Everyone, it's time to get going. Very much welcome to this Key Opinion Leader Hematology event hosted by us at BioInvent. My name is Björn Frendéus. I'm the Chief Scientific Officer of the company, and I'll be acting as your moderator today. We have quite a busy schedule, so I will urge all the speakers to actually stick to their times so we get to the end before it's too late. We're very fortunate today to have a couple of leading experts with us, Guilherme Perini of the São Paulo Hospital in Brazil, and later on after the break, Stefan Barta from Abramson Cancer Center at UPenn in the U.S. This is what the agenda looks like today. We'll kick off with Martin Welschof, our CEO, who's going to say a few words about the company and our two leading clinical assets that we'll discuss today, 1206 and 1808. This will be followed by Guilherme Perini going through and introducing us to the follicular lymphoma treatment landscape, unmet medical needs and future outlooks. Our Chief Medical Officer, Andres McAllister, will give us a clinical update on our 1206 program in lymphoma, sharing some really exciting efficacy data and not the least outstanding safety and tolerability, making this antibody quite competitive amongst a highly fierce field of reagents. Finally, in the first session then, we'll have Sylvie Ryckebusch will tell us how and why it makes sense to develop this triplet in that scenario of follicular lymphoma. We'll have a Q&A session, where people will be calling in. Firstly, and not the least importantly, we'll have the audience posing questions. A coffee break, and following that, we'll shift gears a bit and talk about cutaneous T-cell lymphoma and 1808. Several of you may have attended our pre-ASCO KOL event, where we discussed the unique ability of this antibody to safely induce antitumor immunity, including in cold tumors, via differentiated mechanism. This is a truly exciting antibody also then in hematologic malignancies. That particular session will be spearheaded by Stefan Barta, who will be calling in from the outside. Without further ado, I'll leave the word to our CEO, Martin Welschof, to give us that introduction of the company and the lead clinical assets. Thank you very much, Björn, and I think this is on. Thank you for the very nice welcome and introduction, and welcome everybody who is here in the room and whoever is online. I will keep it short because, as Björn was saying, we have a very busy schedule. Just going briefly through some company background. Obviously, we are focusing on generating the next level or the next generation IO therapies, and we are in a very good position at the moment. We have basically two first-in-class compounds. BI-1808, we discussed a little bit more than a week ago at ASCO, also in the framework of a KOL event, and today, obviously, BI-1206. Both have shown activity not only in liquid cancers, as we discussed mainly today, but also in solid cancer, which is, I think, very exciting. The company as such, just for the audience that maybe never has met BioInvent yet, we are based in Lund, listed on the Nasdaq Stockholm stock exchange. We are roughly 100 people, very integrated company. We do target an antibody discovery with our proprietary F.I.R.S.T. platform, which really has helped us to identify a new exciting mode of actions. We do our own manufacturing. We basically also do formulation and clinical development. Everything under one roof, which is, I think, a very competitive setup. What we are targeting, IO, obviously, is a very exciting market, still growing. On the right-hand side, you can see that there are still a couple of bottlenecks, and what we are doing is really focusing on the number one, the immunosuppressive tumor microenvironment. Both assets that we have have an influence there, as we have shown in ovarian cancer, and as we will discuss today in non-Hodgkin lymphoma, as well as for CTCL. Very briefly before I hand over for the first speaker, to just remind everybody how the pipeline is looking. On top, you will see our TNFR2 platform, BI-1808, that we are currently developing in ovarian cancer, in combination with pembrolizumab, and at some time point this year, we will kick up also the combination with the new standard of care. We presented this actually just a little bit more than a week ago at ASCO. Very exciting data. There will be actually a further update throughout the second half of this year. The program is maturing further. Today, we discuss CTCL, where we see also very exciting monotherapy, which actually positions us in the first line. We will discuss some combination data with pembrolizumab. The first point today will be FcγRIIb in non-Hodgkin lymphoma, where we have very impressive data, more than 80% objective response, long-lasting complete responses, high quality, good duration. For both compounds, I think it is very important, and that is very ignored by the community, very good safety. What you want is good efficacy, but at the same time point, you want to have a good quality of life for your patients, and that is what we have here. Very briefly, since we are not discussing