Good morning and welcome to the Theratechnologies KOL webinar on the SORT1+ Technology and TH1902 for treating advanced solid tumors. At this time, all participants are in a listen-only mode. A question and answer session will follow the formal presentations. If you would like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player, or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this webinar is being recorded and a replay will be made available on the Theratechnologies website following the conclusion of the event. I would now like to turn the call over to your host, Paul Lévesque. Please go ahead, sir. Good morning, everyone, and welcome to this scientific and clinical update. My name is Paul Lévesque, and I am President and CEO of Theratechnologies. First, today, we'll have Dr. Béliveau, who will review why SORT1 receptor is a novel and important target in cancer therapy, t hen we'll have Christian, our Chief Medical Officer, who will present preclinical data, including new data that has never been presented, and then w e'll take your questions. Before we do so, I would like to cover a few slides with you. Next slide, please. I'd like you to refer to forward-looking information, as this is the norm. As you know, our business, like any businesses, comes with risks, so please consult the full forward-looking information before making any decisions. Next slide. Here is an overview of our company. This is important. We are a biopharmaceutical company focusing on the development, commercialization of innovative therapies. We were founded in 1993. We are based in Montreal, but we do have operations in Europe, and in the states. We have a hub in Dublin. We currently have around 165 employees across Canada, U.S., and Europe. We're listed on Nasdaq and TSX, and our market cap valuation at this time is around CAD 350 million. Next slide. I'd like first and foremost to give you an update of where we are and where we are in the development of 1902, which is our docetaxel peptide-drug conjugate, 1904, doxorubicin peptide-drug conjugate. The first one is in the clinic now. We've dosed the first patient in March ahead of schedule. I would like to stress again that we got Fast Track designation by the FDA early into the year. The second one, 1904, is basically evolving, going through preclinical now, and we'll hit the phase I at one point. Next slide. I would like to introduce you to Dr. Béliveau. Currently, he is Scientific Director of the Chair in cancer treatment and prevention at Université du Québec in Montréal. He is Professor of Biochemistry. He has published over 250 abstracts in world-class medical journals. He founded both Andiochem and Katana Biopharma. Katana has developed the oncology platform that will be described to you today. Theratechnologies acquired Katana two years ago. Dr. Béliveau, I want to thank you for joining us today. This is an important day for us and for this platform. I will let you describe why SORT-1 receptor and our peptide-drug conjugates can change the way cancer is being treated today. Dr. Béliveau. Thank you very much, Paul. If I may have the first slide, please. Next slide, please. A new approach in cancer treatment is needed urgently. Of course, chemotherapy is at the center of the treatment of cancer, but it is limited by severe side effects. One of them is the fact that the majority of the anti-cancer drugs that is actually administered to patient is, unfortunately, taken up by healthy tissue. It's only a small percentage of the active anti-cancer agents that effectively reach tumor. Next slide, please. The reason of that is that in classical chemotherapy on the left-hand side of the picture, the drug that is given only passively diffuses into cancer and normal cells. The amount taken up by normal cell is equivalent to that taken up by tumor cells because it's a passive, unspecific process. On the contrary, when we design a chemotherapeutic approach by using drug conjugate, whether these are antibody drug conjugate or peptide drug conjugate, the concept is completely different. In the case of a PDC, the drug, the specific peptide interacts with the receptor, and the changes of configuration of this ligand causes an internalization of the complex and the drug, the cytotoxic, is released specifically inside the cancer cell. Next slide, please. One of the important target, that new target that was identified is called sortilin. It was identified by us and many others. It functions as a transmembrane scavenger receptor. It's an import-export protein. It's involved in the trafficking, internalization of various proteins, and peptides from the outside of the cell to the inside of the cell. It's one of the cell shuttle system. In cancer, it's involved in a variety of processes, including cancer cell survival, invasion, and progression. More importantly, the high level of expression of sortilin has been associated with poor prognosis in a variety of cancers. Next slide, please. An example of this is shown here. All you have to remember if you're not immunohistochemical chemistry professional, you look at the brown color. What we are looking at here is immunohistochemical data that detects with an antibody the expression of sortilin, and this gives a brown color when the amount of sortilin is high. As you can see here, in a normal adjacent breast tissue, there is no brown, so the level of expression of sortilin in normal healthy tissue is nonexistent or very, very low. On the contrary, on the slide in the middle, you can clearly see that when you have an infiltrating ductal carcinoma of breast, the level of expression of sortilin by a measure by the antibodies is high. When we have a metastatic lymph node from a breast carcinoma, the level of expression of sortilin is extremely high. Next slide, please. The sortilin is an attractive novel target for cancer therapy because it's expressed at very high level in a very wide variety of tumor, including breast, ovarian, endometrial, pancreatic, colorectal, melanoma, non-small cell lung, and more recently, we have obtained data showing that one very dangerous cancer in humans, small cell lung, also express high level of sortilin. Next slide, please. You can see on the slide, these are new data that we are presenting that we just obtained recently with the biopsies from patients suffering from small cell lung cancer. You can see, normal tissue, no sortilin as measured by the intensity of the brown coloring, but in the small cell lung cancer, an extremely high level. In immunohistochemical standard, this is very high level of expression of the receptor. Next slide, please. Sortilin is also critically associated with mortality and morbidity. When you do a correlation between the level of sortilin expression and survival outcome, you can clearly see in patient, in human patient, those that have a low level of sortilin have a higher rates of survival than those at the higher rate of sortilin. This is true for all cancer that have been looked at. We have data, epidemiological data that are available now that we can look at this i n all types of tumor where sortilin level of expression is high, the prognosis for these patients is very poor. Next slide, please. This is an important slide because it explains the basic mechanism by which the platform that is developed by Thera is working. We call it the SORT1 technology, and it essentially what we have designed is a peptide that is recognized specifically by a sortilin with very high affinity, and we conjugated this peptide with cytotoxic. When this PDC is recognized by sortilin, it causes an internalization of the complex, and the internalization of the complex in endosomes causes a release of the cytotoxic