Good afternoon, ladies and gentlemen. Welcome to our Nordic Nanovector R&D Day. My name is Jan Egberts, and I'm the Chairperson of the company, Nordic Nanovector. Unfortunately, I was really looking forward to meet you all in person today in Oslo, but I guess unfortunately, because of all the COVID-related travel restriction, that's not possible. However, we'll make the best out of it with using the more modern technology as the webcast, and we obviously will also be available for more intimately answering all your questions. Obviously, COVID had a major impact on our company. We have kept you updated about our recruitments, which suffered quite significantly in the first half of last year, which really started to pick up now, which is very encouraging. Over the past months and years, we have been sharing a lot of information about our PROST PARADIGME, the clinical program with Betalutin. I think it's now also very important to kind of switch gear a little bit and share what our organization has been doing over the period in earlier stage R&D projects, because I think there's a lot of very interesting things we'd like to share with you. Here today with me are Erik Skullerud, our CEO, with his team, and they will share with you some of the program progress I just mentioned that we have made. We're also very privileged to have Professor Dr. Leo Gordon with us today, who's gonna share his experience as a clinician with some of these patients. Professor Leo Gordon, he's the Abby and John Friend Professor of Cancer Research and Professor of Medicine. He's also the co-director of the Hematology Malignancy Program, the Division of Hematology Oncology at Northwestern University Feinberg School of Medicine. Very pleased with all the people, and I think you're gonna be very impressed with the progress we have made over the past year and a half. Having said that, I'd like now to hand over to Erik Skullerud, who together with his team, will share with you some of the project I just mentioned earlier. Erik Skullerud, please go ahead. Thank you, Jan. Also from my side, a warm welcome to all of you. It would have been great to have been in Oslo just like we were a couple of weeks ago, but as Jan just pointed out, there are a lot of issues on travel at the moment, so we're joining you from different places around Europe. There's a couple of us that are sitting in Switzerland, there's a couple of us that are sitting in Belgium, and some of us are sitting in London at the moment. Obviously, Dr. Gordon is sitting over in the U.S. It's really a global conference that we are about to embark on. I don't know how many of you there are, but we are equally happy to see all of you. As a matter of first giving you a little bit of a snapshot of the agenda, if I could have the next slide. We are obviously gonna go through quite a few things during the presentation. We're gonna start with. I will give you a couple of reflections on where I see us moving to as an organization, as a company. As you will know, I joined the company eight weeks ago. I've had a chance to thoroughly get familiar with the organization, with the people, and with the exciting pipeline that we have. I'll give a little bit of a background on where we wanna get to. We will then introduce Professor Leo Gordon, who will be talking about follicular lymphoma treatment, the treatment PARADIGME, and the unmet medical need. That will be followed on by our new incoming CMO, Dr. Pierre Dodion, who will also talk to you about the Betalutin program. This time we will tell you a bit more about our plans on Betalutin as a product, and eventually Betalutin as a pipeline of its own. Because I think it's fair to say that there are several indications that makes this asset really interesting moving forward. Marco Renoldi, my Chief Operating Officer, will share with you a program that we're in the midst of working on our commercialization and potential how we overcome barriers to success. It's a really interesting project in the sense that here we take first the U.S., but then also other countries, and we look at what are the barriers that we need to get across over and above your normal commercialization barriers. This is a really interesting project that we are collaborating with other big industry partners on. Lars Nieba will give you an update on how we're moving forward, both with our supply chain and our manufacturing. For those of you very familiar with biologics and radioimmunotherapies, you will know that the process that you bring these products through your manufacturing is just as important as the clinical development itself. After doing that, we will share insight. And we will also and then finally as the last part of the presentation jump into couple of presentation that will be aim towards our pipeline. Our CSO, Jostein Dahle, will do a part of this, and Maureen Deehan, our Head of Strategy and Business Development will also take you through each couple of assets. So I think we have a very interesting program ahead of us, if I could have the next slide. Just to share with you, first of all, this is our management team, and as you will recognize here, we have an extremely experienced a group of people that we're working with, they have been in large pharma corporations. They have worked with small biotech. Several of them has also worked as consultants and worked in top companies. A wide experience, both in number of companies and also the expertise. I'm really proud to be leading this group of people. Also today will be the first time, as mentioned, you will meet our incoming CMO. You'll see at the bottom here, Pierre Dodion. Let me also now give a big thanks to our outgoing CMO, Christine. Done a fabulous job for us, and we're really happy with what you have done, Christine. She is in the midst of a transition to Pierre. Next slide, please. First, a little bit of an update on PARADIGME. I've seen over the last couple of days quite a few questions from you online. Are we gonna give an update on PARADIGME and on the inclusion? I'm assuming that all of you will now be familiar with the program itself. This is what we have become famous for over the last couple of years. We have spent a lot of time on updating you, and you will see the study design in front of you. I'm not gonna go through any more than that. I am gonna use a little bit of time on the lower line here, where you see what we reported in our last quarterly call, 102 patients included or enrolled in the study. This is now 10 days or eight business days ago. Today, I'm able to add on to this, to this number, but let me spend a few minutes on just telling you a story around the last two weeks. We've had two patients that have been in later stage screening and inclusion, if you want, into the study in this timeframe. Both of these looked really good until approximately mid last week, end of last week. One of the patients in late screening fell through on one of the inclusion criteria, and as such, had to be dropped from the study. The second one, I'm happy to announce, is virtually being treated as we speak. They have their first medication happening in about 36 hours from now, and has been cleared through enrollment. The new number for us now is 103. That's one more patient included over the last eight business days. That is the status of PARADIGME. We will mention PARADIGME on a couple occasions in the presentations to come, but I think it's fair to say that today's focus is more gonna be around what are we doing, to Jan's point earlier, over and above. Next slide. The starting point of this is really our own proprietary CD37 platform. As you will be familiar with, this is something that we have worked on since the inception of the company. CD37 is a really important target in B cells, and for you to believe that this is a viable and an interesting strategy, let me make a couple of comparisons. On a B cell, which is basically the main attack point for cancer treatments in hematological cancers, you have CD20 and you have equal numbers of CD37 antigens. What does that actually mean? Well, if you believe that companies such as Roche, that has made a huge impact by understanding and developing the CD20 platform, if you believe that that is possible for others, I would suggest it's definitely possible for us. We're the leading CD37 company, arguably around the world at the moment. You see over that line, we have five different assets in our development, five different attack points, if you want, towards CD37 as a target, all with different attack points, attack angles, and different ways of altering or attaching, sorry, to the target, to the CD37 target. Obviously, Betalutin is the one that is the furthest on the development horizon. But during the presentations today, as I mentioned earlier, you're also gonna hear more about the other four, and we're gonna give you an update on where we are with them. Just to make it very short, Humalutin, the next one from the left, is a product that really fits very well into our life cycle thinking as far as Betalutin is concerned. This could be a fast follower in hematological indications. It has a slightly different backbone, and we'll speak to that in a second. It is a product that we have developed until IND stage. Alpha37 has the similar antibody as Humalutin, but a different payload associated with it. Jostein will talk both about Humalutin and Alpha37 a little bit later on. The last two over on the right-hand side here are, if you want, our two new babies. It is on the far right, the CAR T program that we announced just a couple of weeks ago. Maureen is gonna touch upon this program in much more detail a little bit later. We are super excited about this program. Why? Because we are, in this case, able to collaborate with arguably one of the most distinguished research institutions in the world, especially when it comes to CAR-T. This institution, University of Pennsylvania, were the ones that initially developed the CAR-T technology, licensed it out to Novartis, and is the base for the Novartis product the way that we see it today. The last of our assets is a pure humanized CD37 antibody, and this is in early stage development. We are really interested in how this is gonna take us forward, as this is a product that may give us also inroads into other indications. As you can see in the vision statement on top here, over and above what we have done so far in hematological cancer, we are also expanding this vision and including immunological disease or autoimmune disease as something we wanna focus on. Not only do we have five different molecules/assets in development, we also target wider disease areas as we move forward. It is pretty obvious that we cannot do this alone. Onto this strategy, we are also bolting on an additional development strategy, if you want, in the sense of seeking partners for these different molecules. You will probably be aware that we have such collaborations with Orano Med on Alpha37. As mentioned earlier, we announced the collaboration with University of Pennsylvania for the CAR-T molecule. We're actively looking for other partners as well in parallel with the commercialization partners, partnerships that we're looking at for Betalutin. This is something that we don't need to spend additional resources on, but we use what we have. Again, if you think about how much resource are we actually spending on this today, the vast majority of our resources is focused on PARADIGME and on Betalutin. That is where our priorities are, and that's what we have to deliver first. I hope you agree with me that the vision that I put forward to you right now is clear. It has a focused strategy behind it based on the CD37 platform. When we are successful in bolting on partnerships to this, it is something that is also gonna create future value for you as shareholders. Next slide. I'm not gonna spend a lot of time on this, because other speakers will touch upon this, in more detail. As you can see here from left to right, you have the same molecules, and from top to bottom, you have kind of how do you describe the different CD37 therapies that we have under development. If I could have the next build, please. Three of these are really based on our heritage radioimmunotherapy background. It is something that we are really good at. It also shows you that although we're starting from the CD37 attack point, we equally have a chance of adding on additional nuclear payloads on them as well. It also shows you from left to right that we are evolving the antibodies somewhat that we are using from a murine to a chimeric in these three boxes. Again, Maureen will touch more upon this in detail. What does that actually mean? You can also see here that we're using IV as the administration form for these three assets. Finally, they're mainly focused on hematology. Although arguably you could say that an asset such as Humalutin may also be used in immunological disease. For now, we have focused on hematology for the development of all of these three assets. Next, please. For the antibody, the humanized CD37 antibody, this will obviously be targeted towards subcutaneous use like most other antibodies. It will have a wider area that it could be used in the sense that here you have a product that potentially could be used in hematology but also in autoimmune disease. It can, it can also be used in addition to our other assets in hard to treat tumors. You could imagine, as a baseline treatment, Betalutin, for example, and then iterative treatments with an antibody to enhance the efficacy of the radiopharmaceutical itself. Finally, if I could have the last build. The CAR-T program, which again focused on hematology, and are also, I would say, cutting edge as far as, oncology/hematology, treatments are concerned. What we obviously hope here is to add value, for you as shareholders, but also to actually take the next step in development of CAR-T treatments. This is for us a next generation treatment when it comes to CAR-Ts. Again, Maureen will talk more about that in her presentation. Next slide. As a last slide before I hand over to Professor Gordon, I just try to depict here, where are we with these different programs. You are all aware of the third line development that we're doing for follicular lymphoma. The row below is the first step towards a Betalutin as its own pipeline, if you want. We obviously have shown interesting results from the ARCHER-1 study. We are currently talking to regulatory authorities for what we would need to do as a confirmatory phase III program based on our BLA approval for Betalutin in third line. That discussion is ongoing. Pierre will talk more about what that looks like and what we are doing moving forward. The next time we speak to the FDA is towards the end of first quarter 2022. We have plans that we'll share with you today around how we're moving forward on our DLBCL strategy. You have both programs, the additional two radioimmunotherapies here, both Humalutin and Alpha37, both of them targeted in towards other NHL indications. There we are now, Humalutin is already at the pre-IND stage. We are just finalizing the final steps for Alpha37 as well in the same frame of getting this to a pre-IND stage. I've just shared with you some of the top-line details for the humanized antibody as well as the CAR-T program that we are embarking on with the University of Pennsylvania. With that, I will stop and I will introduce Professor Leo Gordon to you. We're very, very honored, Professor Gordon, that you have been willing to spend your time with us today. For those of you who don't know Professor Gordon, I think most people online would be familiar with your background. He is an Abby and John Friend Professor of Cancer Research, a professor of medicine, a co-director for Hematological Malignancies Program at the Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine in Chicago. We're very honored to have you here, Dr. Gordon. Thank you for taking time for this, and floor is all yours. Thank you so much. It's a pleasure, it's an honor to be with you. Can I have the first slide? Thank you. My task today really is with the treatment algorithms in patients with relapsed follicular lymphoma, and to really kind of find perhaps a niche or find an unmet medical need for those patients. Can I have the next slide, please? In order to do that, I thought it would be worth discussing a little bit with you some features of follicular lymphoma, talk a little bit about the incidence of this disease, where it fits in the spectrum of the non-Hodgkin lymphomas, in the spectrum of the B-cell non-Hodgkin lymphomas. Talk a little bit about how one makes the diagnosis, going about making the diagnosis under the microscope, and at the bedside. Talk a little bit about certain biological features which might be important and might predict for a favorable or an unfavorable course. That has a lot of impact, I think, on, you know, where we go with second and third line