it today, we developed BI-1206 also in the first line non-small cell lung cancer as well as uveal melanoma, and there we will have the first readout during the second half of this year. I think that should be sufficient, and I think I will directly hand over to you, our first guest speaker, Guilherme. If you want to join the stage, this is to you. Okay. Good luck. Hi and good morning. My name is Guilherme Perini. I'm from Brazil. I'd like to thank BioInvent for the invitation, and I'll try to speak very briefly on a very big topic that it's the follicular treatment landscape, medical needs, and future outlook. These are my disclosures. Some things have changed in follicular lymphoma recently. I think one of them is that now we can probably say that we cure a part of these patients. We expect around 40% of patients to be cured after first-line chemoimmunotherapy. Again, we still treat these patients in first line with chemotherapy plus an anti-CD20. This is standard of care for most parts of the world, right? We know now that around 20% of these patients will eventually have an early relapse, what we call a POD 24, and these are the patients that have a higher risk of multiple relapses, transformation, and, of course, death. While we have not changed a lot in the first-line treatment, the relapse refractory setting has changed substantially because we have a lot of new agents. We have bispecifics. We have new monoclonal antibodies such as tafasitamab. We have small molecules. We already had lenalidomide for a while, but now we have zanubrutinib, golidocitinib, and also, of course, CAR T-cell therapies. I think when we think about the whole journey of the patient with follicular lymphoma, I think toxicity is very important. Safety is very important for the patient. Quality of life and, of course, access. I'm from Brazil, a lot of these drugs are not fully reimbursed in Brazil and in many parts of the world. We have to navigate through all these options so that we can have a long journey for our patients. This is what we call the chemo-free revolution in follicular lymphoma. Since 2019, you can see here most of the new advances that we had in the field are all chemo-free. Except, of course, for lenalidomide in first-line therapy. All that we get here is new agents going out of chemotherapy. There's a reason for that. We're talking about old patients, usually frail, with comorbidities. This is very important when we're deciding what treatment we're using. Bispecifics have already shown to be very active as monotherapy. Mosunetuzumab in a fixed duration have shown in patients in third line follicular lymphoma, third line plus. You have a good progression-free survival. You have a good overall survival. Again, it takes a while to learn how to use these drugs. You have, for example, CRSs. You can have ICANS, long-term infections. That could be a problem. That's the same thing for epcoritamab. Epcoritamab now it's used until progression, so it's another problem for the patients having to go to the center for continuous infusion for one to three years. That could be a problem for these patients. Again, the response rates are very high. A lot of CRs, and of course, very good PFS. Of course, we're talking about using that in monotherapy, but now we're moving to combination therapy in second line. Most of them are combined with lenalidomide, as you can see here. You have epco, mozu, odronextamab all combined with len, with or without rituximab for these patients. Of course, last year we had the presentation of the EPCORE FL- 1. That's the big phase III trial of epcoritamab plus rituximab lenalidomide. EPCORE R-squared, that we say, versus R-squared for patients with follicular lymphoma after one line of therapy. One thing that I want to call the attention here is that when we see these trials in follicular lymphoma, they're usually not the usual population of follicular lymphoma. We're talking here of a population with a median age of 60 years. They're a little bit younger than we think when we think about our daily life, real-world follicular lymphoma. Of course, this is important because these patients are usually younger. They have less comorbidities, but we still see some toxicity. Most of these patients were treated in first relapse. Most of them, of course, received prior anti-CD20, but usually after chemotherapy. As you can see here, this combination is very active. This is a finite therapy. It's one year of treatment. It's very active. Also groups benefit from EPCORE R-squared versus R-squared, and this might be the most talked picture that we had from ASH last year. Very good time to next treatment curves. I'll say that this is not as easy as it looks. We're talking about a young population for follicular lymphoma, of course, 60 years old. First relapse, we have around 30% grade 3 infections. That means patients have to be admitted to treat this infection. We see in a small follow-up. A lot of infections that, of course, might impact the patient's quality of life. This didn't lead to a lot of discontinuations, but this can be very challenging for the patient. As