drug that now diffuse inside the cell, and cause the cell death by targeting microtubules or cancer cell division or so on. The sortilin receptor is cycled back to the cell surface. What we have here is a specific way of entry. We uses the normal entry pathway of a given cell and use it to kill the cell by releasing cytotoxic drug inside the cancer cell. Next slide. That's an important slide because if we first look at the orange, two orange rectangles, you can clearly see that when we inject doxorubicin in an animal model, the level of accumulation of doxorubicin is as high in healthy ovarian tissue as it is in ovarian cancer, and t hat's a problem, and that's a cause. That's an visualization of the side effect of a free drug that is non-specifically directed. On the contrary, when we take the same drug and conjugate it with the Thera proprietary peptide, TH1904, so-called, you can clearly see that in this case, first, on the left-hand side, the level of accumulation of conjugated doxorubicin is now very low compared to free doxorubicin. In the tumor, the level of uptake in the tumor is now extremely high, 6x to 7x higher than it is with free doxorubicin. This indicates that we have a very high level of uptake in the target tumor and very low uptake level in the healthy tissue. In this slide, you can clearly see that we have a therapeutic window. We increase the therapeutic efficacy and we could decrease the side effect because the level of accumulation in healthy tissue is low. Next slide, please. This is a slide that shows the half-life of a given ligand of sortilin. It's called progranulin, and as you can see here, the half-time of progranulin is very, very rapid uptake, inside a given target cell is very rapid. The half-time is four minutes. This is to be compared to an ADC model targeting HER2, for example, where it takes up to 6 hours to 10 hours for the same process to occur because ADC are not internalization rapid process. They are slow process, so in this case, we have a kinetic advantage of using a PDC over an ADC, and that's an important issue. Next slide. One aspect of cancer treatment is drug resistance. A lot of patients die because the patient develop drug resistance. How does that work? On the left-hand side, if we give a free cytotoxic, the free cytotoxic, as I just explained, simply diffuses through the lipid bilayer surrounding the cancer cell, and it is recognized by a defense mechanism that have appeared during evolution, essentially to protect animal cell from toxin produced by plant. This MDR1 protein is a cell defense mechanism that recognize a variety of cytotoxic and just pumps them out outside the cell. Just look at it as a molecular vacuum cleaner that cleans the cell of being intoxicated. When you do this in the context of a chemotherapeutic approach, this is very bad because this multi-drug resistance mechanism make the cell resistance to a cancer agent. On the opposite, when you look at panel B, you can clearly see that if when we use our platform, PDC bound to sortilin, the MDR1 does not see the cytotoxic, because it does not partition in the lipid bilayer, and it's not accessible to MDR1 because it's internalized in endosome, and we have the release cytotoxic that preserves its activity. Next slide. This shows that experimentally, this is what we observe. If you first look at the left-hand side of the picture with the free docetaxel, you can clearly see that the amount of docetaxel is small when it is administered. If you block MDR1 with a specific inhibitor that we call CSA, you can clearly see that the addition of CSA causes a drastic increase of docetaxel inside the cancer cell. This is the proof that docetaxel is pumped out by MDR1. On the contrary, when you use TH1902, the conjugation of docetaxel to a Thera peptide, you can clearly see first in blue that the amount taken up is much, much, much h igher than free docetaxel, indicating a very rapid and efficient uptake of the cytotoxic inside the cell. In this case, the CSA has no impact on the increased uptake of TH1902, indicating that we bypass the MDR1 pump. Next slide, please. Another aspect that is associated with cancer development is the fact that the tumor cannot grow over 1 cu mm when it does not stimulate the proliferation of blood vessel. Blood vessel, because the center of the cell is hypoxic, it has no nutrient, it will eventually die. The tumor mass develops two mechanisms. One, on the left-hand side is called angiogenesis. It stimulates the proliferation of blood vessel, and the hemoglobin, and the nutrients, and the oxygen feeds the tumor and allow it to grow. There is another mechanism by which cancer cell defeat this hypoxic or low nutrients environment, and it's a complex process called vasculogenic mimicry. This is very interesting. This is a new process that very, very few people have reported, but that is becoming extremely important in oncology. In this case, it's the cancer cells themselves that form tubular structures and that divert the vascularization from the normal blood capillaries. The blood flow is now established through the formation of a structure made by cancer cells. This is why we call it vasculogenic mimicry, because it mimics a healthy, normal blood vessels formed by endothelial cells. Next slide. This is an exciting result. This is a discovery from our lab. We were the first one to report that the expression, the formation of vasculogenic mimicry is tightly associated with sortilin expression. On the left-hand side of the picture, what you have is, at zero hour, is simply Triple- Negative Breast Cancer cells that grow in a Petri dish. When we let them incubate in a given condition, they form these at 24-hour left-hand side, these kind of tubular structure, and t his is the expression of vasculogenic mimicry. When we use a biochemical tool that allow us to silence sortilin to destroy the expression of sortilin in this cell, in these cancer cell, you can clearly see that we inhibit, as shown quantitatively on the right-hand side of the picture, we have a more than 90% inhibition of vasculogenic mimicry caused by sortilin silencing. This is the first evidence showing that one key element in the expression of this vascularization made by cancer cell is our target, which is sortilin. Next slide. More importantly, when we try to inhibit vasculogenic mimicry on the, in the pale blue, you see that docetaxel works only at very, very high dose, a plasma dose of docetaxel, which are above its concentration causes toxicity. On the opposite, when you take this TH1902 docetaxel conjugated with the peptide, you have at very, very low dose, picomolar concentration, which are far below what we can measure in the blood. We have a specific very, very high inhibition of vasculogenic mimicry, indicating that we have an inhibition of vasculogenic mimicry by this drug. Next slide. What we have with the SORT1 technology is a first-in-class PDC platform that targets specifically SORT1 receptor, which is a new target in cancer treatment. No drug developed so far have ever targeted sortilin in any type of cancer treatment. We target SORT1 specifically, which is a good target, because as I showed you it's involved with poor prognosis and decreased survival. One advantage of sortilin is that it causes a rapid internalization, and this causes a high concentration of the cytotoxic inside the cell, and that clinically should cause improved efficacy, safety, and durable response. I showed you results showing, indicating you that it overcomes two key resistance mechanism in cancer. It bypass the MDR1 efflux pump and it inhibits vasculogenic mimicry formation. Next slide. What we have here is a platform that allow, very, very