treatments and whether when and if to expect the need for second and third line treatments. We're gonna talk about management algorithms, clearly for relapse patients in second and third line, but I thought it would be important at least to review with you some of the first line options because the first line options sometimes there are many choices for first line options, and they will impact what we do in second and third line. I will try to focus somewhat on patients who are a little bit older or might be too frail for very intensive therapies or for some of the newer treatments that I'll also mention, CAR-T, stem cell transplantation, things of that sort. I'll talk a little bit about the evolving landscape, what else is out there, what's going to be there, and focus on some recently approved agents, perhaps, PI3 kinase inhibitors, which are being used more and more in patients with a follicular lymphoma. Next slide. This, on this slide, you know, this is sort of a pie chart of where follicular lymphoma fits. We can see that it's probably the second most common type of B-cell lymphoma. We estimate probably closer to 80,000 cases of non-Hodgkin lymphoma in the United States in 2021. Most of those are B-cell non-Hodgkin lymphomas, and this is the sort of, for the most part, the pie chart representing the B-cell lymphomas. Diffuse large B-cell lymphoma, DLBCL, is the most common type. Follicular lymphoma makes up maybe 22%-25%, maybe a little bit more now, of the B-cell lymphomas. Some of the discussion we'll have, although we're focusing on follicular lymphoma, many people feel, and I'm among those, that patients with marginal zone lymphoma, although maybe a somewhat different biology and has very similar presentation and the treatment algorithms for marginal zone lymphomas, over the years have mimicked the treatment algorithms for follicular lymphoma. Some of the things that we do in follicular lymphoma may also apply to a marginal zone lymphoma. Next slide, please. As I mentioned, it's the second most common lymphoma in the United States. We have grades which are determined by what the cells look like or what the biopsy specimen looks like under the microscope. I will say that the recent practice of making diagnosis by fine needle aspirates or even by small core biopsies has limited our ability to make accurate diagnosis, and that's something, while very popular, at least here in the U.S., in hematology oncology, along with our pathology, hematopathology colleagues, that's something we kind of try to discourage as much as we can. We often have to repeat biopsies in patients that are seen in consultation for second or third opinions. The grading can be difficult, and that's why we need more tissue and needs hematopathology expertise. I think I would not say may need, but I think does need hematopathology expertise in review. We think of Grade 1, 2, and 3A lymphomas as the indolent type, the type that we'll talk about today. The follicular Grade 3B, we tend to view as similar to DLBCL, the diffuse large B-cell lymphomas. That sort of sets it apart as a different category. While we will say that advanced stage follicular lymphoma is not curable with the standard therapy, this is a disease that people can live with. They may lead a normal lifespan with follicular lymphoma and may die of other disorders or other causes. In many ways, when I, at least when I discuss this with patients that we're seeing, I might compare this to diabetes or compare this to other chronic disorders. They may not be life-threatening. In fact, when we see people for the first time, when the diagnosis is often made incidentally on a CAT scan that's done for other reasons or by physical exam on a routine visit, we stress the fact that this is something that actually may not need intervention right away. Can I have the next slide, please? This is from the NCCN guidelines, which we put together every year and in fact update many times a year. This just gives us some clinical features that we're using for prognostication. There are two major criteria that are basically determined at the bedside, the so-called GELF criteria, which was developed in Europe. It was developed for clinical trials for the now the LYSA group. Basically, these were eligibility criteria for clinical trials. I think this has begun to be used or has been used over the years as a way of predicting perhaps a worse outcome, and maybe our specific indications for treatment. I don't know that we use them that way all the time, but there are features there that I think are important. The number of nodal sites, the involvement of the number of lymph nodes that are involved, any nodal or extranodal, that means a mass outside of a lymph node greater than 7 cm, often is an indication for treatment. The presence of B symptoms, so fever and sweats and weight loss. The presence of a large spleen, although I will say that we see many patients who have a large spleen who don't necessarily require treatment. The presence of pleural effusions, fluid in the lung or peritoneal ascites, fluid in the abdomen, might be an indication of treatment. Cytopenias, a low white blood count or a low platelet count, related either to the large spleen or to infiltration of the bone marrow. The presence of malignant cells in the peripheral blood, and many people view as an indication for treatment. Although I will say that we follow the patients for many years, sometimes with some cells in the peripheral blood. If we do flow cytometry, many patients will have abnormal cells in the peripheral blood, and that by itself does not mean that they absolutely need to be treated. These are some of the criteria that are used. The so-called FLIPI criteria developed by my colleagues in France with different iterations of this. Age greater than 60, Ann Arbor stage greater than three or four, that is more advanced stage disease, hemoglobin level, anemia less than 12, an LDH, lactic dehydrogenase level, which I find very useful and important in management of patients with both large cell lymphoma and follicular lymphoma as an indicator of more aggressive disease. When that is above the upper limit of the laboratory normal, that is a negative prognostic factor, greater than five lymph node sites. If you can see the right part of this chart, it gives you some indication of the lymph node areas and how to measure those. I will say that although the FLIPI criteria are extremely useful for clinical trials, at the bedside, it's not commonly used, I think, to sort of make decisions about treatment. I think we tend to use a gestalt, I would say, which includes many of the FLIPI and GELF criteria, but I don't think that most people are charting the number of lymph node sites at the bedside to make decisions about whether patients need intervention or not. Next slide, please. This gives you some idea of what I talked about earlier about the grading. Basically, the grading of this disease is determined by how many large cells are present. The more large cells that are present, the more like large cell lymphoma this is, and the more aggressive it might be. You can see follicular Grade 1 and Grade 2 with small numbers of large cells, Grade 3 A on the bottom, on bottom left, and Grade 3 B on the bottom right, gives you an indication that if there are sheets of large cells, the more large cells, the more it's tending toward large cell lymphoma. We tend, as I mentioned, to treat Grade 3 B as we treat large cell lymphoma. Most of the discussion that we'll have today has to do with follicular Grade 1, Grade 2, and Grade 3 A. Next slide, if I may please. This is how the diagnosis can be made with immunophenotyping, that is, specialized flow cytometry techniques that are used to distinguish follicular lymphomas from some of the other B-cell lymphomas. There's two antigens which are really helpful, CD5, cluster designation five, or CD10, helps us make that distinction. Patients who have a CD5 positive disease tend to be more likely to have mantle cell lymphoma or chronic lymphocytic leukemia, small lymphocytic lymphoma. Patients who have CD10 are more likely to be a diagnosis of follicular lymphoma. CD10 is an antigen that's present in the germinal center of the lymph node, and the germinal center of the lymph node is where we think that follicular lymphoma originates. These are helpful, and I won't go into any more detail about these, but I think the diagnosis, although it can be tricky sometimes, with an experienced hematopathologist with an adequate amount of tissue, this diagnosis can be made pretty readily. Can I have the next slide please? This is just like a very, you know, high, if you will, aerial overview of what our, some of our goals are. We'd like to, if we decide that patients need treatment, and I will say, probably maybe as many as 50 or 60% of patients that we see initially don't necessarily require treatment because they're not symptomatic, they don't have bulky disease, they don't have any of the criteria that I just showed you. In those patients who do require treatment, the goal is to get a good quality remission. If we can get a complete remission, that would be ideal. To reduce the tumor load and induce an initial response, to maximize that response by sometimes using some kind of consolidation. A fairly controversial area in hematology oncology is whether patients with follicular lymphoma should have maintenance treatment or not. That's. I'll show you some data on that. That's a, it's an evolving discussion, and actually, I'll show you some in a minute, has been impacted quite a bit by the pandemic, by COVID. Next slide, please. These are data from Gilles Salles, from France, now in New York at Memorial Sloan Kettering. These are the data from the so-called PRIMA study. The primary endpoint of this was three years, and the study was basically randomizing patients who were treated with chemotherapy up front for follicular lymphoma, randomized one to one to receive a maintenance treatment for two years with Rituxan given every two months versus observation. If you look at the progression-free survival endpoint at three years, there's clearly a statistically significant difference at say 36 months between Rituxan maintenance and observation. This has led to a fairly widespread use of maintenance therapy. What this study did not find, however, was is there a difference in survival? Up till now, there has not been a difference in that trial in survival in patients receiving maintenance therapy. Next slide is a meta-analysis published by Vidal et al in the European Journal of Cancer in 2017. With all the caveats of meta-analyses in place, I will say that they did find, if you look at sort of the left graph, an improvement that was seen at about six or seven years in overall survival in those patients who received maintenance therapy in green compared with those who did not in red. Quite a bit of debate. I will say that the pandemic has made a major impact on the decisions for maintenance therapy. Just some point of interest, we know that a patient who has COVID, normal individual gets infected with COVID in about 20 days will clear if you do multiple PCR swabs. Patients on Rituxan take 100 days to clear. While Rituxan is among the safest drugs that we use in oncology, when it comes to COVID, it's probably one of the most dangerous drugs that we use because it limits our B-cell immune response. We have adjusted, I think, at least in the U.S., and I think this is true around the world, decisions about maintenance treatment, and we have been more reluctant to recommend maintenance treatment if there's not gonna be a major difference in overall survival. We have even adjusted our decision-making about when to initiate treatment. I think we've moved that sort of line that we cross about needing treatment over to the right in the era of COVID. That's I think something important to remember. Next slide, please. These are we get to update these, as I mentioned, NCCN guidelines, and sometimes I find it hard to follow the algorithms in the NCCN guidelines myself. This is just another way to look at it. If you look at the top, there are some patients who present with early stage disease, say a single lymph node or a lymph node area. In general, the recommendation has been those patients should be treated with radiation, involved site radiation, because data from the Princess Margaret Hospital in Canada suggests that if you wait 10 years, you follow those patients, 50% or 60% of them may still not have recurrent disease. We think that radiation might be curable in a group of patients with very early stage disease. Anytime I mention radiation, obviously we always think about how this could translate to radioimmunotherapy. Radiation, involved site radiation, I think is important. Some people might use immunochemotherapy with Rituxan or perhaps chemotherapy with or without radiation. I think that's reasonable, but I think in really truly early stage disease, radiation is probably the preferred treatment. You might, however, observe patients if the radiation would involve an area that might not be amenable to or safe to give. I'm not sure I would necessarily give somebody with a mediastinal behind the sternum presentation involved site radiation for stage one disease. Those patients might be observed. If the disease then progresses in the yellow vertical bar here, then they can progress either without transformation, they may stay follicular lymphoma, or they may progress with transformation in the green box on the right. If they're transformed to large cell lymphoma, you know, overall, about 30% of patients will transform to large cell lymphoma if followed long enough, clinical trials, chemo. Those patients should be treated as large cell lymphoma, clinical trial, chemotherapy with rituximab, possibly with radiation. Those patients are candidates perhaps for a allogeneic or autologous stem cell transplant or even now CAR T therapy with the three agents that are now approved in large cell lymphoma. If patients have either bulky stage two or more commonly advanced disease stage three or four, as most patients with follicular lymphoma present, if you look at the brown box on the left, and then the brown box in the middle, clinical trials, of course, if clinical trials are available. Bendamustine and Rituxan has, I think, replaced R-CHOP. Rituxan and CHOP chemotherapy is the most commonly used regimen in follicular lymphoma, based on the data from the German studies. Rituximab alone, probably my most commonly used regimen in patients who might need treatment and have stage three or four disease. The R² regimen, that stands for Rituxan and Revlimid, Lenalidomide and IMiD, which is active in this disease, and sometimes local radiation, and then, I think most commonly, observation. I will say, once you've made the decision to treat, that's when we talk about whether we should do maintenance or not. There were data from actually my colleagues from the Netherlands in the early FIT trial using radioimmunotherapy as consolidation, using Zevalin as consolidation. This is a discussion of Betalutin. I'll say, and I'll say this many times, whenever I mention radioimmunotherapy, it's a bit of a pipe dream because we don't have radioimmunotherapy anymore. Zevalin is, at the least at the moment, not available, at least in the U.S., and I don't know if and when it will become available. Either consolidation or extended dosing maintenance therapy with Rituxan, with the caveats that I mentioned during COVID. If we look at the bottom left in the gray box, elderly or patients who we don't think can tolerate aggressive chemotherapy may be treated with Rituxan alone. That's a commonly used regimen. That would be my probably first-line treatment for the most part, chlorambucil or Cytoxan, these are oral, can be oral alkylating agents, or perhaps radioimmunotherapy. If we had it, there were data from the group at University of Michigan with I-131 radioimmunotherapy where that was given safely and with excellent results. That's not available either. That's a general overview. Can I have the next slide? I wanted to focus on the patients who we didn't think were candidates for aggressive treatment, just to hone in on this. Rituxan or which is again my first choice, chlorambucil or radioimmunotherapy if were available, that can be followed by either observation or Rituxan as a maintenance treatment. If patients then progress, either after just their initial induction therapy or after a maintenance therapy, once again, they can progress with transformation. I think a rebiopsy with a good sample of tissue and not a fine needle aspirate, but a biopsy, can make the distinction most of the time between transformation to large cell lymphoma, DLBCL, or just progression with follicular lymphoma. If they're transformed, then we should be treating them like large cell lymphoma. If they're not transformed, then we have some options. Some of the