I like to say, it kind of adds another layer because the patient has infections and then have to do immunoglobulin repositions another time in the hospital. It kind of makes things a little bit more complicated. Tafasitamab has also been tested, TafR-squared versus R-squared. Tafasitamab is anti-CD19 naked monoclonal antibody. It increases the PFS and increases the duration of response and the time to next treatment. It's a more mature data, and it doesn't add that much toxicity compared to the bispecifics. It adds a little bit more of diarrhea, a little bit more of constipation, but it's not that important. Again, it's a balance between efficacy and toxicity in these patients. On the small molecule, what we have approved now is the combination of obinutuzumab with zanubrutinib based on the ROSEWOOD trial. They're running a phase III confirmatory trial. It's called the MAHOGANY trial. The problem with this trial is that the comparator arm is not that good. It's obinutuzumab monotherapy. It's not something that we usually do as a standard of care for relapse refractory follicular lymphoma. Again, a younger cohort of patients, median age of 63. And as you can see here, the responses are better with zanu obinu versus obinu monotherapy. What's important is this trial is because most of the trials with BTK inhibitors in follicular lymphoma didn't show a lot of responses. This is a proof of concept that BTK inhibition might work in follicular lymphoma. Again, good curves, but a very weak comparator arm. What is good about the BTK inhibitors is that we're familiarized with the toxicities. They're usually very well tolerated, especially the second generation one, so you don't see a lot of heart toxicity, cardiac toxicity, arrhythmias, and other things. What about the new generation of bispecifics who have anti-CD19 bispecifics? This is surovatamig from AstraZeneca, been shown a phase II trial to have very good response rates and PFS. Again, that same problem with the bispecifics. You have to manage ICANS, you have to manage CRS. It's not something that you can do, for example, in a community hospital in the countryside of Brazil easily. Right? Now they're running their phase III first-line therapy, the SOUNDTRACK-F1, comparing with a standard of chemotherapy, investigator choice of chemotherapy. Again, a lot of new trials on bispecifics in first line, and some of them compared with chemos, added with chemos, some of them compared to chemo, some of them with lenalidomide. It's a lot of things going on in the follicular setting. As my colleague from MD Anderson said to me, we face an era of abundance and a chaos of choice because there's so many things going on, so many options that we still have to see what we're going to do to our patients. My personal take on that is that we have improved a lot the overall treatment of follicular lymphoma, including patients with multiple relapses. Allogeneic transplant is something that we don't even consider anymore for these patients. However, we may not forget that most of the patients that are treated in clinical trials are not really the patients we're seeing in our clinics. Our patients are usually older, more frail, they have more comorbidities, and of course, we have to talk about access and infrastructure. It's not that easy to do bispecifics, especially in combination if you don't have a hospital where you can admit your patient with infections, if you can do IVIG reposition and things like that. In the end, I think what the patients want is just two things. They want to live longer, and they want to live better. We cannot forget about the better, right? I think all new agents, all these new treatments, we have to focus on increasing PFS but not compromising quality of life or increasing the risk of complications, especially infectious complications that we see that's a problem these patients have three, four, five lines of therapy. We also have to think that most of the bispecific data that we have now, it's probably what we're not going to do in the future. They're mostly monotherapy, in third-line therapy. Probably are moving to first-line therapy. We have to address this post bispecific scenario because there's going to be a reality in a few years, right? We need new options for that. Of course, we have CAR T, but CAR T is a different story. Access to CAR T in the real world is way different from what we see in the trials. Not more than 20% of patients that are eligible to CAR T receive CAR T in the U.S. You can imagine in Brazil, for example. Of course, chemo-free is not trouble-free, right? We need longer follow-up to address long-term toxicities. We just have had a big follicular trial stop, for example, with tazemetostat, due to a strong concern of secondary neoplasias, including AML and ALL. I think we need to address these toxicities in the long term because that will be very important. With that said, this is my hospital in São Paulo. If you guys never been to Brazil, you should, especially now there's the World Cup. It's going to be very, very, very a lot of parties going on. Again, thank you again for having