importantly, to build a targeted therapy, increased efficacy, a better tolerability. These two points, it means a drastic increase of the therapeutic window that allow drug to be developed. All of this makes SORT1 technology a very flexible platform for the development of a variety of drug to treat cancer. I will now ask Dr. Marsolais to present the next result concerning this platform. Thank you, Dr. Béliveau, and good morning, everyone. Welcome to this session on TH1902. Next slide, please. Before I get into the description of kind of a summary of the preclinical results obtained so far, and the new results that we just announced this morning in the metastatic model, I would like to describe our technology. What we have done is, as Dr. Béliveau explained, we're targeting the sortilin receptor. There are natural biological ligand that attach to that sortilin receptor. What the team has done is that we tried to, or we synthesized a number of smaller peptide to mimic the natural ligand of sortilin, and we found the best one that would attach properly to the receptor, that would internalize, and that would be released specifically inside the cancer cell. We have built a 17 amino acid peptide, and based on the hundreds of peptides that we have done, this is the best one. The other part which is important is the linker, the blue link between the red dot and the peptide at the bottom. You have different type of linker. You can have one which is very solid, which is the one used very often in the ADC, and you have some that are cleavable. Because our receptor is internalizing the drug rapidly, we wanted to have a cleavable linker, so once inside the cancer cell, the cytotoxic or the anti-cancer drug would be released very rapidly as well to stop the cell division. Finally, in terms of, h ere we have the two red dots, but it could be any type of anti-cancer. We can conjugate about any anti-cancer drug to this technology. Next slide, please. As Dr. Béliveau explained, we have a specific way of entering the cells. We're bypassing MDR1 mechanism. We can also act on vasculogenic mimicry. If we're looking specifically at our lead compound, which is docetaxel attached to that technology. Once inside the cell, the docetaxel is released, and will act directly on the microtubule to stop the cell division. That's working exactly with like the free docetaxel. It's only that it is entering the cell in a very different way. The other thing that we're studying at the moment is we don't know because once the drug is entered inside the cell via the endosome, how long does it last? Docetaxel half-life is very short, about four minutes. With this technology, we need to understand, and it looks like we're increasing the concentration of the cytotoxic inside the cell. It might have an impact also on the length of time it will remain in the cell, which would be very important for improving the treatment of cancer patients. Next slide, please. So far we've been comparing most of the time our technology to cytotoxic. Those are the first new drug peptide conjugate that we have synthesized. We really have a new chemical entity and for many reasons. First, we enter the cells, only the cancer cells, via the sortilin receptor. We have shown clearly that we can significantly increase the concentration of the anti-cancer drug inside the cytoplasm of cancer cells. We're bypassing MDR1 mechanism, which is an important resistant mechanism of cancer. Dr. Béliveau just mentioned the vasculogenic mimicry structure, which will be also very important because many cancer, once they become resistant to, example, anti-angiogenic treatment, will develop a lot of VM structure. If we can inhibit those VM structure, it will be important for efficacy. We have shown that we also have a better inhibition of the cancer cell migration. This is something very different and completely new. We also have a different PK profile. We release much less free docetaxel in the blood of the patient, therefore decreasing the adverse event linked to those cytotoxic. We really think based on the data that we have so far that we can significantly increase the therapeutic window. At the moment, cytotoxic, you need to give them at a dose where it will induce a lot of adverse events. Based on the data that we have, we will be able to give a drug either at higher dose or at dose where we should see minimal adverse events. Finally, we have very good intellectual property on the entire platform, all of the combination, and all of the drugs. Next slide, please. One last thing, it's, we also have shown in the in vitro model that TH1902 kills cancer cell much faster than docetaxel alone. That's what you see on the left-hand side. On the right-hand side, what we have done in the same type of in vitro testing, we have put a natural ligand to sortilin. Once we put the natural ligand, we can see that we compete with the effect of TH1902, which means that TH1902 enters the cancer cell only via the sortilin receptor. Next slide, please. Before I start describing all of the animal model that we have studied so far, I would just like briefly to explain how it works. We take nude mice to which we inject under the skin cancer cells that are coming from a specific cancer. In this case, a triple-negative breast cancer, but you can buy different type of cancer. Once it is inside the, the skin, it will start to grow, w hen it reach about 1 cm, we start treating the mice. As you can see specifically in that example, if you give a placebo or the vehicle, you can see that the tumor is growing very fast. At some point, you need to kill the animals, because you cannot leave them with that size of a tumor. In triple-negative breast cancer, docetaxel is a good treatment, you can see that it is working fairly well. This is the yellow line. The problem with docetaxel, you need to give it at the maximum tolerated dose, and you can give only three doses of docetaxel. After that, you have to stop because the animal are losing weight, and they're not healthy. You can see that it takes a bit of time, at some time the cancer start to regrow. With TH1902, the safety profile is much better. There are no impact on the weight of the mice. In this experiment, we stopped after five cycles, and you can see that there's a long-lasting effect. Also very important, it doesn't show much on this graph, but you can see that the tumor size are shrinking or tumor are shrinking with TH1902, and v ery important is long-lasting effect that we see with TH1902. Next slide, please. In order to study the or look at what we had done, what like we had seen, the increase of the cytotoxic inside the cancer cell, we said, "Well, we should test it. If we give less TH1902, it should still have a positive impact or kill the cancer or the cancer cells, and docetaxel well." This is exactly what we have in this presentation. When we give docetaxel at a quarter of the dose, it doesn't have any cytotoxic impact on the cancer cell. When we give TH1902, which is the equimolar concentration of the quarter of the dose of docetaxel alone, we see that we have a very, very good antitumor effect. The safety profile is extremely good. We stop the experiment after a number of days or weeks but, o f course, it would have been possible to continue that experiment for a longer period of time. Next slide, please. Same in melanoma, s ame thing again, d ocetaxel works, but as soon as you stop, the tumors start to regrow. With TH1902, once again, we can give more and longer. Once again, we stop not because we had seen adverse events. It's only because we needed to, like, stop the experiment at some point. You can see once again in melanoma that we have long-lasting effect with