things that we didn't do in first line, or we thought we couldn't do in first line, we might begin thinking about now doing in second line. Rituximab, lenalidomide or Revlimid and Rituxan or R². Once again, radioimmunotherapy if it were available. Possibly PI3K inhibitors, local radiation or sometimes best supportive care. If they don't respond or progress at that point, really that is an unmet need, and I’d even say the first relapse is an unmet need. Shall we think about resurrecting radioimmunotherapy? Shall we think about radioimmunotherapy in combination? These are patients who might not be candidates for something like CAR-T therapy, although we've seen in recent data that patients who are older, say over 65, and treated with CAR-T have a similar outcome with similar toxicities to patients who are younger. I think it's not out of the question, but more difficult. Next slide. Just to go over once again for first-line therapy, bendamustine-Rituxan, Rituxan-CHOP, Rituxan with CVP, basically CHOP without the adriamycin, Rituxan and Revlimid, R squared, or obinutuzumab, which is a different monoclonal from Rituxan, probably maybe with a little bit more efficacy in chronic lymphocytic leukemia, and a suggestion based on some recent data that it might have more activity than Rituxan, actually, together with lenalidomide. For patients again who may not be able to tolerate Rituxan alone, chlorambucil and Rituxan, and possibly radioimmunotherapy. Next slide, please. Consolidation or extended doses, Rituxan maintenance with the caveats, obinutuzumab maintenance, as in the so-called GALLIUM trial, where it was given after a chemoimmunotherapy, obinutuzumab was given for two years of maintenance. Other options, a shorter maintenance course. In Switzerland, they did the initial Rituxan, then the Rituxan every eight weeks for four doses. Basically a shorter course of maintenance therapy. Next slide. I think one thing to point out about second-line treatment, there have been some recent data that sort of substantiated I think most investigators feeling that if patients relapse within 24 months or early after their initial treatment, the outcome may not be as good. And that's been confirmed in a trial that Carla Casulo published from sort of a data analysis of a large data subgroup of patients, and then was substantiated by the Mayo Clinic group, that patients who have progression of disease at 24 months, or the so-called POD 24, have a worse outcome. In general, second-line treatment is whatever wasn't done in first line. If you gave R-CHOP first line, then bendamustine-Rituxan, if you gave bendamustine-Rituxan, then R-CHOP, or R-CVP or Revlimid and Rituxan, possibly Revlimid and obinutuzumab. In more frail patients, single agents, I think is the order of the day. Rituxan alone, obinutuzumab alone, chlorambucil alone, Cytoxan alone, or possibly, again, radioimmunotherapy alone as a single agent. Next slide. This represents the current thinking and state-of-the-art, if you will, for the POD 24 group. These are patients or that I mentioned who relapse within 24 months. There is a large intergroup trial led by the Southwest Oncology Group comparing either obinutuzumab, the alternate monoclonal anti-CD20 monoclonal antibody, with CHOP if patients had prior bendamustine, and with bendamustine if patients had prior CHOP. The second arm is umbralisib, one of the PI3K inhibitors we'll talk about in a moment. The third arm is Revlimid, the IMiD, plus obinutuzumab. Just to remind you, I've talked a little bit about Revlimid, where that came from. Revlimid is an IMiD. It's, you may be familiar, you probably are familiar with its cousin thalidomide, which was used in the 1950s and 1960s as a sleeping aid and led to birth defects, significant birth defects. It was kind of obviously put on the shelf for many years, but resurrected again as Revlimid, as thalidomide, and then the 2018, 2019, 2020 version, lenalidomide. What was forgotten about thalidomide early on is that it had major immunologic effects, enhanced T-cell function, and had effectiveness in B-cell disorders. That's why it's used, and it's a very active agent. This is the current landscape of POD24. Next slide is talking about landscape. This is basically gives you some rough estimate, we won't go into these in any detail, about some of the agents that are being either approved or in the pipeline for follicular lymphoma after second line. These include some of the bispecific antibodies. It includes some third and fourth generation BTK inhibitors, Bruton tyrosine kinase inhibitors, which would seek to improve upon the results with ibrutinib, which is down on the bottom left in a red dot on the slide with only about a 30% response rate. Disappointing response rate in follicular lymphoma. I think people are trying to look at the next generation of BTK inhibitors to see if we can improve the response rate. This gives you some idea of what's being tested. What's approved is in blue and pipeline therapies are in red and in orange. Next slide. Third line and subsequent treatment, PI3 kinase inhibitors, copanlisib, duvelisib, idelalisib, and umbralisib is fourth line. I'll talk a little bit about those in a moment. The EZH2 inhibitor, tazemetostat. It's approved now by the FDA in third line, if patients have the EZH2 mutation, that can be relatively easily tested for on tissue specimens. Interestingly enough, in an unusual FDA approval, if patients are wild type, not mutated, the clinician has the option to use this drug if they determine that there are no other options for treatment. How that's defined, I think, is fairly loosely, obviously in the eye of the clinician. Basically, I think tazemetostat is available and approved for anybody with follicular lymphoma whom the clinician feels there's no other good options. Then CAR T therapy based on data from the ZUMA-5 study, which I'll show you in a moment, axicabtagene ciloleucel or Yescarta, is now approved in the U.S. by the FDA for follicular lymphoma and certainly has some promise. Next slide. We'll go to third line approved and pipeline therapies, a similar matrix with ibrutinib now being tested together with the checkpoint inhibitor nivolumab on the bottom left, and then some of the other drugs, the PI3K inhibitors I mentioned, duvelisib, umbralisib, idelalisib. On the right part of the slide, you start to see some of the CAR T agents. The allo agents are now. People are beginning to look at off-the-shelf allogeneic CAR Ts. You know, I would say, not necessarily for elderly or infirm, but these are patients that might go to a transplant if they're younger and healthier. The allo CAR Ts and the autologous CAR Ts may be reasonable options for those patients, even older patients. Next slide. The PI3K inhibitors, the first generation, idelalisib, second generation, umbralisib, and another experimental drug. The dual PI3K inhibitor duvelisib are the ones we'll touch on briefly. The next slide. Umbralisib is inhibitor of PI3K delta and casein kinase 1 E, and a difference in structure and other characteristics from idelalisib and duvelisib, which are approved in follicular lymphoma. This is the most recently studied and generated quite a bit of excitement. Next slide, we'll show you the study that generated that excitement. The issue is that this drug has to be given until unacceptable toxicity or in the study, of course, withdrawal of consent. The primary endpoint was safety. The maximum tolerated dose and some PK pharmacokinetic data. Secondary endpoints were what we're all interested in, overall response rate and duration of response. I will point out something. If you look at the bottom of the slide, this I'll bring up as we talk about these in a minute. Infection, Pneumocystis jirovecii prophylaxis was permitted but not mandated. I think it should have been mandated. The next slide gives you a waterfall plot of the responses, and you can see, and if you focus on the pink in follicular lymphoma, you can see that there were reasonably good responses, better than 50%, say, in a significant number of patients, but most of the responses were between, you know, 5%-50%. Not really quite meeting the mandate for at least a partial response. Next slide. This summarizes some of the PI3 kinase inhibitors, the competition, if you will, or some of the competition for radioimmunotherapy. It's given daily, orally, but Grade 3-4 hepatotoxicity is reported, diarrhea and colitis in about half the patients, more than half the patients. About 10% of patients had Grade 3 or life-threatening neutropenia, skin reactions in a small number, but 10% of patients had PJP or cytomegalovirus infections. I would advise that everybody on these drugs should be on PJP prophylaxis with Bactrim at least, and should be checked on a monthly basis for an activation of cytomegalovirus infections, just like we check our allogeneic bone marrow transplant patients. These drugs interact with CYP3A inhibitors, so there's a fair number of drug interactions that we have to be aware of with this drug. Next slide. Duvelisib, similar. It's twice-a-day dosing, but hepatotoxicity, diarrhea and colitis, pneumonia, skin reactions, infections, again, with PJP and cytomegalovirus. Again, concerns about the use of concomitant drugs which are CYP3A inhibitors, for example, azoles. If you look, there are many, many drugs over the counter that are CYP3A inhibitors that can interfere with duvelisib. Next slide. Copanlisib, recently presented, published by Martin Dreyling from Munich, with exciting data, except this is a drug that's given intravenously on day one, eight, 15, and then every month. Well, actually, three weeks out of every month forever. So it's an IV drug given every three weeks out of four forever until progression. Hyperglycemia is an unusual, and hypertension are unusual complications, but again, infections with PJP and cytomegalovirus, and again, interaction with certain other drugs. The activity of this is 50%-60% responses and maybe 30% complete responses. When people... I've been in meetings where people take a poll of what would be your choice of agent for relapsed follicular lymphoma. Everybody says PI3 kinase inhibitors. Then everybody says, "Well, what would be your choice if you didn't have to give it for the life of the patient on an IV basis three out of four weeks?" I would say radioimmunotherapy. Next slide. Histologic transformation. I mentioned earlier these patients can transform, and they may be candidates for CAR T therapy. We'll finish in just a moment. I wanted to highlight this a little bit because I think this is here to stay, and I think exciting data. The chimeric antigen receptor, which is where CAR comes from, is basically mimicked after the normal T-cell receptor. This has evolved. If you look at the right side of the slide, the scFv is the place where the I think the next slide. I'm sorry. Yeah. This mimics the T-cell receptor. The chimeric antigen receptor on the right, the scFv is the place that recognizes the target antigen, for the most part, CD19, but studies now with CD20, CD22. All of the approved drugs are CD19-targeted, and follicular lymphoma is ubiquitously positive for CD19, so a perfect target. People are now manipulating the costimulatory signal in yellow on the right, whether it's CD28 or 4-1BB or OX40, impacts on how active this construct will be. Next slide. I wanted to show you the data on ZUMA-5. These are data that Caron Jacobson from the Dana-Farber presented recently. If you look at the overall response rate, 76%, 92% overall response rate in 104 patients. If you look at the follicular group, it's very similar. This is all patients. It's made up follicular and marginal zone. In the middle part of this graph, follicular lymphoma, 84 patients, 80% complete remission rate, 94% overall response rate. Excellent data. Next slide. The duration perhaps is not as good as we'd like. It starts falling off at about 10, 11, 12 months. The advantage of this treatment, just like radioimmunotherapy, is that it's a one and done. It's a one-time treatment, and there probably are some patients that are gonna be cured, we hope, by this approach. I think this is here, and I think it's actually since there are preclinical data suggesting synergy between cellular therapy like CAR T and radiation, I would envision some trials where radioimmunotherapy might be combined with CAR T therapy. Next and last slide. This is just what we saw earlier. we tried to do is talk about the incidence of this, the diagnosis, a little bit about the biology, and talk about first, second, and third line treatment with a bit of a focus on patients who were older and perhaps couldn't tolerate more aggressive treatment. The evolving landscape, I think many agents out there. I certainly think, doing this for many years now that there's a role that has been missed for radioimmunotherapy either as a single agent or perhaps in combination with other agents. And some of those might be the recently approved agents, such as CAR T therapy. I wanna thank you for your attention, and I appreciate the opportunity to talk about this. Thanks very much. Thank you so much, Dr. Gordon, for that highly educational and interesting presentation. I know you have patients to tend to. You have your rounds, so we'll not be able to do a Q&A today, but really appreciate your insights. Thank you so much. Thank you very much. I appreciate the opportunity. Next we'll let our new incoming CMO, Pierre Dodion, give you some insights around our program on Betalutin post third-line FL. Pierre, I'll let you take it from here. All yours. Thank you very much, Erik. While we are loading the slides, I would like perhaps to express the privilege to be able to speak to all of you. As you know, I joined the company relatively recently, and I'm really impressed by the number of activities, interesting activities that have been conducted and that will be pursued in the future. I'm looking forward to collaborating with all of you, with my colleagues at Nanovector, and also of course with the investigators who are participating to our clinical program. My task this afternoon will be to evaluate the potential of Betalutin beyond what we are already doing, i.e. The PARADIGME program which as you know is conducted in the third line setting in follicular lymphoma. If you move to the next slide, please. This is a schematic conceptual cartoon trying to illustrate where we could go. The blue box represents symbolically the current activities in third line follicular lymphoma, and one expansion pathway is quite clearly to go to earlier lines in the treatment PARADIGME, first and second line, but also possibly down the road in the first line setting. On the other side, we could also expand and this is shown by the curve pointing to the right top corner. We could expand to diffuse large B-cell lymphoma, DLBCL, starting with advanced disease, i.e. patients in the third line setting. We are going, nothing prevents us to expand further to earlier stages DLBCL. Of course, DLBCL has a special place in the overall landscape of non-Hodgkin lymphoma because, as indicated conceptually by the slide, this is the largest non-Hodgkin lymphoma subtype. Finally, nothing prevents us to move as well to smaller indication. I'm representing here the particular case of, among others, but the particular case of marginal zone lymphoma. Let's address first follicular lymphoma. If I can have the next slide, please. Then the next one. Can we move to the next slide, please? Very good. Thank you. I'm sorry, could you go backward by one slide? Great. Thank you. We are focusing our interest on, in terms of clinical development, on the patients in the second line setting and more specifically on frail patients. This has been discussed in details by Dr. Gordon, but typically those patients, elderly patients with comorbid conditions, typically do not tolerate aggressive treatments like combination chemotherapy, and very often are treated with single agent treatment, in particular, single agent rituximab. What I'm showing here is that single agent rituximab for these patients is not at all a bad option. If you look at the efficacy data, on the left side, you can see a complete response rate of 5%-15%. A median progression-free survival of approximately 14 months. It does work to some extent, but clearly there is ample room for improvement. The curve on the right side is an illustration coming from one of the most important study in this field, testing single agent rituximab in red versus a combination of rituximab plus lenalidomide, the so-called R² program, which was presented by Dr. Leo Gordon in his presentation. Next slide, please. The other attractive feature of rituximab is that overall, this is a well-tolerated drug. You have in the top part of the slide, a list of adverse events that can be induced by rituximab, things like infusion-related reactions, fever, lymphopenia. The most important point is that in the vast majority