me here, and it's really an honor to be here. Thank you. Thanks a lot, Professor Dr. Perini, for that great introduction and to the needs that are really still remaining in this field. I think it's a perfect segue for our Chief Medical Officer, Andres, to let you know how competitive we are, both from an efficacy and safety perspective. Thank you. Thank you, Björn, and thank you, Guilherme, for that really good introduction because that's exactly where we think we're playing. We're super happy about that. This is what I will talk about. Basically, combining our antibody BI-1206 with rituximab and acalabrutinib. You will see the data. Just a short reminder of years of work led by Björn and his team, where basically illustrates what happens with when you there was this conundrum in NHL, in non-Hodgkin lymphoma, where you treat patients with rituximab, patients stop responding, but you look at the cells, and they still have CD20, very difficult to explain. This is one of perhaps the most important mechanism of resistance, and that's exactly what we're addressing here. When CD20 is recognized by rituximab and FcγRIIb on the tail, that basically creates a trimer. It's internalized. You lose CD20 from the surface. If you look at expression, it's still there, but it's no longer there where it needs to be. By blocking FcγRIIb, as depicted on the right-hand side, you can expect to retain CD20 on the surface, and therefore, rituximab can do its job continuously. We think this is really important in driving resistance to rituximab, which is, by the way, a great drug described by many clinicians as a glass of water. There was attempt in terms of, for instance, ofatumumab, which was the second generation, but then followed by obinutuzumab, which basically increased the affinity to Fc gamma receptor IIIa. The important thing we feel is inhibiting, blocking FcγRIIb, which when you look at it inside the tumor, that is the most highly expressed. Very important and overlooked mechanism of action. This is basically what led us to think about the study that I'll describe. As Dr. Perini expressed, there was obinutuzumab in the recent ROSEWOOD study led to an objective response rate of 45%. In the same study, if you combine it with zanubrutinib, the objective response rate was 69%, so an improvement on that responses. There was earlier data in the field, initially some ibrutinib studies, but followed by studies with acalabrutinib in follicular lymphoma where it was excuse me, where the data was not great. There was sort of this feeling in the community that actually BTK inhibitors would not work in follicular lymphoma. We had actually seen in our doublet study, and I'll show you the data in a minute, that we had already a very nice increase too with respect to obinutuzumab. If you compare the first line, 45%, versus rituximab plus 1206, 59%, we already had a really nice increase. We figured in the context of the ROSEWOOD study, we figured if we add a BTK inhibitor, that's likely to drive very nice responses. That's the rationale. Basically, this is the doublet data, and what you can see is in follicular lymphoma, you have a very nice response rate, and you have already a PFS of about 12.5 months. That was already very enthusiastic data. We set out to do the triplet, and as we have mentioned before, we did a subcutaneous formulation that allowed very simple getting rid of most of the toxicity, and that was a great decision that we took a few years ago. We went on to try two different doses of BI-1206 in combination with rituximab and acalabrutinib, and then we completed the cohort of up to 30 patients, which is what we had set out to do. This has been completed, and basically what we're looking here is at the data of that we obtain when we do the triplet. First thing that becomes evident is that it works across the three different indications that we're treating in these studies, marginal zone lymphoma, follicular lymphoma, and mantle cell lymphoma. That's already very interesting. The overall response rate is 83%. That's very impressive with a 48 complete response rate. Importantly, in follicular lymphoma, you see 81%, so it works really well in follicular. Again, this is something that can work across the different malignancies, and this is an important feature of this drug. With a complete response rate of 44%, importantly, and as I will describe, and as Dr. Perini was pointing out, this is a very safe, no CRS, no cytokine release syndrome, no neurological toxicity, no increased neutropenia, no increased infections. Really hitting the tumor, hitting what's the concern for the patient, and allowing those patients to live a better life, which we think is a key component of this. This is the swimmer plot and the spider plot, and you can see the response is basically just saying the same thing as what I was telling you before. Importantly, we made this treatment for a year, and I think Dr. Perini pointed that out. You don't want patients to be on treatment forever when especially we're talking about these often indolent diseases. Patients want to get their treatment and go on with