TH1902 and the tumor continue to decrease. Next slide, please. In order to up the bar a bit because we have seen that it was working well in different number of cancer, we tested the drug in colorectal cancer. It is known, there are a lot of literature showing that docetaxel alone does not work against colorectal cancer in human. In this model, this is what we're seeing. If we give the MTD of docetaxel, 15 mg/kg, you can see that the yellow bar, it's increasing or the tumor is increasing almost at the same rate as the vehicle. However, when you administer TH1902 at the equimolar concentration, we stop the growth of the tumor, and most importantly is that we still see the long-lasting effect. Maybe not as long as in the other treatment, but once again, it would have been possible to continue to treat those animal with TH1902, which is very, very impressive in terms of results. Next slide, please. We also looked at pancreatic cancer. It is known that there's not too many treatment. Well, there are no very good treatment for pancreatic cancer, and w e did the same thing, comparing the quarter of the dose, better efficacy with TH1902. With the full or the maximum tolerated dose, once again, we see a more rapid shrinkage of the tumor once treated with TH1902, as well as a lasting effect once we stop the treatment with TH1902. Next slide, please. Finally, and this is, I think, one of the last models, we did it in about 6 models or 7 models, and w e also tested the drug in endometrial cancer. What you see on that slide, once again, it's the same thing. At a quarter of the dose, docetaxel does not work. TH1902 has better efficacy, not necessarily the optimal, but very good efficacy. Once we give the equimolar of the maximum tolerated dose of docetaxel, you can see that docetaxel has an efficacy at the beginning, but the tumor starts to regrow while on treatment. With TH1902, after four treatment, you can see that there's a significant decrease in the tumor size. There's also this long-lasting effect that is there for a significant period of time. At the beginning, we only had the results of the TNBC and the long-lasting effect in one model, and we didn't know exactly how to interpret that data. Now we have more than six different tumor models. We always see the long-lasting effect and we think that it could be explained by potentially four things. First of all, we've shown that there's a significant increase of the concentration of the cytotoxic specifically inside the cancer cell. That could be one of the reason. Dr. Béliveau described the mechanism of resistance that we're bypassing, then that could be another one because the cells eventually would bypass the treatment with docetaxel or become resistant to docetaxel. We also are affecting VM. Not sure the RBM. We couldn't identify in those tumors the RBM but this is also another mechanism of resistance. Finally, this is what we're studying at the moment to find out what's happening with docetaxel inside the cell when it is internalized via the endocytic pathways. Does it stay for a longer period of time? We're looking into this, but if we increase the half-life of docetaxel inside the cancer cell, that would be very important for long-term treatment for human. Next slide, please. We also talked a lot about the safety and it is well known that the cytotoxic will induce neutropenia. It is a very important side effect that limits the use of those drug. First of all, at some point, you can no longer increase the dose of the cytotoxic because you're killing also the blood cell or you're lowering significantly the neutrophils in the blood. The other thing is that you usually see also cumulative toxicity then that at some point, four, five, six cycles, you need to stop the chemo treatment because you have cumulative toxicity, and it takes a long period of time for the patients to recuperate from those toxic effect. What you see on the right-hand side is a graph showing that once you give to the, a nd this is in the animal. If you give docetaxel at the maximum tolerated dose of 15 mg/kg after one cycle, you see significant neutropenia. After the second one, it's worse, and eventually, this is why you have to stop because you have cumulative toxicity. If you look at the blue lines with TH1902, when we give the equimolar concentration of docetaxel, there's absolutely no neutropenia, and this is up to six cycles of treatment. This data was also confirmed in our tox program in the rat. We were able to give up and as far as 3x the dose of docetaxel before we start seeing similar serious adverse or decrease on neutrophils. That will be important, and as Dr. Béliveau mentioned, this is the way we can potentially increase the therapeutic window of those cytotoxic or anti-cancer drug. Next slide, please. On this slide, we're explaining what we see, e ven though we have a drug-peptide conjugate with a cleavable linker, there's very little release of free docetaxel in the blood, which is very important to control the adverse events. We know that we're specifically entering only the cells that are expressing the sortilin receptor. Those are very, very compelling results, and we hope to reproduce those as well in our human studies. Next slide, please. I will now get into the new results, but before I get into those new results, I think it's pretty well known that cancer, there's better chance to treat cancer when you diagnose your cancer as early on as possible. Like melanoma, you can remove it, and it's much better. Colorectal cancer, if you do endoscopy on a regular basis and diagnose the colorectal cancer right at the beginning, you have a very good success rate. Once you start having metastasis, this is mainly cancer cells from your primary tumor that will go in the blood circulation, and attach to different organ, and start building other tumor in those organs, your chance of survival is extremely low. Next slide, please. The one thing which is very particular about the sortilin receptor, it is also associated to what I just said is the number of sortilin receptor on the cell surface is increasing with the advancement of your cancer. You can clearly see on that slide that in the normal skin, you don't have much of the sortilin receptor, almost none. Stage 2, stage 3, more, and stage 4, you even have more sortilin expression, which is good also for the first-in-human that we're doing. You know that for the first-in-human, we treat resistant patient that have metastasis. If there are more receptor, we potentially have a better chance to show efficacy in comparison to other drug in the hard-to-treat patients. Next slide, please. In order to test the efficacy of TH1902 in the metastatic model, we use a standard model. What we do, we take cancer cells from skin cancer, melanoma, and instead of injecting them under the skin of the animal, you can see on the left-hand side that when you do something like this, there's absolutely no cancer in the lung after 14 days. If you inject those cells in the blood circulation of the animal, you can see that you have a lot of metastasis specifically in the lung. That's a standard model. The more cells you inject, the higher the number of metastasis that you have. For our experiment to test TH1902, we have used a 125,000 cancer cell injection. Next slide, please. The results that we've obtained with TH1902, once again, are very striking. If you look at the left-hand side, inside the black bar, you have a lot of metastasis. This is you inject the cancer cells in the vein, and you wait 14 days, and you kill the animal, because this is the only way you can look at the efficacy of the drug. Docetaxel also has an effect, then If you look at the two bars in the