of the cases, up to 90%, these events are actually mild or at times moderate. At the bottom of the slide, I'm also drawing your attention, as it has been done by Dr. Gordon, to the fact that besides rituximab, there are other single agents that are being used in that setting. For example, chlorambucil with or without rituximab, cyclophosphamide with or without rituximab, and obinutuzumab, et cetera. In summary, rituximab does work and is certainly used in these frail patients in the second-line setting. It is reasonably well-tolerated, but there is clearly ample room for adopting better treatments. If we move to the next slide, we have at Nanovector piloted the combination of Betalutin plus rituximab in this patient population. This has been performed within the so-called ARCHER-1 study. We are talking here in terms of patient population of patients with follicular lymphoma, who have received at least some of them more, but at least one prior regimen, and with the primary objective to evaluate the safety and tolerability of the combination of Betalutin plus rituximab. Of course, we have also looked at a secondary objective to preliminary anti-tumor activity. In the middle of the slide, you have the study scheme. In the middle box, you can see the administration of Betalutin preceded and followed by rituximab as per the FDA-approved regimen, and then followed by continuation rituximab in those patients who achieve at least stable disease or partial response or complete response. The results of that study are summarized at the bottom of the slide, and actually, we have generated quite attractive data with actually all the seven patients achieving a response. This includes five complete responses. Not bad at all for a population of patients with resistant disease. These responses seem to be quite long-lasting. six patients have still an ongoing response. Out of these, five patients have passed the two year or 24-month assessment. Furthermore, the combination of Betalutin plus rituximab showed actually a very good safety profile, not really different from that of single-agent Betalutin. The data suggests a pretty good, a pretty attractive level of activity with an excellent safety profile. Quite obviously, these results play an important role in forming the design of our confirmatory phase III study in follicular lymphoma. Coming to that particular study, if we can move to the next slide, please. We have been evaluating several options for the next phase of the clinical development of Betalutin in patients with follicular lymphoma in the second-line setting, and more specifically in failed patients who are not eligible for aggressive therapy. For those who are curious, you can see at the bottom of the slide a partial list of these aggressive treatment options. These are pretty much identical to those mentioned by Dr. Gordon. You can see they are CHOP with or without rituximab, the combination of bendamustine, et cetera. If one consider all patients in the second-line setting, some of them will be eligible for these aggressive treatment regimen, but many others will not. These patients not eligible for aggressive therapy are those who will be randomized in our study between rituximab alone, the standard of care, and the combination of rituximab plus Betalutin. The primary endpoint is likely to be progression-free survival. The beauty of this approach is that this program will serve, number one, as a confirmatory randomized trial as part of the possible post-approval commitment that we might receive from FDA in a third line setting based on the PARADIGME study results. As I said, it will also constitute a data set that could lead to the approval of Betalutin in combination with rituximab in the second-line setting. That realizes typically the label expansion that I was talking about in my introduction. As mentioned by Erik in his introduction, we are in close contact with regulatory agencies, in particular with the FDA, to finalize the various elements of this study design. More to come, but suffice to say that we are very excited by this approach. Next slide, please. Let us turn ourselves now to DLBCL or diffuse large B-cell lymphoma. Next slide, please. Just a quick reminder, as already mentioned, DLBCL is the most common form of non-Hodgkin lymphoma. It's about 30% of the non-Hodgkin lymphoma, at least in the U.S., are DLBCL. It is typically an aggressive form of lymphoma that involves the lymph nodes as well as other organs. I'm not going to go into the details of the treatment of DLBCL. Suffice to say that for newly diagnosed patients, the goal is truly to cure them. This is typically achieved by a combination approach combining multi-agent chemotherapy, the so-called CHOP regimen, combined with rituximab. Many patients also receive high dose chemotherapy followed by stem cell transplantation. Unfortunately, many patients despite this aggressive treatment still relapse and move to the so-called second and third line setting. Despite many years of clinical research, the treatment of these relapse patients remains a challenge. Therefore, this group of patients is a significant unmet medical need. You have at the bottom some indication about the commercial opportunity for second- and third-line DLBCL, and you can see that this is by no means a small group, about 23,000 patients per year for second line, 11,000 patients per year in the third line. These are the data for the six key markets, EU five and the U.S. That is approximately 50% more than the market of second-line follicular lymphoma. That is just to show you the importance of the DLBCL patient population. Next slide, please. This is intended to give you a very brief snapshot of the treatment approach for DLBCL as Dr. Gordon focused mainly on follicular lymphoma. As I said, on the previous slide, the first-line treatment is typically a combination of chemotherapy and rituximab. In the second-line setting, there is a quite long list of agents with relatively poor activity. This may be changing now with the introduction of newer agent, but it remains also an area of very intense clinical research. I will show you in a moment, some recent data about two particular classes of newer agents. In a third-line setting, the situation is even worse and is typically an area of clinical research. Next slide, please. I'm sure that many of you have heard about CAR T-cell therapy bispecific antibodies. I'm mentioning these two classes because they represent examples of treatments with, yes, quite substantial activity. If you look in the middle of the slide, you can see there the objective response rate, the complete response rate, progression-free survival data, overall survival data. You know, when one is talking in refractory patients or relapsed patients about complete response rate of 40%-50%, two year survival of 50%, one cannot deny that this is indicative of pretty good activity. However, at the same time, the toxicity of these agents is quite substantial. This is featured in the bottom part of the slide. Grade 3-4 toxicity of various sorts, cytokine release syndrome, neurotoxicity, infection, neutropenia. You can see that virtually for all of these, we are talking about ranges between 5% and 20%. Accessibility may also be an issue. These treatments are not necessarily given in every single medical center. And also the financial burden in terms of acquisition costs may be quite tremendous. I'm sure that you've all heard about the cost of CAR T-cell therapy. Now, you may perhaps remember what Dr. Gordon said about a third class, i.e., the PI3K kinase inhibitors. In fact, I could have easily added a third column about the PI3K kinase inhibitors as a class because it's providing pretty much exactly the same picture. Some very good activity, but also quite substantial toxicity. Quite obviously, yes, one would wish to be able to administer these treatments to every single patient in a third or second-line setting, but the reality is that elderly patients are simply unable to tolerate these quite aggressive treatments. Next slide, please. It's just providing more details about what I said as an overall approach. I'm not going to spend too much time here. Fundamentally, in the second line setting, you can see that there is now one combination that has been approved, tafasitamab plus lenalidomide combination. CAR T-cells are moving along as well as bispecific antibodies. Clearly there is still a need for better combination therapies, and very importantly, that have an acceptable safety profile, especially for frail patients. In the right column, I'm providing data on the third-line setting. Again, some information about CAR T-cell treatment that we already discussed. Some information about drugs called polatuzumab and rituximab. Bottom line is that again, these refractory patients, particularly in the third-line setting, may very well represent a unique and very attractive spot for Betalutin, especially in elderly and frail patients, and therefore provide us a way to enter the DLBCL segment. Next slide, please. Just like in a follicular lymphoma. May I have the next slide, please. Previous one. There is apparently. Yeah, thank you very much. We have also initiated clinical activities in the field of DLBCL. This particular study is named LYMRIT-37-05. In fact, we have performed a phase I study in 18 patients with relapsed or refractory DLBCL patients. 16 of them were evaluable, with the goal, quite obviously, to investigate the safety profile, determine the maximum tolerated dose in these patients, and also to detect initial signs of activity. You have the kind of dosages that we explored as part of this study in the four boxes that are displayed on the slide. Next slide, please, is actually showing the critical results of that study starting from the bottom. Importantly, we have been able indeed to establish recommended phase II dose. The exact numbers for lilotomab and Betalutin are indicated on the slide. In terms of safety and tolerability in the right top corner, we found that Betalutin is actually very well tolerated and compatible in a consistent manner with all previous studies. Then finally, and importantly, as illustrated in the left, top corner, we did see interesting clinical activity. In particular, we reported two complete remissions at two highest dose levels. Again, considering the kind of patients, resistant, refractory DLBCL, we view that as a very encouraging. Next slide, please. Where do we go from there? Well, one very attractive option in our mind is to combine Betalutin with other agents. This also led to successful development for some other drugs, three of which are listed on this slide. Tafasitamab on the top, polatuzumab in the middle, and rituximab at the bottom. You can see in the middle the kind of efficacy data achieved with single agent, and we are showing here the overall response rate 26%, 56%, and 22% respectively. Then on the right, you can see the clear increase in terms of activity when these drugs are combined with partner drugs. In particular, tafasitamab with lenalidomide, polatuzumab with rituximab and bendamustine, and finally, obinutuzumab with rituximab, leading to response rate of 60%, 63%, and 50%. At times more than the double of the response rate achieved with the single agent. If we move to the next slide, we, I think based on all those considerations, that the most important, the most attractive option is to explore a combination of Betalutin in a third-line setting in the form of an exploratory phase II study. To be complete, we have explored other options, in particular, escalating the dose of Betalutin further, which by the way, could be actually achieved as part of the proposed phase II study or exploring a Betalutin as a consolidation agent. These options are there, but again, we feel that the combination approach is really the best one. Coming with that to my next slide, which basically recap that again. Can you show the next slide, please? That third line, the DLBCL in frail patient is really the focus of our clinical research in these patients. We are working on the identification of ideal combination partners, taking into account both efficacy, existing efficacy data, but also tolerability data. As I said, we could very well increase the dosage of Betalutin, and we are engaged in multiple consultations with external experts to optimize the study design. Thank you very much. Thank you so much, Pierre. Two pieces of logistical information before we move to Marco. First of all, we're gonna have a break after Marco's presentation, so that we can get a little bit of a coffee or a bio break for people. Secondly, if you have questions, please feel free to submit them, and we will handle that at the end of the session, for everyone. Without further ado, I wanna move to Marco Renoldi, our COO, who will speak to you about one of the initiatives more on the commercial side that we are developing at the moment. Marco. Yes, hello. Good afternoon, everybody. I think it would be a shame if we were unable to use the great clinical development work that the company has done so far and make it available to patients. For that reason, over the past few years, we've invested time and resources to understand both the drivers and the barriers to the integration of radioimmunotherapy into the continuum of care for lymphoma patients in preparation for launch. I will share today the findings from the most recent initiative. May I have the next slide, please? I think, as we all know, radioimmunotherapy is a targeted approach to cancer care, with the potential to improve both progression-free survival and quality of life in many tumor types. We're proud to have generated data with Betalutin that makes us confident that radioimmunotherapy can make a difference also to NHL patients. On the other side, we are also aware, and I think Dr. Gordon mentioned that some radiopharmaceutical therapies are underused, despite the significant potential they can offer. Our effort has been targeted to understand the barriers to adoption and, most importantly, to find solutions. Some of these barriers, we are well aware, are not necessarily related to the product. Rather, they are systemic. So the solution, the mitigation, can only be obtained through policy interventions, which require a coordinated effort. For that reason, we are indeed partnering with medical societies, patient advocacy groups, and also with other biopharmaceutical companies that operate in this space. May I have the next slide, please? In 2019, a U.K.based health policy organization named HPT started a very interesting project, with one specific goal to raise awareness around targeted radiopharmaceutical therapy, which they called radioligand therapy. Actually, radioimmunotherapy is one form of radioligand therapy, and Betalutin is one example of radioimmunotherapy. The key findings of their preliminary research are shown in the blue chart on the right of this slide. What they found, what HPT found with this research, was a set of barriers to integration of radioligand therapy into cancer care. I think it's reassuring to see that what HPT found out really validates the previous research we had done in this space. The same barriers we had previously identified and had started to work on. I will just name a few, which I believe are particularly relevant. Number one, the low awareness of this technology among the younger generation of physicians. Number two, the insufficient number of authorized users, for example, nuclear medicine specialists, who can deliver the medication. At number three, the unclear referral models through which patients are basically referred from hematologist oncologists onto nuclear medicine specialists. Next slide, please. For the above reasons, in late 2020, we decided to partner with HPT We felt they had done a really neat job. We decided to partner with them, and together with another important pharmaceutical company, we decided to co-fund, to provide funding support to their follow-on project. The goal of the new project was to develop, in collaboration with a series of international experts from both the U.S. and Europe, and Dr. Leo Gordon was one of them, an assessment framework. Basically, one assessment framework per country that would allow the evaluation of the readiness level in each specific country to integrate novel radioligand therapies, radioimmunotherapies, but most importantly, because that's what is important, to guide any required changes. Next slide, please. The readiness assessment framework. A situational analysis for the U.K. and one for the U.S. This situational analysis contains a clear articulation of the barriers requiring policy interventions, but in addition, a series of background documents and exploring in depth specific domains. To name a few, governance, regulation and reimbursement, service provision, and so forth. If I can make a parallel, it's almost like a CT scan. So the situational analysis identifies