their lives. If they can get a safe treatment, if they don't have all these concerns, well, all the better. We fixed it to one year, and that's exactly what we're doing. By one year, basically, the treatment stops. This should be also very convenient for the patients and the clinicians. By the way, this is a two ml subcutaneous inoculation given on the same day as rituximab, extremely convenient. Takes one minute to do that. We feel that this is important. Concerning the patient population, the patient population where you've seen that data is not early stage disease. It's actually patients who have, Dr. Perini told you about the importance of POD24, and we see in this patient population that 62% of the patients had POD24. Showing that this is a particular— It's aggressive. What we're seeing in this patient population is aggressive disease. A number of the patients were refractory, 25%, that is also an important component. Just look at the toxicity because obviously, as we have been making this point, this is key. I think the key component here is 4% of discontinuation rate due to adverse events related to the drugs. This is a triplet. 4% is performing really well, and I'll show you that in a minute. Here is the safety and tolerability profile. On the very top, you see thrombocytopenia. That was something that we were concerned at the beginning. We did a great deal of work, both clinical and non-clinical, to understand what happens. We know that the antibody does not destroy platelets, that's very important. It was very important. In that context, we have never seen any bleeding associated with these platelet drops. The platelet drops are transient. The platelets recover rapidly, and then it's totally okay. We think and have preclinical evidence that the platelets are actually sequestered, and by the time the Cmax goes down, basically the platelets are released and remain active. It's totally something that we now understand a lot better and feel very confident that this is not a problem. Aside from that, the profile is basically what you can expect of these three drugs. Initially when we were dosing the drug IV, we saw some liver enzyme elevations. We basically don't see them or they are moderate now for the most part. This is, again, a very manageable safety profile without causing any trouble. Again, I want to stress this point because you don't have cytokine release syndrome. You don't have neurological toxicity. You don't have the step-up dosing. You don't have to have other drugs on your left-hand side to treat those patients. Basically go to the hospital, get their treatment, go back home, and live the best life that you can offer those patients. That's our idea. Just this slide to show you slightly how this compares with others. In terms of efficacy, we are right up there where many of the compounds that Dr. Perini mentioned. Many of these compounds achieve that with lenalidomide, not a great drug, and yet our compound is right up there in terms of efficacy. In terms of safety, look how it compares the green bar versus the other bars, and that's where we think this compound has a great positioning in the community. As Dr. Perini mentioned also, most of these patients, 80% of follicular lymphoma patients are treated in oncology practices that are outside of the hospital. That's where you need to be, and that's where this convenient and safe approach can be very relevant. Just to state here that obviously, we don't have yet enough data to show the PFS, but the PFS has not yet been assessed. For the durability, it was 12.5 months, so that's very good. This is just basically a recapitulation of what I wanted to tell you. In terms of timelines, final slide. We have now fully enrolled the study. We will have the full data set during the second half of this year. Our idea is to go have a type C meeting with the FDA to discuss the data set, but in particular, the dose, and also to propose a pivotal study design. We will be requesting breakthrough therapy designation, and we will be pretty much ready to push on the button and start a pivotal study whenever we can do that. Thank you, and thank you, Björn. Thank you. Thank you, Andres, for that great walkthrough of our clinical data. Hopefully it's really evident that we seem to be addressing several of the concerns that Dr. Perini had just raised in his talk. Now, it's time for Sylvie Ryckebusch, our Chief Business Officer, to walk us through how this fits in from a marketing and commercial perspective. Thank you. Thank you, Björn. First slide. Oh, it's me. Okay. All right, this slide illustrates a phenomenon with which you may be familiar in our industry, which is called asset herding, showing the number of different assets being developed against the most popular targets. It's a structural problem across oncology, and it's particularly bad in B-cell lymphoma. The majority of development programs chase the same targets, CD20, CD19, and of course, the CD3, CD20 bispecifics. When a mechanism fails, the value destruction is very significant. The collapse, for example, of the PI3Kinase class, which is a recent