middle, the green and the blue, we did an experiments where we inject the drug an hour before injecting the cancer cells and see if it would prevent the attachment or formation of metastasis. You can see that docetaxel blocks about 50% of those metastasis, but TH1902 is better, and there's only about 25% in comparison of the vehicle. After that, what we did, we did the pre- and the post-treatment. In that model, we give a bit lower concentration of the drug, but we give it more often. You can see that docetaxel, even with pre- and post-treatment, the post-treatment doesn't make much or doesn't add to the efficacy. The post-treatment with the TH1902 is significantly increasing the efficacy against metastasis. If this is reproducible in human, that is certainly something that would change the treatment of cancer patients. I will now describe where we're at with the first-in-human and the design that we put to test the drug, which is a standard one. Next slide, please. As you know, we announced that the first-in-human will be done in patient with refractory advanced solid tumors. We are enrolling all comers, and there's a reason for that. We need to enroll all those. We will do a biopsy and look if those cancer cells or metastasis are expressing the sortilin receptor. We'll do the correlation at the end of treatment to see which patients are responding the best, the one that are significantly overexpressing sortilin a bit or none at all, then that's something which is important. That was also requested by the FDA. We started the dose escalation at 30 mg/m². I'll go in more details in the next slide. We're enrolling one patients, sorry, c an you go back to the previous slide? We continue to increase the dose up until the time that we reach the maximum tolerated dose, and that will be the dose that will be used in the phase II. At the moment, our protocol include also a basket trial, a second part with the right dose, including four different type of cancer: TNBC, gynecological cancer, colorectal cancer, pancreatic cancer with 10 patients each. That protocol was submitted at the same time that we requested the FDA Fast Track designation. We obtained that designation but with a broader indication to some extent than what we're expecting. The FDA allowed for that Fast Track for all solid tumor, advanced patients that are expressing the sortilin receptor. As soon as we have data in our first-in-human, we will interact with the FDA to see what will be the best way to do the next step with this program. Next slide, please. I just wanted to take a bit more time with you to explain how the first-in-human is working and where we're at with our study, and when we're expecting potentially to see some either safety signals or efficacy signal. The first patient, as I mentioned before, received 30 mg/m². That patient was, as you know, dosed at the end of March. After that, we dose escalate. We double the dose of TH1902 for every patient until we will have an adverse event of a grade two that could be lower neutrophils, it could be a skin rash, it could be anything. It is an adverse event that needs to be linked or potentially linked to the treatment. Once we reach that adverse event, we will enroll three patients until we have a serious adverse event. Once we have a serious adverse event over three patients, we slightly reduce the dose, and that will define our dose. The one thing which is very important to understand on that slide is we are getting very close to doses that are equivalent to the dose of docetaxel, which is used to treat human. Our drug is a bit bigger than in terms of the correlation. 230 mg of TH1902 is the equivalent of 100 mg of docetaxel. We are getting very close to dose area. At the beginning, even after only the first cycle, as I've shown in the animal model, if we don't see neutropenia, that will be a very good sign. That means that we can continue to dose escalate, give more drug. That will also give us a sign that we can most likely give more cycle. Instead of stopping after five or six, we potentially have a chance to give more cycles to those difficult to treat patients. What we think based on the recruitment at the moment, patients are recruited every about four weeks. There are two sites that are active. Three additional sites will be activated in June. We think that we might reach those docetaxel toxic dose the end of the summer and the beginning of the fall. After that, we need always to wait a few cycles to look at the efficacy, b ecause you might see early efficacy, and you need to ensure that it is sustained. We think that we should be able to read or to have a bit of an idea about the potential efficacy of this new peptide-drug conjugate in the fall of 2021. I will now turn it to Paul for the concluding remarks. Thank you for your attention. Well, thank you, Christian, and thank you, Dr. Béliveau. This was very informative and very compelling, may I say. We've learned a few things now. We've learned that the sortilin receptor is not a marginal receptor. It's a very important receptor. And the preclinical data that Christian just reviewed, it's very compelling. Obviously, now, we're very excited to going into the clinic to see how it's going to perform. Before actually I turn to your questions, I'd like to cover a few more slides just to actually give you a sense of additional opportunities that we have, and where we are now with TH1902. Next slide, please. You know, by now you see how powerful this platform can be because we're really challenging the mindset, challenging the way, you know, a medicine can actually enter the cell because this SORT1 receptor is so powerful that we can concentrate the cytotoxic agent within the cell. What does that mean? Well, it means that if we get additional safety, can we actually challenge the dosing schedule? I think this is very exciting. Can we challenge the therapeutic window altogether? I think the answer is yes, and that's the type of excitement that we have when it comes down to the future. Christian talked about the mode of action. Once docetaxel gets into the cell, what is the fate of conjugate? What happens afterwards? We would like to actually elucidate that better. That's one thing that can be ahead. You heard by now that we have some very specific expertise when it comes down to conjugation. We can actually add, having, you know, a linker that is very specific, add, you know, cytotoxics medicines or peptide, and then actually have other peptide-drug conjugates. That would be very exciting. Another one is to say, what is the rationale for combination therapy? Over the last couple of years, immunotherapies, you know, has gone, you know, far in establishing themselves in some cancer types at different stage. We know that they have limitation as well. If we were to combine that with our SORT1 technology, how can we synergize? Very exciting discussion to have. Last but not least, it's, you know, are we going to need a companion diagnostic, what it could look like, and in all of this to say that we could improve the patient selection. As we're going to unfold the clinical data, that is going to be interesting to actually ask ourselves that questions, those the patients, and see if there's, you know, additional activity when the SORT1 expression is over a threshold, for instance. Next slide. Here is where we are with TH1902 and what you should expect moving forward. We are now, and Christian did a good job to actually, you know, describe the dose escalation. We get a lot of questions, why are you doing it this way versus another way? The dose escalation, I keep saying it, there's no place for creativity. We're doing it the way it's prescribed by the agency, and we're