the problems and indicates the most laser-focused approach for removal of the problems. You will agree with me that this is a unique tool as we prepare to launch our product, because it will ensure that eligible patients can benefit from the treatment. Next slide, please. I would like, at this point, to share with you a glimpse, just a very high-level overview of the most important findings of the U.S. based situational assessment. You see on the left certain barriers which were spotted, and for each of the barriers, a clear set of intervention plans was identified. You see that on the right. We call them policy implications or policy interventions. This is the beauty of this approach, that we can identify areas, barriers where we can directly act upon. I'd like to focus on the three ones which are highlighted in red on the right column. Number one, our effort to ensure that treatment guidelines include any approved radioimmunotherapy as soon as technically possible. We hope that as we prepare to file our BLA with the FDA, we will be able to ensure that guidelines include these solutions for treatment of lymphoma patients. Second, to ensure the awareness of this treatment, collaborate and partner with patient advocacy organizations to create very patient-friendly information so that patients are aware of this novel type of treatment and appreciate the advantages that a one only administration can provide to them. Number three, last but not least, supporting medical societies to develop easier, more streamlined referral and treatment pathways. Our goal is very simple. Our goal is to create a multidisciplinary approach so that hematologists who normally see the patient and nuclear medicine specialists who need to receive these patients for the treatment with radioimmunotherapy can have a seamless dialogue, and we can ensure a consistent approach across different settings of care, both in academic sites and in the community practice. Next slide, please. I think we are proud of this project. We are proud to partner with HPT. We are proud to be a co-funding partner with another important pharmaceutical company because we're together in an effort to drive policy change. I think we believe that creating a more receptive environment to radioligand therapy or radioimmunotherapy, whatever you want to call it, will ultimately benefit patients because those who are eligible for these therapies will be granted access. Next slide. I hope I've been able to share with you the most important findings from this project. I wish to thank you for your attention. I'd like to suggest for those of you who are interested to learn more, to please visit the website, radioligandtherapy.com. Thank you very much. Thank you so much, Marco, again, for this great presentation. I hope you're starting to get a feeling on the multitude of different areas we're working on, the different dimensions that we're working on. Before we break for a short break, let me take this opportunity to give a big thank you to Marco. Some of you will not know, but he is going in retirement as of 1st January 2022. He has obviously been a cornerstone in a lot of the efforts that we have done as a company since, I believe, back in 2014, Marco. A big thank you for that. We obviously wish you all the best for your retirement. I'm equally happy to also say that you have decided to stay with us for two days a week on a consulting basis, so we won't lose your great knowledge and your great contribution. For now, thank you. All the best for your retirement. We're gonna take a five-minute break, guys. I'll be back at 3:45 P.M. I know some of you have to fill up on popcorn and Coke, I believe I saw on social media. Feel free to do that, and we'll be back in five minutes and continue with Maureen's presentation. All right, are we back online? I think we can move on with the next few presentations. I hope you can hear me out there. Yep, great. Thank you. We're about to get started again on the second part of our presentations for today. Little mistake from my side just before we went into the break. We're gonna move to our manufacturing/supply chain now and have Lars give a short update on what we are doing with that and how we are progressing with that. This is an important part of how we develop our readiness for the upcoming BLA as well and then move to Maureen after Lars. Without further ado, Lars, all yours. Thanks, Erik. I tried to look like Maureen, but it didn't work out. That is why we had to change. But seriously, thanks. Good afternoon, everybody. It's really a pleasure for me to be here on stage and to walk you through our journey to BLA and to launch readiness. Can I ask the next slide, please? What does CMC stand for? Chemistry, manufacturing, and controls. What does it cover? It covers all aspects from production, including quality and regulatory. Why is CMC important? The easy answer in essence is what Erik also mentioned earlier, without the substance, you can't treat the patient. Seriously, CMC has become more and more important for regulators, and many successful clinical programs fail to receive immediate approval due to CMC issues. We at Nordic Nanovector are working hard to avoid this. CMC is important to us because it impacts our patients. It is important to our IP and of course, later on for our margins. We have regular meetings with the health authorities, and it is really an integral part of our company. That is why the overall CMC strategy is really important for our overall success. As you know, we have no own manufacturing capabilities. Let me have the next slide, please. Here are our key partners. That covers more or less where we are active in. We are a Norwegian company. We have two partners in Oslo, and one is Diatec, the other one is IFE. We do have a partner in Germany, which is ITM. We have two partners in Spain with Liof and 3P Bio. We also have partners in the U.S. with Macrocyclics, and we are in close interactions to finalize the contracts also with Cardinal Health for our later on distribution. What you can see, our supply chain is already pretty global. Can I have the next slide, please? Let me walk you and give an overview about our journey to launch. First of all, the PPQs. What does PPQ stands for? It's process performance qualification. It is a requirement to demonstrate and validate the robustness of our process, and very importantly, in a suited facility which is GMP conform. Next in line is then that we have to prepare all of our documentation for submission, the so-called BLA preparation, and we have to prepare our facilities for the so-called pre-approval inspection. In parallel to that, we have to set up our commercial supply chain. We have to define all of our business processes to that to be able to supply in all countries. We have to define, for example, something like stock policies, having the right planning systems in place and so on and so forth. Where, of course, Marco Renoldi and Erik Skullerud are very keen on is that we are ready at time of approval for an immediate launch so that we can really supply and give the medication to our patient. Last but not least, as I mentioned, it's also important for our margins. We already start focusing today on our efficiency and effectiveness of the entire supply chain to not only have a robust process, but also to reduce costs. May I have the next slide, please? So I know it's a reminder for most of you. Here's our manufacturing process. As most of you are aware of, we have two independent products. The one is called lilotomab, and the other one is called Betalutin. Let me start first with lilotomab. We start with our production in Oslo at Diatec, where we produce the crude. We're then moving further to the drug substance, the purification at 3P in Spain. We do have the filling at a company called Liof. That is our final product for lilotomab. For Betalutin, we do have the first step. The first two steps are the same. We then add DOTA chemically to it, which is brought by Macrocyclics to Spain. We then do have the filling for the so-called lilotomab satetraxetan at Liof. We couple it with lutetium, which is coming from ITM in Germany. We do have our final product done at IFE with Betalutin. What you can see is that is our overall manufacturing process, which we are currently validating. Can I have the next slide, please? As mentioned before, it is not only important to have a good and robust process, it is also extremely important to have good facilities for the so-called pre-approval inspections, of course, but also in general for producing to GMP. Let me go and give you an impression about where are our partners. Let me start with Diatec Monoclonals in Oslo. I wanted to say here in Oslo, but unfortunately we are here in Switzerland and instead of being, of course, in Oslo. But what is Diatec? We have developed together with Diatec a robust production process. We have invested together into the production facility, which is GMP-certified by the Norwegian Medicines Agency. We have Class B and Class C rooms. Overall, I think we are making very good progress here for both the process and the facility. Can I have the next slide, please? Moving on in our value chain, we move to 3P Bio, which are in Pamplona in Spain. The facility itself is GMP-certified by the Spanish agencies for the manufacture of biological products and also the release of sterile products. But more importantly for us, 3P has invested into a new state-of-the-art facility which we just visited, which really looks great, and our product is produced now in the new facility, which is really good news for us. Let me walk you to the next partner. Next slide, please. Which is Liof, which is about 80 km away from Pamplona. Also there, Liof is GMP-certified by the Spanish health authorities for aseptic and filling and release of sterile products. Liof has a state-of-the-art filling line and it was already inspected by the FDA in a pre-approval inspection. Also there, a very good quality what we are getting. Now let us move back to Oslo. Can I have the next slide? IFE. IFE has also done a lot of work over the last years. It has invested into a new manufacturing line for our Betalutin production. The picture here is showing actually the very new line where we are very proud of. Our product will be manufactured in that line and of course, IFE is also GMP-certified by NoMA. Overall I think, we have not only a robust process, but I think also all of our partners have really good facilities in place, where we can do a lot of work in there. Now, going to the next slide. As mentioned in the beginning, the one thing as a process and the facilities, but which is also very important, is really to bring the product to the patient, and that is the supply chain. Now, how have we set that up, and what is important to look onto in the supply chain if we are setting up a commercial supply chain? What you can see here is how we will move our product from place to place. Now, we start at Diatec with the crude. We will go by plane down to Spain so that we can produce there the bulk drug substance. Then we will move it to Liof, which is 80 km away, again by plane back to Norway. Then we have to bring it from IFE very fast into the U.S. As you know, we only have about seven days of shelf life after the production. We have chosen a very strong partner in the U.S. for our commercial supply chain. We want to move ahead with Cardinal Health, which has a lot of radiopharmacies, and they are very active in the U.S. and very well known for that, and we are happy to have them as a partner. From there, we can bring it into various administration sites in time. As a supply chain, it's not only that. What you also need to be aware of is that you have to look on critical raw materials, your safety stock policy, your secondary sourcing, and so on and so forth. Underneath, you can see some of the very important, but of course, it's only a snapshot, a glimpse on where we are looking for. One thing is, for example, the monoclonal antibody medium for production at Diatec. The other part, of course, is the DOTA, that it is in time at 3P. What some people are forgetting is the primary packaging. You need to think about we have vials and stoppers, which looks really basic, but of course we have to have enough from them because if we don't, then we can't fill. All of that, we would need to look into it. There are other primary packaging sources. There's also some additions to some buffers like Recombumin, all of that needs to be looked on. Of course, lutetium always have to be fresh there in time. We are working very closely, not only with ITM but also, of course, thinking about second suppliers and so on and so forth. Finally, at the administration site, what you should also not forget is infusion filters. There's a long list which we are currently looking on and how we prepare ourselves to be ready for the launch and the commercial supply. Can I ask the next slide, please? Now, where are we? You always hear a lot from Malene and where we are, that CMC is working on the PPQs and so on and so forth. We are fully on track with our process performance qualification. We are also on track in preparing for our BLA submission. As you have seen, we have already started to set up the commercial supply chain because that takes also a while if all of the things are really in place for the launch. We haven't done the launch, but we start to prepare for it. Where everybody is interested later on is to having good margins, and we are already thinking about how to improve our cost of goods. That is at conceptual stage. With that, I hand over back to you, Erik. Thank you very much, Lars. I think as you can see, one thing is the clinical development, the PARADIGME study. It walks hand in hand with our CMC, our manufacturing development. This is really a hand in glove. It is a matter of really ensuring that on one hand we get the clinical results that we have, but on the other, that we also do the right things in order to ensure that the product gets developed and produced, manufactured well. This was a bit of a glimpse into what Lars and his group is working on at the moment. Now we're gonna switch gear completely. We're gonna let Maureen take over and talk to you about our two most recent little babies, our first, the monoclonal antibody that we are developing and a humanized antibody. On the other, our CAR T co-development or our collaboration rather with University of Pennsylvania. Maureen, on to you. Many thanks, Erik. Yeah, I'm very, very excited now to have the opportunity to give you some headline information on where we are with these discovery programs. Next slide, please. Could I have the next slide, please? Apologies. Thank you. This is a build slide. B cells, also known as B lymphocytes, are a type of white blood cell, and these play an extremely important role in adaptive immunity. Hit the button, please. There are multiple antigens present on B cells, CD19. Next again, please. CD20. You've heard both Professor Gordon and Pierre talk about these today. Also, hit the button again, please. CD37. Yes, CD20 is very well-recognized, and as we all have heard of rituximab was actually approved in 1997 for cancer. You've also heard today about some CD19 therapies, such as Monjuvi and the CAR T therapies, Yescarta and Kymriah. At Nordic Nanovector, we focus on CD37 because it's also a major antigen on B cells. You will see from my subsequent slides that other people are active in this space. Where we really have an advantage is that we've been working in this biology for over a decade. Next slide, please. Now I wanna talk to you about the B cell development process, which is shown on the uppermost panel of this cartoon. You can see from the far left, from the stem cell in the bone marrow to the far right in the plasma cells, there's multiple stages that are involved. When you look at the middle panel in this figure, you can actually see that individual B-cell lineages can be associated with particular B-cell malignancies, as shown in green. What I'd like you now to focus on, please, is in the bottom panel where we show levels of CD20 and CD37 expression and CD19. What's really important is that CD37 expression in the B-cell lineages overlaps identically with what you see from CD20. You see expression from the pre-B-cell to the early plasmablast, where the CD19 is expressed broader. Why we think CD37 is a better choice of candidate is that you don't really want to, with the therapy, knock out all of these early pro-B-cells because it's still important to be able to mount an immune response. CD37 expression is very attractive for a novel therapeutic. Next slide, please. What I want to do from this slide is just also to remind you that despite the fact that CD37 is almost exclusively expressed on B cells, that there is also an immunomodulatory potential, that there's also an impact on other important immune cells such as macrophages, T cells, dendritic