example, caused the discontinuation of a number of approved and late-stage programs, leading to hundreds of millions SEK of capital destruction, essentially. Even when a class successfully reaches the market, companies then have to struggle to fight for market share. BI-1206 is not in that race. This is the only clinical-stage antibody targeting FcγRIIb. We're in a class on our own, and we think that that's a very important component of the commercial value of this program. Dr. Perini has already talked a bit about follicular lymphoma, and particularly the treatments, but I'll just talk a little bit about the epidemiology. A few specific points. Follicular lymphoma is the most common indolent non-Hodgkin lymphoma. There are about 60,000 treated patients across the U.S. and Europe. There are over 28,000 new cases per year. What's very important to understand about this indication is that this is an indolent disease. What does that mean? It means that patients live with the disease for a very long time, and they cycle through treatments. They live with the disease, they cycle through treatments. It's chronic and relapsing. Even though, of course, maybe there are more cures today, still a large fraction of the patients do relapse and have to get treatments over and over again. Every patient from a marketing perspective is a recurring multi-line opportunity, which means that the longer a patient stays on your drug, and also whether they come back to the drug, is actually important for the economics of the program. I'm not going to repeat. The problem of going last is that I'm repeating what other people have already said. Just briefly, Andres has taken you through this. I'll just summarize. We're seeing response rates in the 80s, complete response rates in the mid-40s, 100% disease control, durable responses, low discontinuation rates. In addition, I'd like to say that compared to our projections a couple of years ago, our data's actually looking better than what we predicted. It's actually looking better as the data matures, which is really, really good news for this program. We didn't actually plan a trial to measure PFS or overall survival, but the early responses that we're seeing are extremely positive and lead us to the conviction that we have a very durable treatment on our hands. Of course, the safety and convenience has been already mentioned with potential for infusion-free administration. Again, Guilherme Perini has already mentioned the treatment landscape. It has shifted decisively in the last 18 months. Second-line follicular lymphoma used to be treated with R-squared, lenalidomide and rituximab. It's now defined by this new wave of chemo-free combinations. They've raised the efficacy bar, but they've done it at a cost. As it's already been mentioned, cytokine release syndrome, high-grade infections, step-up dosing, first-cycle hospitalization, and discontinuation rates for some of these treatments approaching one in five. This safety cost is precisely the gap where we see our treatment fitting in. As Guilherme Perini said, as these treatments move into earlier lines, it's actually creating an opening for what comes next. What comes next, we think, is we have a very competitive treatment. This is one depiction of the competitive field and where BI-1206 plus rituximab plus acalabrutinib fits. On the Y-axis, we have overall response rates. On the X-axis, we have discontinuation rates due to adverse events. What we can see is epcoritamab, which has shown these really outstanding responses, is up in the upper-left quadrant, where this is actually high efficacy but high toxicity corner of this graph. We've got R-squared. We've got a couple different data points for R-squared, depending on the trials. They're increasingly outclassed on efficacy, relatively tolerable, not wonderful. Then we have BI-1206 plus triplet in the upper right-hand quadrant. The upper right-hand quadrant is the safe place to be. It's the good response rate with a safe treatment. That's where we are all by ourselves, the way that the quadrants have been drawn here in that corner. This is actually a commercially very valuable place to be. I would like to emphasize, because this is something that is often ignored by our industry, safety is not a soft benefit. It's actually a commercial multiplier. For example, in CLL, the second generation BTK inhibitors actually took the market from the incumbent not on efficacy, but on tolerability. Right? Low discontinuation means patients complete the therapy. That means you sell more cycles of your drug. That means that you have more patients that are eligible. You have the frail patients that are eligible, the elderly patients. Avoiding the CRS avoids the inpatient burden that drives up the cost. People also don't talk about the cost of these bispecific therapies. There's actually an additional cost linked to just treating the side effects, right? The hospitalizations, et cetera. Every approved bispecific requires step-up dosing, and the labels recommend hospitalization or inpatient monitoring on drug initiation. We don't have any of this. This is really a commercial multiplier for the sales of our drug. This is the actual reality. This is a survey that was done of U.S.