moving along. We're going to find our maximum tolerated dose, and that will inform how we approach the part B. The part B is expected to be a basket trial. We have a plan for this, but as soon as we get, you know, significant safety and efficacy data, that will challenge the way that we're going to move forward. By the end of the year, in the fourth quarter, we should see these early signs of efficacy and safety, and therefore, that will inform the basket trial. We want to be starting the basket trial in Europe and in the states in early 2022. That's our plan. I would like to leave you with this impression that is very important. We got the Fast Track designation by the agency and our goal is to ensure that we are in constant conversation with them so that we can accelerate the development of TH1902. Is that going to be in one cancer? Is that going to be in different cancer types? It's too early to say but our job is to ensure that we can give this new ammunition to patients and HCPs. Let's now actually turn to your questions. Tara, we are ready to go now with the questions from people on the line. Thank you, Paul. At this time, we'll be conducting a question and answer session moderated by John Matalone of LifeSci Advisors. If you would like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. Please hold while we pull for questions. You can go ahead, John. Okay. Thanks very much, Tara. Our first question reads as follows. What are the potential advantages and disadvantages of a peptide conjugate approach versus an antibody conjugate approach? Well, thank you, John. That's a question that we get, you know, very often. I think Dr. Béliveau alluded to that. Dr. Béliveau, do you want to go first? Maybe, Christian, you want to complement? Okay, yeah, I think there is a big difference between the two because ADC basically are designed to bind to cancer cell surface receptor that do not internalize or internalize very, very slowly. The cytotoxic that is attached to the antibodies mainly release outside the cancer cell and needs to diffuse through the cell or the cancer cell membrane to stop the cancer cell division. On the contrary, our PDC is designed to be rapidly internalized because it targets import, export transport system, the sortilin receptor, that is specifically expressed in cancer cell. It rapidly increases the concentration inside the cancer cell. That should cause an increase in the efficacy and safety of the drug. You have to remember that the half-life of a given substrate for sortilin was in the order of minutes and we see the induction of apoptosis within a couple of hours compared to tens of hours for ADC. There are very good advantages in using a receptor of the kind of sortilin to have a better efficacy in terms of cancer treatment. Maybe only one thing to add, i f you look at all of the ADCs that have been approved, in order to work, because they're still diffuse or they internalize less rapidly, they have to use cytotoxic molecule that are way more potent than docetaxel. The first ADC design with compounds like docetaxel or irinotecan were not working. In our case, it's very different. It goes inside the cells very, very rapidly, and increase the concentration of docetaxel, which works well. They are very two different concept, but using the sortilin receptor, PDCs are better to be used with that receptor. Great. Thanks. I'll read the next question. Next question reads as follows: are the SORT1 positive drugs likely to be more effective in later stage cancers if, as I understand, later stage have increased overexpression of sortilin receptors? Yeah, again, that's a very good question. Dr. Béliveau, do you want to go first? I mean, that's speculative, but that's an interesting one. Go ahead. I think, yeah, that's a very important question, and that's an issue that we're very excited about, because generally in cancer, we have all sorts of defense mechanism. In this case, this is, to my knowledge, the third case that we have an increased expression of the target as the condition of the tumor goes worse. If we have an increased expression of the target as the evolution of the tumor, it means that we should have a better response because we would have increased uptake by these cancer cell. That's a key issue because often for many cancer that we talk about, but especially for small cell lung cancer or ovarian cancer, the patient are detected at a late phase of tumor evolution, and they already have all sorts of resistance. These are the one that where sortilin will be highly expressed so we will have a better efficacy at the late phase. This is the prediction that we should do according to the preclinical data that we have. Christian, a few words to say? Well, the only other thing I would add is the only other thing that we have in vitro that would support this, is the results that we have seen on the cells that are forming, the vasculogenic mimicry. We know that there's a significant overexpression of the sortilin on those cells. If it's the same thing in advanced cancer or metastasis, well, there are good chances that it can work also in very hard to treat patients. Yeah. We have seen expression going from 40% to 90% according to tumor type so a v ery important receptor. John, go ahead with the next question. Yes. Thank you. The next question reads as follows: how is the linker only cleavable inside a cell? Is there any evidence of cytotoxic agents being released outside the cell? I think, Christian, you showed some data associated with that in the presentation. Yeah. Go ahead. It's you need an enzyme to cleave this cleavable linker and it has a higher concentration inside the cancer cell. What we have seen in the animal needs to be confirmed in human, but it's less, or it's about only 1% of that docetaxel which is released in the bloodstream. At those levels, it's like there's no toxicity. If this is what we're seeing in human, it means that we have a high concentration of TH1902, like attaching to the receptor, getting inside the cells, but leaving very, very small concentration of docetaxel in the circulation, therefore minimizing the potential adverse events linked to docetaxel. Great. I'll read the next question. Next question reads as follows: is anyone else looking at sortilin? If not, why not? Has it been a difficult target? I think this is a question for Dr. Béliveau. Dr. Béliveau. We will. Many people have looked at sortilin expression, but they generally look at it in terms of clinical expression, correlation with patient survival or a basic biochemical mechanism of action in terms of cell biology. We were the first one to think of this receptor as a target for cancer. There are no other drugs that have been developed so far or that are being developed presently that are targeting this receptor. This is why we were the leader in this field and I think that Thera is pursuing this issue. I think it's really a new platform, amd I think that we have, we are attacking a new target, and I think we will see positive results because of this. When we need to attack cancer, we need to find new strategy to circumvent the ability of cancer cell to invade our standard chemotherapy, and I think sortilin receptor is one of them. Thank you. I think with what we have, again, it needs to be confirmed in humans, but we certainly have something that looks like a first in class, and a best in class, challenging the way cancer can be treated. The next question reads as follows: if the SORT1 positive drugs show promise, would the development of a diagnostic test in parallel to the drug studies be the way to maximize the impact of the compounds? It could. I think I alluded to that in the type of opportunities that