cells, and neutrophils. Now there's a lot of literature that really explains that CD37 has an important role not only on the B cells, but it can also impact these other important immune cells. Next slide, please. To date, you've heard all about our important role in working on radioimmunotherapy. Now, with the radioimmunotherapy, what we do is we use the CD37 antigen as a docking station, so the radioimmunotherapy molecule is an antibody with a chelator and the radioisotope. Essentially what happens is the radioimmunotherapy comes along, docks onto the CD37 receptor, and then the radioactivity can be incorporated within the cell and also kill other cells in the environment. This is a very clever and effective way of targeting B cells. What I want to do next is explain to you how, by exploiting a humanized anti-CD37 monoclonal antibody approach, what we actually do is we target the CD37 receptor pharmacology. Next slide, please. To do that, I just wanna do a little bit of a recap refresher on antibodies. This is a diagram of an antibody structure, and an antibody is composed in green of two identical heavy chains and in blue, two identical light chains. Through disulfide bonds and non-covalent interactions, you have this typical Y shape that you can see in the figure. That's what you'll recognize as an antibody. I want to bring your attention to the two circles on the top, the variable region, which the circles are around those square boxes, and then in the bottom in red, the constant region. Next slide, please. Okay, as this next slide becomes visible, what I want to do next is to talk to you about the different types of monoclonal antibody. What you can see on the left-hand side is that there are mouse murine antibodies, monoclonal antibodies, and the first murine monoclonal antibody approved was in 1986, and it was an anti-CD3 antibody for a kidney transplant indication and also Betalutin or antibody component of Betalutin. Lilotomab is also a murine antibody. When we move across to the chimeric antibody, you can see in the cartoon I explained previously, what you can see here is in the chimeric, the area that I called the constant region in yellow is actually now from a human, and the blue, which is the variable region, is from the mouse. Moving to the right, when you actually have the situation where more of the variable regions are human and you have less than in the chimeric, that is the humanized antibody, so you have predominantly a human structure. Could you hit the build, please? Again. Also again, please. Really what this means is what. Why we're really excited about having a humanized antibody to complement what we have is because, with murine antibodies, and potentially with chimeric, there is the increased chance of having immunogenicity. Therefore, that does limit you because there is a risk if you give multiple injections. One of the key reasons why we are pursuing a humanized anti-CD37 monoclonal antibody is because it will support multiple injections, which will be important for some acute indications, but it also moves us into a market for chronic diseases because we know that in the chronic disease situation, that often you have to repeat your administration. This is why we are particularly excited about this approach. Next slide, please. We've been working on this program, and I now wanna just give you an update on where we are. We've generated multiple anti-CD37 leads with different effector functions. That means different killing mechanisms, and I'm gonna talk to you, describe that a little bit better in the next slide. Where we are from the process is that we're finalizing our lead candidate selection, and that is based on a range of criteria, including in vitro activity, in vivo activity, manufacturability assessment, because Lars wants to make sure we choose the antibody with the best characteristics to take forward for production, and also we are ranking our leads based on other anti-CD20 and other anti-CD37 antibodies. Now in the slide that we're looking at, in this cartoon on the left-hand side, that's your typical Y-shaped antibody that I've explained to you. I want to let you know that these monoclonal antibodies have got four mechanisms by which they can kill a tumor cell when they engage. If we start at 11 o'clock on the blue tumor cell, what you can see happen is you can see the antibody's inverted. You see the arms are now interacting with the receptor, CD37 receptor on the tumor cell, and the tail is sticking out. What can happen is this type of engagement causes receptor signaling of a lot of death signaling pathways, so you can have a direct death effect. If we move round clockwise, then you see a process called antibody-dependent cellular phagocytosis. What happens here is that the tail, Fc, interacts with the cell, the green cell called a macrophage, and it tells the macrophage, "Eat me." The macrophage is involved here and starts to eat the tumor cell. Moving round to 3:00 on the right-hand side, there's also another process called complement-dependent cytotoxicity. What happens here is that the antibody engages with a protein called C1q and causes this cytotoxicity. If we move down to the bottom left, the fourth process is called antibody-dependent cellular cytotoxicity. What happens here is that the antibody engages with other immune cells called natural killer cells. What happens is it can elicit these natural killer cells to release granules, which kill the cell. We filed a patent on our leads. Where we are just now is, as I told you, we're choosing our lead candidate. Because it's commercially sensitive, all I can tell you at the moment is that we have come up with a series of leads where we've optimized each of these killing functions, and I can let you know we've come up with some really interesting molecules. Where we are just now is that because it's commercially sensitive, what we will do is we look forward to presenting further data to you in 2022 on the lead candidate that we've selected. Next slide, please. In oncology, I'm using this slide really to point out to you that for a monoclonal antibody, the top 10 therapy areas for monoclonal antibodies are shown in this figure. You can see here that for oncology, almost 4,000 monoclonal antibodies are being developed for oncology indications. Next slide, please. The reason why we are developing the humanized anti-CD37 is because we want to utilize this antibody and the benefits it has to strengthen our radioimmunotherapy platform, and namely to strengthen Betalutin. Because we believe, you've heard from Pierre, he's got ideas about how to do some combination treatments with Betalutin and some of these more aggressive and difficult-to-treat tumors where we know that a single injection, such as we see in follicular lymphoma, might not be enough. Betalutin could be a good induction therapy, but because again, the fact that it's based on a murine antibody, we really feel that we might not be able to give multiple administrations. Where this monoclonal antibody will prove extremely beneficial in oncology is that we'll be able to treat some of these difficult-to-treat subsets of patients, such as the relapsed refractory DLBCL patients. Or also, it gives us the opportunity to try to go to earlier lines and to have a treatment for frontline NHL. We could use the humanized monoclonal antibody as a maintenance therapy after administration of Betalutin with the aim of extending both the rate of response as well as the durability. You heard Dr. Gordon talk about it, and you also heard Pierre, and that's this idea here where we could actually use the monoclonal antibody as a maintenance therapy. Next slide, please. We have the opportunity in oncology, but because B cells also have an important role in immunology, and in fact, immunology is the second highest therapy area for monoclonal antibodies, we intend to also explore this market opportunity. Autoimmune diseases in particular have been predicted to have a market share of $150 billion in 2025. We truly believe that this is an area that we should explore for our humanized anti-CD37 antibody. Next slide, please. Why? Why do we have reasons to believe that we should do this? Because of some analysis that we did a couple of years ago in-house with Clarivate Analytics, where we worked on a program where they looked at CD37 expression in a whole range of different autoimmune diseases. What we came up with was the five listed on this slide as being areas where CD37 is expressed at higher levels. We have Sjögren's syndrome, we had severe asthma, colitis, psoriasis, and a systemic lupus erythematosus. What we are doing now is considering doing further data mining to really look to see are there other sensible immunological diseases that we could target from both a scientific and clinical rationale basis. Next slide, please. We want to look at what the large pharma. Erik mentioned this earlier. Large pharma have been extremely successful in their anti-CD20 approach to extrapolate into autoimmune diseases. We want to look and see if there's any lessons learned for us in CD37. In this slide, I just want to recap for you where these CD20 molecules are playing currently. Rituximab has a marketing authorization for RA, but also for other immunological diseases. In fact, rituximab is in clinical trials for progressive multiple sclerosis. Obinutuzumab, the kind of second-generation anti-CD20, is not currently FDA-approved to treat lupus, but may be described off-label. It's also being looked at for lupus nephritis because it's one of the most serious complications of the lupus condition. In addition, moving to the right-hand side, the Novartis molecule, ofatumumab, is in clinical trials for progressive multiple sclerosis and also rheumatoid arthritis. Again, what we will do is utilize the expertise that the larger pharma are working in this area too, to really come up with a sensible plan. First indication will be for an oncology, but to look to further extrapolate into some of these other autoimmune diseases. Next slide, please. It's not just us that share opinion in the value of CD37 as a target. There are other companies also active in this area. GEN3009, the Genmab molecule, which I'm sure you're all aware of, it's a biparatopic dual HexaBody molecule, and that was recently partnered with AbbVie, and they're at phase I/II for hematological cancer. In the summer this year, we became aware of another molecule from a company called Sound Biologics, PSB202, which is actually a CD37/CD20 bispecific antibody, and that's at phase I for hematological cancer. The molecule that I'm sure you've heard of, you're most aware of because it's been around longest is the CD37 ADC from Debiopharm, which was in-licensed from ImmunoGen, and that's currently phase II for hematological cancer. Again, different molecules are in clinical development that target CD37, but our molecule will have different properties, and we will be able to share that target product profile with you in 2022. Next slide, please. Again, just a summary. The patent's been filed. The lead candidate selection is ongoing, and as I explained, the first indication will be hematology, and we have an IND date planned for 2023. Next slide, please. My last couple of slides, I want to talk to you now about our CD37 DOTA CAR T-cell approach. We're working with UPenn. Erik already told you earlier, one of the reasons we were particularly enthused about working with UPenn is that they are the pioneers of CAR T-cell therapy. Of course, the first CD19 CAR T-cell came out of that UPenn, and that was the first CAR T licensed by Novartis. We know they're an excellent group to be working with. Next slide, please. The collaboration aim is to harness that CAR T experience and also to utilize the CD37 expertise that we have at Nordic Nanovector, and as I explained to you, over a decade of experience there. We're also interested because the CD37 CAR T-cell landscape is less competitive. You heard, Dr. Gordon already said there's a lot of molecules that are CD19 CAR Ts. We think this is a good space to play in. We also believe that the UPenn technology may have an important safety feature, and I'll describe that in the next slide. What's exciting for us in this collaboration is that we will have the option to license in this CD37 DOTA CAR T-cell therapy. Next slide, please. The next slide is really just to highlight the unique properties of this technology, and if you can hit the button on this. Thank you. The UPenn have a universal immune receptor T-cell, UIR T-cell. What this is, if you think back to what Dr. Gordon said, essentially, you have this single-chain Fv molecule, and you have CAR T-cell signaling elements fused to it. You also heard that he said that new generations are really working in the T-cell signaling part. The difference here with this UIR is, in addition to having the binding domain, the T-cell signaling, there's also a DOTA binding domain, and DOTA is a chelator molecule. What happens is that the blood is taken from the patient, the white blood cells are collected, and basically, the T-cells are collected, and this construct is introduced into the T-cells, and then they can be infused back into the patient. Unlike the CAR T-cell technologies that Dr. Gordon and Pierre mentioned to you earlier today, normally when you do that, when these T-cells are put back into the body, they start to proliferate. With the technology we are using, they cannot because they have a DOTA binding requirement. If you could please hit the build again, please. What happens for us. And again, please. What we have in our system is that we have an anti-CD37 DOTA antibody. Again, taking you back, the T-cells are in the body, they can't do anything. This anti-CD37 DOTA antibody is injected in. This antibody binds to the CD37 cells on the B cells, and the DOTA is exposed. Then the T-cells can engage with the DOTA, and then they can start to proliferate. This really does have the opportunity to mitigate existing limitations, and you saw some of this already mentioned a series of adverse events by Pierre. What this means is by being able to titrate in the amount of antibody you use, you can regulate the degree of T-cell proliferation. What that means is that you can have some control over potential toxicities, such as cytokine release syndrome and also neurotoxicity that some patients experience with these agents. This project has just started. We're really excited to see what data we have. In conclusion, we're excited to be able to present on both projects next year to you. I really hope, as investors, that you're excited to see that we've got some new molecules with new angles, new target product profiles. Hopefully, these new molecules will complement what we already have in our platform and also build on it. All that leaves me to do now is to thank you very much for your attention. Thank you very much, Maureen, for that interesting presentation. Excuse me. I hope you appreciate our two latest additions to our pipeline. We are excited about this. We believe this adds very nicely to what we already have. In order to complete that picture also from what we already have, I'd like Jostein Dahle, our CSO, to take you through an update on Betalutin as well as Alpha37. Jostein, please. Humalutin is a CD37-targeted therapy for the treatment of non-Hodgkin lymphoma. Next. In Humalutin, we have used a chimeric version of the lilotomab mouse antibody that is used in Betalutin, the NNV3 antibody. It binds equally well to the CD37 antigen as lilotomab. The blue part of the antibody is human, while the red part is murine. 