think my question is for Dr. Davar. You were speaking about the TLR7/8 agonist, and I just want to make sure I understand. I think you mentioned that the mean systemic half-life was nine days, and then there was a lack of accumulation. You also mentioned that there was a narrow therapeutic index, and I'm just wondering if you could elaborate on that, and then also how that would have an effect with the combination program with IL-2. Thanks. If you look at TLR7/8, right? 7/8 has been around for about 20+ years or so, right? Really quite long. Dennis Klinman was one of the first guys that developed 7/8. If you talk to Dennis will tell you that if he had to pick between two agents to cure cancer, he would put his money on 7/8. It's interesting that in the years since Dennis Klinman cloned TLR9 has been more active. The reason that nine has been more out there is actually because of the broader therapeutic index of nine. What you typically see with any kind of TLR7/8 program is that there's going to be essentially a J point or a hockey stick in the response analysis. That's what happens when you have supra-threshold stimulus of essentially a key cytokine where the receptor is actually endosomal. All right, TLR9 and TLR7/8 endosomal receptors. You keep stimulating, what happens is you see effective type one cytokine, type I interferon production, then you have overstimulation, the pathway switches much more, MAP kinase pathway activation, cell shuts down. TLR7/8 has got a narrow index. It's just inbuilt into the nature of the drug, okay? When you start drugging the pathway, so what like, you know, if you look at that paper by Novartis, it's in CII, Cancer Immunology, Immunotherapy. First author is Filip Janku, who was at MD Anderson at the time, and is now in industry. What they showed really elegantly, you conjugate this to a HER2 linker. You have effect, you have PD, you even have some regression of tumor, but you have pretty horrible toxicity. The toxicity is almost always cytokine release. The question is: how do you overcome that, right, for a seven, eight agent? The key thing is, firstly, you pick the right seven, eight, so you pick a potent one. Two, if you can keep the drug where the tumor is, and you can avoid giving it systemically. I'm not here to say that if you give the drug systemically, the way Seven and Eight Biopharma is doing seven, eight, that you're gonna have problems. I don't know what they're doing. I'm not here to speculate on other companies. What I'm saying is that if you give the drug using a carrier and you administer it intratumorally, i.e., not systemically, you have local concentrations of the drug over time without high systemic concentrations of the drug. What you're likely to see within that limited experience is optimal effect of the drug within the therapeutic index that allows you to have effect without tox. I think we are seeing that here. Does that answer your question? All right. Jenner? If I could elaborate a little bit on that. This is one of these classic examples that Ascendis, where there is a lot of information in literature that we can study. For example, resiquimod has been studied in the hep C setting as an oral tablet, and from there we know exactly what level in blood that starts causing systemic toxicity. We could do exactly what Dr. Davar is saying and say, "All right, so we put this amount in the tumor with this type of linker. We know it will enter a systemic circulation at a certain rate, but it will be such when it then dilutes into the full compartment of the body, it will be well below the toxic concentration. We know the linker release rates, we know the volume of distribution for resiquimod, so we can very adequately precisely calculate this. We know that we can have very high levels in the tumor and very low systemic exposure. This is why we can have this very potent local activation without seeing anything systemically. I think we have time for a couple more questions. I know Tim has one from online, so maybe go to Tim. Okay, from, one of our, webcast listeners: Is there a possibility for IL-2 with TransCon to be administered in subcutaneous form or in a setting like a physician's office, ultimately? What directs the current administration method in setting for a treatment? You want me or you? Okay. We had a vision that we could use TransCon IL-2 as basic as an outpatient. What we did, we basically went into a primate study, looked, "Can we give this subcutaneous?" Yes, we can give it subcutaneous. We think that is actually one of the vision we have behind TransCon IL-2 β/γ. It can give as an outpatient, not only in an IV center, but basic also as the patient itself. We believe that is really the future for immune stimulation compounds in the... Specific, if you go into the neoadjuvant setting, it could be a major breakthrough that you basically could do it in this setting. Stina? Yeah, I want to add to it. You know, I think we are very excited about potentially developing the subQ formulation for TransCon IL-2 β/γ. I think all of you are aware that, you know, majority of cancers, with some exceptions like lung cancer, are diagnosed in the early stage. In order to keep patients from having cancer recurrence, what can we give to patients? Multiple different tumor types have adjuvant treatments. Adjuvant treatments are oftentimes given to patients for six months, one year, longer than that. Imagine if you're an outpatient trying to keep your cancer from getting recurrence, having a subQ formulation beats having IV formulation all the time. Speaking as a clinician, and I think Dr. Diwakar Davar would agree, we are looking at developing our subQ formulation, particularly with the vision to develop it in an adjuvant setting. In chronic treatment. Well, which is chronic treatment. Yeah. Yeah. Any final questions? One in the back. Hi, thanks for the presentation. This is Joyce Zhou, here on behalf of Yaron Werber from Cowen. Maybe just one on your IL-2. As you look forward to moving your IL-2 into multiple indications, how are you thinking about prioritizing it as a monotherapy versus as a combination therapy? Thank you. Yeah. That's great question. As I had mentioned, you know, we believe that tumors may have the best response to combination treatment. There is, in our phase II dose expansion, you can see we actually prioritize developing, evaluating for a transformational efficacy. Really, we're looking for transformational efficacy in combination setting. We will always be required to demonstrate single agent contribution in that combination. We believe that there is going to be clinical activity as a monotherapy in various tumor types, but we also believe that to maximize benefit for patients, likely will work best in a combination. In that development process, we will have to tease out single agent contribution. Okay. I think with that, we'll wrap up. Thank you all for coming here, thank for all the people online. It's a pleasure. If you have further question, if you want to have more clarity, the deck, as Scott said, will be online. We are always open for questions, so we can have a good, positive discussion about the data we have generated. Thank you so much for being here. Thanks, everyone. Thank you. Thank you.