we have ahead of ourselves. If the threshold of SORT1 expression is always very high, you know, in the end, maybe it won't be needed. It's an interesting questions to ask. Christian, do you want to say a few words? Yes, what we're doing, we knew about this. What we're doing at the moment, we're working with one of the best lab that work on other diagnostic tools for histopathology. What we're doing, the progression of that test is going extremely well. We will do the correlation. We will look at the effect of the drug, looking at the expression of the receptor, and eventually we'll see which levels you need to have the efficacy. That's something that we will do. As Paul is saying, in some cancers, the expression of the receptor is in 90% of the patients, endometrial cancer, ovarian cancer. Maybe in a group of a different cancer, we won't need the diagnostic test. Maybe in others, where colorectal cancer, at least at the beginning, in early stage of the cancer, if it's 40%, 50%, we might need this. That test will be done and will in all clinical trials that we will be doing. At the time of the phase IIb, we will already have a fairly good understanding of the link between the efficacy, and the diagnostic tests, or the results of the receptor expression. Thank you. Okay, I will proceed to the next question. Next question reads as follows: how does SORT1 compare to folate receptor in terms of a cancer target, which is also overexpressed in many different tumor types and is used in similar technology, ADCs, for example? While PDC uses a peptide, a small moiety, and is easy to manufacture, how does it compare in potency and specificity to the ADC approach? Dr. Béliveau, do you want to go first? I mean, it's essentially comparing ADC with PDC, if I understood well. It's the difference between two receptors. The folate receptor. Oh, I'll let you answer. Paul. Christian, do you want to go? I'm sorry. I didn't look at the folate receptor, the one thing which is very different with our receptor, the sortilin receptor, it's one of the only receptor that has that scavenger particularity to import large protein inside the cell. It is really the basics of the mechanism of action, where this receptors is internalizing large protein all the time. We mimic the protein, we get inside the cytoplasm, and it's very different. For that reason, we think that the PDC is the best way because at the moment, based on the curve that I've shown in the animal model, the half-life is about an hour. You give a large concentration, penetrates, and is internalized only inside the cancer cells. After that, there's no more drug, no more toxicity for the patients until the next treatment. We think it is the best approach. Great, t hanks, I'll proceed to the next question. Next question reads as follows: what exactly do you think lies behind the vasculogenic mimicry? Your PDC isn't silencing SORT1, the SORT1 gene, so what exactly is going on? Is it saturating SORT1 or internalizing SORT1 and stopping it returning to the surface? Are you thinking of this as a second MOA for the drug? Dr. Béliveau. Yeah, that's a good question. That's a very complex question. We understand very little, the molecular mechanism underlying vasculogenic mimicry. I think that the expression, the involvement of sortilin I showed you today is one of the few molecular handle that we have on this process. I think your question is extremely important, and I think it can indeed, as you have seen, you have seen the huge difference in free docetaxel compared to 1902 in terms of nanomolar versus picomolar range. I think that it, the vasculogenic mimicry results, clearly, show that we have a completely different mechanism of action in terms of the conjugated drug. It partitions differently inside the cell, and it will affect cell constitution, cancer cell constitution in a different manner than the free drug. I think vasculogenic mimicry could well be one of the way that we can establish the specificity of the whole platform. Maybe I will add one thing is there's publication, more and more publication. Even when we started to work with Dr. Béliveau about two years ago, we didn't have, like, that much publication in vasculogenic mimicry. There's been some very good scientific publication about three months or four months ago showing that if you use anti-angiogenic drug, one of the main mechanism of resistance is vasculogenic mimicry. If we think about treating cancer patient always with combination treatment, TH1902 could become a very good partner or combination therapy for many, many different type of treatments. Great. The next question reads as follows: the docetaxel peptide conjugate is a very promising drug candidate based on the results generated to date. Not every protein can be targeted with a small molecule. Because it is a transmembrane receptor, do you think it is possible to develop a small molecule chemotherapeutic to target sortilin receptors, SORT1 receptors. Looking at the sortilin receptors, particularly the SORT1 protein, do you know if there are any other proteins that have very similar homology? Okay, so the first one has to do with having a different payload that would be just like a small molecule. I think this is the questions. Dr. Béliveau, what would be your reaction to this? I think, we can, t he easiest way to design a specific protein interaction is through peptide. Of course, with the computer-assisted software, we can look at a bank of various small molecule that could work in the same manner. You have to remember that this internalization receptor is using a peptide, and a protein as its substrate, so it is more normal, more relevant to look at the peptide structure than small molecule structure. There are no, nothing that would, you know, block us from looking at smaller molecular structure. I think there was a part two in the question that had to do with SORT1 receptor and maybe having identified something similar. I s that the nature of the question? Christian, is that what you heard? I think this is what I've heard but I'm not sure exactly what's like kind of the intent of the question. Could it be related to toxicity, because if you have other receptors that are similar where the drug goes. The one thing I can say is in the animal model, in the tox study, that we were able to increase our TH1902, give it a much higher concentration, up to 3x. It doesn't have any signs of toxicity that are not related to kind of docetaxel then therefore this stage doesn't look like TH1902 is internalized in other cells that would lead to adverse events, at least not significantly. Yeah. I'd like to say also that, you know, we have yet to see some limitation to 1902, which is a big surprise. Christian said that a few times. We see efficacy in some cancer, such as colorectal cancer, where normally docetaxel doesn't actually have an impact. This is going to be interesting for whatever additional development that we're going to have to take in place or put in place to complement whatever 1902 can be used for. At this stage of the game, we've yet to see some limitations so much that probably this door that allows us to get into the cell is so unique and effective. Next question. Yes. The next question reads as follows: have you tried PDX or patient-derived xenograft models? Christian? Yeah, n ot at the moment, but we're working on those models. Those are the type of models that we want to do in the future. There will be, like if we're working on different aspects or research of the drug that will most likely, d ata will be submitted for AACR next year. Great. Next question reads as follows: can you comment on potential tumor types to be included in the phase Ib basket study? At