70% of the mouse sequences have been removed, and therefore the antibody has lower immunogenicity potential, higher therapeutic effect, and longer half-life in blood than lilotomab. For Humalutin, we use the gold standard chelator DOTA for chelation of Lutetium-177, as in Betalutin. The intellectual property rights are covered by a composition of matter patent and a combination patent application. GMP processes have been established to manufacture NNV3 and Humalutin for clinical trials, and the regulatory dossiers have been completed. Humalutin is a next-generation anti-CD37 radioimmunoconjugate that is tailored for treatment of non-Hodgkin lymphoma. Next slide. In a mouse therapy experiment, NNV003, in the orange curve, was more effective than lilotomab, in the blue curve. In this study, we injected 100 mcg of the antibodies two times a week for four weeks to each mouse. We used quite high doses, but they were tolerable. The mice were injected intravenously with REC-1 mantle cell lymphoma cells before the treatment started, and we got 100% survival by treatment with NNV003 and 60%-70% with lilotomab, while all the mice in the untreated control group died because of cancer between 50 and 70 days after start of treatment. Human antibodies bind very well to most effector cells, and like Maureen talked about, and that is why we get an effect in this therapy experiment, while most antibodies do not bind to human effector cells. In humans or patients, we do not expect, and also we haven't seen, any therapeutic effect of lilotomab, while we expect to see an effect of NNV003. This higher therapeutic effect of NNV003 than of lilotomab might enable use of NNV003 for both pretreatment and predosing. We don't need to use rituximab like we do for Betalutin. Next slide. With the radiolabeled antibody Humalutin, we use much lower doses of antibody, only around 4 mcg as compared with 800 mcg in the experiment with only naked antibodies on the previous slide. Here we also have exactly the same mouse model as in the previous slide. It's actually a leukemia model since we inject the cells intravenously, and we actually do not expect so good effect of Humalutin in this model because the range of the beta particles is too long for treatment of single cells in the blood. It's better suitable for larger tumors. You can see in the green curve that when we treat with only 4 mcg or 0.167 mg/kg of NNV3, we still get some effect of the naked antibody, around 40% survival. So it's quite potent on its own in this model. The gray curve is the untreated control group, and you see that all the mice dies within 70 days after cell injection in this experiment also. The orange curve shows the effect of a non-binding antibody, and the red curve shows effect of non-binding antibody labeled with lutetium. As you see, there's no effect of these two treatments. They just follow the gray control curve. In the light and dark blue curves, you see the effect of treatment with Humalutin. There was a significantly increased survival compared with the control groups, but effect was not significantly higher than the effect of NNV3. Okay, so we could have increased the doses, you might think, but we have used SCID mice in this experiment, and those mice are inherently very sensitive to radiation, so therefore, we couldn't go higher than 100 MBq/kg. Next slide. In this experiment, we have changed another mouse type, nude mice, that tolerates radiation much better, so we can go up to 500 MBq/kg. In addition, we have changed to a subcutaneous tumor model with tumors under the skin on the two flanks of each mouse to resemble a lymphoma tumor. Even though we have used the same cell line here, REC-1 cell line again, and much higher doses of the NNV003 antibody, we get no effect of the naked antibody in this model as you see in the two green curves. Also no effect of the non-binding antibody or the radiolabeled non-binding antibody in this aggressive model. You see it's much more aggressive when we have it on the flanks. When we have tumor cells on the flanks than when we inject intravenously, all the mice dies because of cancer after around 30 days after cell injection. The reason for no effect of the antibody this time is probably that it only binds to the outer surface of the tumor and do not reach the inner cells of the tumor, which then grow as they want. The beta particles from Humalutin on the other hand, they reach the inner tumor cells. Here you really can see the benefit of the cross radiation that one beta particle can hit multiple tumor cells. Therefore, the effect of Humalutin is significantly higher than all other treatments in this aggressive tumor model. Next slide. A way forward for radioimmunotherapy can be in combination with other drugs. In this study, we have looked at the combination of Humalutin with olaparib. Humalutin results in DNA damage, and olaparib inhibits DNA damage repair. This should potentially be a very good combination. Next. A beta particle from Humalutin induced a single-strand break in the DNA. The cells will start to repair the break by recruiting a protein called PARP to the damage site. Olaparib will inhibit PARP, and you get an unrepairable double-strand break, and the tumor cell dies. Here's the double-strand break. We tested the combination treatment in seven different NHL cell lines and found the combination to be robustly synergistic in four of seven cell lines. Conditionally synergistic in two cell lines and antagonistic in one. We have not been able to find out exactly why the combination was not synergistic in a DOHH2 cell line, but this could, for instance, be related to different DNA repair pathways involved in this cell line. In preparation for clinical development, we have made a GMP-grade companion diagnostic for Humalutin. It is based on the NNV003 antibody labeled with the PET tracer Zirconium-89 that emits a positron instead of an electron, and can therefore be used for PET or scintigraphy instead of using Humalutin. The benefit with this is much better image quality, lower radioactive dose to the patients and shorter imaging protocols than when using Humalutin itself. Far, we have shown that imaging with 89 zirconium NNV003 can accurately predict whole body distribution of Humalutin in mice by comparing data of the two molecules. We have developed a GMP procedure for manufacturing, and the molecule is ready for use in the clinic to predict radioimmunotherapy distribution in patients. With clinical 89 zirconium NNV003 imaging, we can help identifying response to Humalutin, we can predict Humalutin-mediated toxicity in healthy tissues, and we can optimize those regimens for Humalutin. Next slide. The key takeaways are that Humalutin has lower immunogenicity, which may allow for multiple dosing. We have developed a robust GMP manufacturing process and completed pre-clinical and CMC dossiers. A higher therapeutic effect of NNV3 than obinutuzumab may enable use of NNV3 as pretreatment. We have shown therapeutic effect of Humalutin in different animal models and a synergistic effect when combined with the PARP inhibitor olaparib. A zirconium-89 NNV3 companion PET diagnostic has been developed for dosimetry studies in the clinic. Next slide. In the second part of the presentation, I will present the status of a pipeline candidate, Alpha37, for treatment of chronic lymphocytic leukemia and non-Hodgkin's lymphoma. Next slide. Alpha37 also consists of the chimeric anti-CD37 antibody, NNV003, but this time we have conjugated it with the chelator TCMC, which chelates the alpha particle generating radionuclide lead-212 much better than DOTA. This is a collaboration project with Orano Med. Lead-212 is an alpha particle generating radionuclide with a 10.6-hour half-life. An alpha particle consists of two neutrons and two protons and has a charge of +2. It interacts very strongly with biological material, and therefore you only need one to two alpha particles to kill a cell. An alpha particle has a very short range of less than 100 um. Alpha particles are therefore optimal for treatment of disseminated disease like CLL. Next slide. NHL has already been covered by the other speakers, but I would like to go a little bit into the treatment and unmet medical need in CLL. CLL is currently mainly treated with the Bruton's tyrosine kinase inhibitor ibrutinib, both in first line and second line of treatment. Anti-CD20 antibodies in combination with chemotherapy and with the BCL-2 inhibitor venetoclax are also used in first line. Venetoclax is also used alone in second line, and anti-CD20 antibodies are also used in combination with venetoclax or in combination with the PI3 kinase inhibitor idelalisib in second line. There are already many treatments available for CLL. Next slide. However, there are still large unmet medical needs in CLL. In a new report by Decision Resources Group, treatment options against new targets and with new mechanisms of action for the high-risk patients with P53, 53 mutations were highlighted as an unmet medical need. Alpha37 is a new treatment with a different target and a unique mechanism of action different than currently approved treatments. One unmet need is also discontinuation of ibrutinib therapy because of adverse events and intolerance. A well-tolerated radioimmunotherapy can be an alternative treatment for these patients. Another unmet need is a lack of complete response, especially in old and frail patients, in the high-risk patients and in patients treated with chemotherapy. As you know, CLL cells are very radiation sensitive, and they also have a very high CD37 expression, so radioimmunotherapy could potentially give higher complete responses. Tyrosine inhibitors are oral therapies, and they pose compliance issues because the patients have to take the tablets every day until disease progression. A single injection radioimmunotherapy will secure compliance, and then you are finished with the treatment. There are absolutely unmet medical needs in CLL that can be met by radioimmunotherapy. Next slide. Market analysis shows that there is a significant opportunity in second-line and third-line setting of CLL that total of around 27,000 patients. There are around 10,000 high-risk patients with P53 17p mutation in second- and third-line, and there are around 11,000 patients in first- and second-line that discontinue ibrutinib therapy. The available treatment options in high-risk and ibrutinib-refractory patients are not satisfactory. The entry indication for Alpha37 should be in these two settings because here the unmet need is high, and the regulatory pathway will probably be easier. Next slide. Therefore, the preclinical development strategy was designed to evaluate effect of Alpha37 in ibrutinib-resistant and ibrutinib-sensitive mouse models. In an ibrutinib-resistant mouse model, mice were treated with daily high doses of ibrutinib, and you can see in the green curves there was no effect of ibrutinib because the curves overlap with the gray curve, which is the untreated control. This data confirms that the model was ibrutinib resistant. The Lead-212 labeled cetuximab is not binding to the cells, and there was a small effect of this treatment, as you can see in the purple curve. The effect of Alpha37 was very high in this experiment, with 100% survival when we treated with 15 µCi of Alpha37, as you can see in the yellow curve. The orange curve shows treatment with 20 µCi Alpha37, and here the treatment became a little toxic, so the maximum dose should be 50 µCi for these mice. NME three did not have any effect in this experiment, as you can see in the blue curve, because they used TCMC conjugated antibody, and that destroyed the binding to the effector cells. The data indicate that Alpha37 has potential in ibrutinib-resistant refractory third-line CLL. Next slide. We tested an ibrutinib-sensitive model. We treated mice that had been intravenously injected with tumor cells with increasing doses of Alpha37 and with the non-binding antibody cetuximab labeled with lead-212. This model is about five times more sensitive to ibrutinib. Median survival was not reached for Alpha37 treatment, and after 27 weeks, the survival was 70%-90%. For the control treatment, the median survival was only around seven to eight weeks. You can see in the purple curve that there was no effect of the non-specific cetuximab antibody labeled with lead-212 in this experiment and no effect of the NNV003 TCMC conjugate either. The data indicate that Alpha37 can have potential in ibrutinib-sensitive second-line CLL. Next slide. In the end of 2019, we started a project for phase I trial and got Eurostars funding for it as well. The goal of the project was to finalize the package of work and documentation that is needed for starting a clinical trial. We are getting very close to reaching that target now and have only the last part of the finalization of the GMP methods for production of the antibody conjugate and Alpha37 itself and the documentation around this left to do. Next slide. The key takeaways are that Alpha37 is an alpha particle emitting anti-CD37-targeted therapy for CLL. It is superior to ibrutinib and effective in both ibrutinib-resistant and sensitive mouse models. The preclinical data and unmet medical need suggest to focus on high-risk and/or ibrutinib-resistant refractory CLL as the entry indication because here the unmet need is high and the regulatory path may be shorter. There is a clear unmet medical need and market opportunity for Alpha37 above and beyond this entry indication. Yeah. Thank you. Thank you, Jostein. In conclusion of today, first of all, a big thank you to the team for giving these updates. I hope you share our excitement over what we're trying to achieve with our SWIDER CD37 platform. Again, we have seen examples of this in the past. We have seen other companies do similar things to what we are starting, the journey that we are on. Let me give you one other example. There was a company called Forty Seven who did very similar things to what we are doing, but for a CD47 rather than CD37. This company got acquired by Gilead and is now a big part of Gilead's success. I think, again, if you look at where we are, our attack point, our unique area of focus, it's a good starting point. Hopefully, we have also been able to give you a feeling for the different parts, the different angles that we have, these five different molecules that we can use to target the receptor in different ways. Both some that have been in development for a while and others that are fresh off the bat that we have great faith in for the future. The third part is in the area of which diseases we can target for patients. We have already done a lot of work in hematological disease, but we are also looking at how we can expand this to autoimmune or immunological disease. That is where molecules such as our humanized antibody will find its place in the sense that these diseases will likely need iterative treatments over time. And as such, a humanized antibody will be a better fit, potentially than a radioimmunotherapy. All in all, again, thank you for taking the time today. Thank you for joining us on a day that seems fairly lackluster in other ways, with the stock markets around the world going down significantly on the basis of news that we saw this morning from Moderna. Obviously we're interested in that part of how the world is working as well. We hope that all of you are safe. We hope that all of you are enjoying what we've been able to share with you today, and we look forward to your questions. I'll probably now let's open the channel for questions. What we'll do is I'll try to answer as many as I can, but I will obviously add on people in the team as we need over the next few questions. If I may ask for the questions, please. Thank you, Erik. We'll get started with the Q&A session. Just as a reminder, ladies and gentlemen, if you do have a question, please do submit it via the question box on the website link. Just to begin with, we have a number of questions around PARADIGME, but the first question is asking why are you not publishing the preliminary complete response, partial response, and medium duration of response data together with top-line data for PARADIGME? Yeah. Thank you for that question. This is obviously a question of what data do you have available when we have our preliminary results, and that will purely be on the primary endpoint. More analysis will need to be done for the secondary endpoints, and this will take time. Hence, we can only give updates on the preliminary endpoints when we initially give the results. We will not have the data in a detailed enough fashion to say anything about these other endpoints up front. Again, feel free to look at how other companies are doing this. This will be exactly the same as any other company that is finishing their pivotal trials. Unfortunately, this has to take time. Thank you. The next question relates to screening numbers, and is asking, since you've previously mentioned, in presentations, the number of patients in screening, can you give us a rough estimate on how many there are in screening at the present time, given your previous statements that the patient pool is one of the most promising that you've seen with regards to PARADIGME? Yes, I don't think we have given any numbers as such, but we stand by our comments around that we see a good number of patients in screening. As I mentioned in my update on PARADIGME, when we did our Q3 update, it takes about three months for us to get from the first time we see a patient until they are officially included. Again, as an example of what I just mentioned previously today, the patient that we are enrolling as we speak has been on our radar for quite a while, but it's only now that we are able to say that they're actually included. There are several other examples of this, but we have not, nor will we talk about the exact numbers. Again, the example I used on the patient that actually did not enter this study is hopefully a good example, and I hope you understand why, rather than going in and talking about all of these numbers in detail, we would probably not give you a very confident answer if we were to do so, 'cause they fluctuate a lot. Some people go into the study, a lot of people also do not go into the study. That is the nature of doing clinical research. Some patients will find their way into the study, others will not. From a totality point of view, we do see a lot of patients in screening also as we speak. Thank you. Just moving on to a question around enrollment for PARADIGME. Given the current enrollment update that you've given for PARADIGME at this point in time, how confident are you in still meeting the timeline with guidance for top-line data in the first half of 2022? As mentioned in the update as well, we are eight days post our Q3 update. We are still as confident as we were in our Q3 update. With the additional patient, I think for those of you that are more into run rates, you also see that we continue on the same road as we have been in the last few months. May I also remind you that, you know, the quarter that we have ahead of us, last year we included 14 patients. I am not saying that we're gonna do that again, but it should also tell you that these numbers are fluctuating, and we may very well have such a number also coming up in this coming quarter. Thank you. A further question on PARADIGME relates to the impact of COVID, and is asking specifically whether you can provide any color on the ongoing impact from COVID. In particular, are you seeing missed follow-up appointments within PARADIGME? Is there any issue in terms of enrolled patients becoming infected with COVID, which can impact outcomes from the study? My first comment, I will reiterate what I said in Q3 as well. You know, so far, we have seen limited impact of COVID on patient numbers in the study, and we continue to see that similar picture. I think it's also fair to say that due to the emergence of the Omicron variant, I think many of us are still waiting or all of us are still waiting to see how this will pan out. Again, as mentioned in the Q3 report, you know, we saw a similar picture of rising numbers last year in Q3 and into Q4 of COVID patients. We saw more patients included in late Q3 and into Q4 last year. As such, we don't see necessarily that this would change this year. Again, I would put the caveat on that, the new strain of the virus may affect it, but we don't know that yet, nor have we seen it yet. Thank you. The next question relates to the confirmatory phase III study following ARCHER-1, and asks, "Will this study be done by Nordic Nanovector alone, or will there be a financial or medical partner, and possibly with the supply of rituximab for completion of that study? A very good question, and there is obviously a lot of unknowns to the answer of that. Number one, will there be a partner? As we get the results of PARADIGME, and assuming that what we believe will be the case, we will have partners. If they will be part of the confirmatory phase III, it's still too early to say. That will depend on the deal that we will be doing. On the second hand, with regards to rituximab itself, obviously there are different providers of rituximab. You have a whole lot of biosimilar companies at the moment. So purely from a costing point of view, the cost of doing this study now would probably be less than what it would have been just a few years ago. Again, it's too early to comment exactly on what this is gonna look like. It depends on the PARADIGME results. It depends on partnership deals. It depends on what those are gonna look like, the structure of them, et cetera. That's all we can say really at this stage. Thank you, Erik. The next question, again relating to PARADIGME, is, can you say something about what you think would be an acceptable overall response rate to target in order to meet the endpoint for the study and gain an approval for Betalutin? Short answer, no, we can't. From competitive reasons, we wouldn't necessarily talk about that either. This is something that, you know, in looking at our clinical data and eventually our strategies, this is something that we would need to internalize, analyze, and therefore optimize as we go to market eventually as well. Thank you. We'll move on to a couple of questions on Alpha37. The first of those is that at the previous R&D Day, Jostein expressed the view that the data, the early data around Alpha37 was some of the most promising data that he had seen. The question is this statement still valid? Can you explain how the company intends to benefit from moving the program forward? Well, I'll let Jostein talk in a little bit about if he still stands by his statement. I know he is extremely excited about Alpha37, and whenever we have a conversation, he keeps on reminding me about that. I think it's fair to say, you know, this is a molecule that we have a very good partner on, and that should speak for itself with regards to the results of it. Secondly, this is an alpha emitter, not a beta emitter, and as such, it is differentiated from other products in our pipeline. But Jostein, with regards to how excited you are about the data, do you still feel that way? Yes. I think it's the best data I have seen. The data haven't changed, so it's extremely good data. Great. Thank you, Jostein. Just as a follow-up question on Alpha37, can you give any guidance on the timeline for being ready for IND approval and the start of clinical studies with Alpha37? I think Jostein alluded to this. We are really nearing the endpoint of the data package that we would need. Our estimation, and we are in close dialogue with our partner, Orano Med, on this, we had a big meeting as late as this last week, is that we believe that we'll be able to do this in the first half of 2022. It may even be earlier. In this sense, it's a little bit too early to say. As you did see in Jostein's slides, we do have a few more steps to complete, but we're making extremely good progress as we speak. Thank you. Moving on to the CAR-T CD37 program, can you describe in any more detail at what stage you're at with regards to the collaboration with UPenn? Are there any in vitro and in vivo studies that you can discuss at this point in time? Just following up on that, is there any timeline for how this program is likely to progress, going forward into clinical development? Can you put any timeline on that at this early stage? Thank you. With regards to the collaboration itself, the expectation is that we'll be able to give some indication on where we're going in the next 12 to 18 months. What that exactly will look like is more we will assume that we will kind of show what is the molecule, what does it look like. We may even be able to give some early-stage results. I believe Maureen said in her presentation that when we get to the R&D Day 2022, we will likely have an update for you. More specific than that can I not be at the moment. We did publicize the deal, and was it 2.5-3 weeks ago now. It's obviously very early days, but we're suggesting that at least in the next 12-18 months, you will see something around what this is giving as results. Was there a part of the question I didn't answer, Fraser? No, I think that's fine. Thank you, Erik. There are a few questions around your ongoing discussions with partners and essentially, these questions really ask, can you give any further updates at this point in time to any of your ongoing discussions with these partners? I would say, like I said in the Q3 call as well, we have several conversations ongoing, and I reiterate what we said back then as well. We can't talk about which companies we're talking to, what kind of companies we're talking to, but for obvious reasons, we're hoping for different types of deal, and I said that in my introduction. Different types of development deals depending on the molecule in question, and depending on geographic area in question, for Betalutin or for other parts of our portfolio. Thank you. There's one further specific question just regarding the announced retirement of Marco Renoldi, just asking, do you have in mind who his successor will be at this stage? I have in mind, but that's where it will stay for now. Thank you. That completes most of the questions that we have online at this stage. There is one further question that is directed at Dr. Gordon, which he may wish to answer in his absence, which is asking which patients would you use Betalutin in, assuming the data holds up from the phase IIb readout from PARADIGME? It should probably be directed at Dr. Gordon. What I will say is this, and I said it in my introduction for why I joined the company as well. I have very seldom seen a company that has been as prepared when it comes to how we have characterized the patient, where the unmet medical need is, and how we therefore are able to target this unmet medical need. It's very, very seldom that you can see that in a company that are in phase IIb. That usually comes much later. I believe the organization, way before my time, have done an incredible job in outlining exactly that. I also do believe that that is where patients should benefit the most for it, so that's where I would hope that most physicians would prescribe it. I don't wanna put words in Dr. Gordon's mouth. It is probably something one would follow up with him directly on. Thank you. Just a general question, which asks, could you give any outline as to the anticipated news flow that we might expect over the coming year, other than for PARADIGME? Yeah. I would look at this space. Let me take a step back. I've spoken to several of you, several investors via email in Norwegian and in English. I've spoken to some of our biggest investors around what they are expecting from us, and one of the things that they have told me over and over again is be more transparent. Give us updates when you can. As an example, I believe today is the first time that we have ever gone out with an update on PARADIGME outside of the quarterly updates. This is our intention moving forward. That's not to say that we're gonna give updates every single week on what's happening with PARADIGME or anything else for that matter, but we will try to the best of our ability to communicate more with you, our investors, and to give updates continuously. I'm not gonna promise that we're gonna give updates on PARADIGME inclusion every day or every week or every month for that matter. I believe that, and again, I hope I've been able to make that point, inclusion for PARADIGME is going up and down almost on a weekly basis. To try and do this more often than the quarterly updates, I believe would be foolish of us. Secondly, with regards to other news, items and what you should expect from us is we want to keep an open communication with markets. We wanna ensure that you get the updates when we have the updates. What exactly will come when, I will not be able to say now. I am still two months in the job, and I know that people around me are working very hard on creating results as much as they can, but you have my commitment that we're gonna do the best that we can to communicate as much as we can with you. Thank you. We're really reaching the last set of questions now, Erik, which really center around the competitive landscape, and are asking, first of all, can you give a broad overview in terms of an update around the competitive landscape? Then there are a couple of specific questions which relate to how you view the indicated risk-benefit profile of bispecifics such as the CD3, CD20 bispecifics, and relate to some other more recent data from competitor programs, and in particular, a PI3K called zandelisib from MEI Pharma, where evidently some data has been released earlier today. Broadly speaking, could you give an update on the competitive environment, and are there any specific comments around the bispecifics? Yes. Again, thanks for that question. With regards to the competitive environment, we mentioned this again in Q3, in our Q3 updates. And what we see both in the last few weeks' worth of data, the last year's worth of data, and what is expected over the next year's worth of data, is that the positioning that we have chosen, initially for Betalutin in the space of follicular lymphoma, it is still an area of significant unmet need. What have we seen get into this area, already? We have seen CAR T products, but as Dr. Gordon said, he would, and our impression is also that his colleagues, other prescribers, will mainly use this in younger patients. There are still significant toxicity around these regimens, and although progress is being made in how this is managed, I think he gave a clear indication that this was only for a smaller group of patients. The other part of the CAR T treatments in general is that they are extremely expensive, about $500,000 per injection. As such, this is a significant burden for payers to pay. As such, again, it will remain an area of high selection when it comes to who's gonna receive these kind of products. From a PI3K point of view, I think again, Dr. Gordon and I believe he presented the vast majority of data that exists in that space. On one hand, far from the same type of efficacy as what you have seen with CAR T. But on top of that, significant toxicity as well. That seems to be the case also in some of the, at least the later PI3K inhibitors. I'm gonna ask Marco in a second to talk about the data that has come out today on MEI. I haven't been able to read through that myself, to be honest. But I think again, it kind of confirms what we have seen with other PI3K inhibitors as well. The last group of, or there's two more groups of products that Dr. Gordon was touching upon as well. One is EZH2 inhibitors. Here you obviously have a highly selected group of patients that can utilize the drug in the sense that you only have significant response rate in patients that have the mutation in the gene to begin with, and that's about 15% of patients. Finally, with the bispecific antibodies, again, I think he was also pointing towards the risk benefit in the sense of, yes, good response, but on the other hand, and I believe Pierre also talked about this, significance of toxicity associated with them. As such, I know it's a long answer, but hopefully, if you look at all of these potential competitors, I think we're very well-positioned. I would add to that as a final point, personally, I don't see CAR Ts as a direct competitor, nor do I see bispecific antibodies as a direct competitor. That basically leaves us with the PI3K inhibitors as a competitor. Again, I believe Dr. Leo Gordon confirmed this. With regards to the latest one, maybe I ask you, Marco Renoldi, to talk a little bit of what you have seen in that data. Yes. Thank you, Erik. I think we've seen the data provided by MEI Pharma earlier this morning about their phase II TIDAL trial. I think the results were not unexpected. The data, the efficacy data are aligned to the upper end of the efficacy range we've seen with PI3K inhibitors in the past. Actually not very different from the data that we have generated with Betalutin in our LYMRIT-37-01. An overall response rate in the 70% range, if I recall correctly, the press release, and a complete response rate in the 35% range. I think the median duration of response was not reached, so not provided by the company. I think what is important to remind is the side effect profile this agent is still associated. 10% of the patients in the trial were discontinued due to side effects, and we saw Grade 3 and Grade 4 adverse events, which are very typical of the class. We don't see any really different feature in terms of the safety profile of zandelisib. We read about adverse events that led to discontinuation in the GI tract, so diarrhea and colitis. I read about pneumonitis, I read about hepatic alterations. A safety profile, which is very much aligned to the safety profile of the PI3K inhibitor class. It's a good class. It's a class of agent that are effective. Is this the right drug for the patients we're trying to serve? We don't think so. Umbralisib came to the market with a similar promise, but it was associated exactly to the same type of adverse events the prior PI3K inhibitors were associated. The market uptake to date seems to confirm that, physicians understand that, and patients as well. Thank you, Marco. Thank you, Marco. Thank you, Erik. That concludes the questions that we have, that have been submitted online, so I'll hand back to you for any concluding remarks, Erik. Yeah. Just a big thank you, partly to the team here internally for their development of material, their presentations today, and the dialogue with all of you that we've had today. Secondly, to all of you out there that have dialed in to listen to our presentations, our discussions, we hope this was what you were looking for. As mentioned to begin with, we're looking for a transparent communication with all of you. We're looking to give you updates as often as we can. We're looking forward to a new R&D day in 2022 to give updates on the different projects that we have outlined today. Thank you very much for your support as investors. Looking forward to the onward journey. Thank you so much.