the moment, as I mentioned briefly before, it was endometrial, gynecological cancer. The ovarian endometrial are expressing the receptor at the same level, t hat was one of them. We decided also to have a try colorectal cancer, TNBC, and pancreatic cancer. The only thing is, based on the Fast Track that we have obtained from the FDA, as soon as we have data in human that are showing some potential efficacy in different tumor types, we'll probably need to have a meeting with the FDA to see how we can improve, change, or slightly change the design of the study in order to get to the approval as fast as possible. The objective to move with the phase Ib was to gain more information on efficacy on specific tumors. If the efficacy is linked with the receptor, we'll want to find a design to go as fast as possible to the market. If there's one tumor type that respond better in the first-in-human, we would like to launch the phase IIb/III trial as fast as possible in that tumor type. My response is really we need to look at the data in first-in-human, discuss with the FDA, so we can go as fast as possible to get this drug approved. Okay. The next question reads as follows: can melanoma get incorporated into the active clinical trial? The preclinical data looks strong. Did it miss out due to timing of the IND application, or is there another reason for not including it? No, there's no reason. At some point for the phase Ib, we decided to see in which kind of tumor type we would go. We picked cancer where there's a high unmet medical need. Melanoma in the earlier stage, there's a lot of treatment, it's working well. There's more melanoma in terms of resistance or refractory melanoma. As I said before, as soon as we have signs of efficacy, we'll probably go to the FDA and see which cancer should be or cancer type should be enrolled in the study. Next question reads as follows: can you talk about the stability of your peptide? Do you have to modify it in any way? Well, not at the moment. Based on the results that we had in human, we, sorry, in the animal, we can see that the half-life is about an hour, which is long enough to bring enough drug inside the cancer cell. At the moment, we think that we have a very good peptide or peptide-drug conjugate that works extremely well and is stable. Next question reads as follows. Do any human organs express sortilin to be of concern? Sorry, Paul. This goes to the question that I said before. We know that neurons will express sortilin, but the drug peptide conjugate does not cross the blood-brain barrier. In the other tissue it can be expressed, but at a very, very low concentration. Even if the drug gets inside those cells, as an example, doxorubicin goes in every single cell of your body because it diffuses through the cell membrane. It doesn't differentiate, as Dr. Béliveau said, between a healthy tissue or a cancer tissue. We're not concerned but the tox data that we have done in the rat also confirm that there are no significant or serious adverse events are directly associated to TH1902. Okay, the next question reads as follows: i f potentially better response in advanced patients, would you initially target relapse refractory patients? Why all comers in the clinical trials? Okay. Well, we'll start with the all comers. We often have that question. I would like to clarify this. In our discussion with the FDA, the FDA wants to have all comers, because they want to know if there's a correlation between the activity, and the like the expression of the receptor. As it was mentioned before, in some cancer, the expression of the receptor is in the area of about 90%. In some, like colorectal cancer or pancreatic cancer, is in the 40% or 50%. As the cancer progresses, the expression of the receptor is higher. Maybe even if our first in human, maybe an average of 70% or 75% of the patients would express the sortilin receptor, that will give us an idea if the efficacy is linked with the expression or not. Even in our earlier discussion for the phase Ib of this trial, the FDA also requested that even if we go in a specific tumor type, that we don't choose the patient based on the receptor, because it is important to understand what is the expression of the receptor to generate the efficacy, and if there's none, does it work or it simply doesn't work? Those are important scientific question. It won't delay the, I think that there could be a concern about longer trial or more patients. It won't delay the recruitment. At the moment, in the first in human, the recruitment is going extremely well. By the end, once we will reach the dose or the maximum tolerated dose, we will probably have a total of 25 patients. There will be enough patients expressing sortilin receptor to have a fairly good idea about the potential efficacy of the drug. All comers, we don't select the patients based on SORT1 expression, but we do dose the patients to know what is their SORT1 expression along the way. Absolutely. We do a biopsy on all of those patients at the beginning, and we'll do more biopsy as the patients are being treated, either on metastasis. We want to understand what is, what is happening to that receptor. Okay, we have time for one more question, and that question reads as follows: y ou are advancing four indications in the phase II of your TH1902 trial. Sorry, I just had a technical glitch here. I apologize. I lost that question. Let me read this question. Is it possible that TH1902 could mean cancer could be treated as a chronic condition such as diabetes or HIV? Oh, wow. That's some people are even more ambitious than we are. I mean, we are certainly very hopeful that this is going to be bringing significant addition to the arsenal of therapies that doctors are using, mixing to actually tackle cancer today. I think the unmet medical need is huge. Our goal at this time is to ensure that we foresee when we can add value and where we can add value the fastest possible way. Boy, if we could actually deliver on that one day, I think that we're going to make Dr. Béliveau and the first researchers that actually identify SORT1 and designed the peptide very, very happy, along with the patients that will actually benefit from it. Okay. That concludes our question and answer section. I'll turn it back over to you, Paul. Well, I mean, thank you very much. The set of questions tells me that there's a huge amount of interest for this. I would like to thank Dr. Béliveau for joining today, a g reat addition to explain, you know, the genesis of this, where it started, and the identification of that SORT1 receptor that is not a marginal receptor, but rather one that allows us to actually target cytotoxic medicines within the cells. I hope that you're as excited as we are when it comes down to seeing the potential. We've got 1902, we've got 1904 following, we will continue. We have an expertise in peptide. We have an expertise in linkers. We have an expertise in trying to actually design peptide drug conjugate that can actually add additional value to the 1902 that is already in the clinic. From this point on, it's about execution. I said it before. You have our commitment that we're going to drive the clinical program as efficiently as possible, and we're going to be in constant interaction with the FDA, so that we can see how we can best accelerate this, and bring it to the market within a decent period of time, as we know that the patients are waiting and as we know that there's a high unmet medical need. Again, I want to thank you for joining today. Again, stay tuned because we're going to have key milestones, and we'll be in contact with you as soon as we see something significant developing. Thank you very much again.