-based clinicians in community hospitals. What U.S.-based clinicians in community hospitals are saying, 88% of them are saying that it's very challenging to access and administer CAR T in that setting. This is in the U.S., right? This is not in other parts of the world. 59% of those clinicians in community hospitals in the U.S. saying that it's very challenging to access and administer bispecifics compared to the academic setting. A few numbers here. There are 5,000 community hospitals in the U.S. 55% of oncology care is delivered in those settings. Okay. This is actually a very important market opportunity, which we think we can capture with our treatment. Some numbers here. We had done a market research study, a primary market research study with Eversana Consulting a couple of years ago. We've revisited that, and we've refreshed it to take into consideration the current market. We have estimated very conservatively SEK 700 million sales globally, not including China, for second-line follicular lymphoma alone with BI-1206. This is conservative. It doesn't take into consideration a number of upsides, including obviously the potential in other indications, because obviously BI-1206, its potential is not only in follicular lymphoma, but also in other lymphomas and of course, potentially even in solid tumors. We also have, of course, orphan drug exclusivity in the U.S. and Europe. We have a very conservative pricing estimate based on a small premium to obinutuzumab, which is not really standard of care, and this is an older drug that was approved years ago. We think this is actually a very realistic, and possibly on the low side, estimate of the market potential for this drug. In summary, BI-1206 is a rare first-in-class mechanism. It's in a market that's actually crowded with a lot of me-too approaches. It addresses one of the largest indolent populations in lymphoma, where revenue recurs across years and years. It occupies a very valuable position in second-line follicular lymphoma, real efficacy, safely, community-friendly, high tolerability. This is not, again, a footnote but a driver of commercial value. We are de-risking this in real time as the data actually continues to improve. We think we have a really competitive profile for our program, and we look forward to keeping you updated as the data develops. Thank you very much for your time. Sorry? Yeah, no. Okay. Thanks a lot, Sylvie. Yeah. Maybe I will ask actually all of the speakers, thank you so much for staying on time, guys, to the stage, we'll have a question and answer session, I'll try and direct questions to whomever I seem most appropriate. Yeah, please fire away. This is your chance of getting Yeah. Thank you. Could you comment a bit on the clinical future development for this BI-1206, the path timeline for phase II-B, phase III, et cetera, commercial start is, I saw 2030 was the projection. In our estimates here, we've based the modeling on a 2032 approval. This of course, depends a bit on financing and our ability to actually bring online a large number of clinical sites worldwide. These timelines are a bit dependent on how quickly you can enroll patients, but that's what we've estimated. Yeah. Andres, you want to comment something or? From the execution standpoint, we feel confident that the competition is huge, obviously. There is phase III studies, everyone is trying to place their compound, there is a lot of muscle in those companies that are doing it. In that respect, something that we did a couple of years ago, we decided to go to Brazil. We thought that was a great decision. We have had great engagement from the clinicians over there. Basically, we were able to complete the study within timelines. We feel confident that if we are in a position to push on the green button, we will extend that to other places where we think we can have a good footprint and extend the activities that we do in places like São Paulo. São Paulo is 15 million, something like that, 10- You see the whole metropolitan area is 20 million people. 20 million-30 million, how you define the- Will the focus be to out-license and make another big pharma to develop it further into the phase III, or? Maybe for Martin? That's in the cards, obviously. The current plan is basically to be ready for the pivotal study in non-Hodgkin lymphoma next year. As we speak, we have partnering discussions around that program. Maybe one comment is that we've generated data with acalabrutinib. That was the BTK inhibitor that was at hand for us because AstraZeneca showed interest. The potential development is not restricted to acalabrutinib. You could imagine something different if a different partner came around. That wouldn't complicate the execution because we already have sufficient knowledge on the dose of BI-1206. We have understanding of how it works. It would just basically, as has been done in other instances, you would just need to do a little bit of a lead-in safety and then go on with your pivotal study. It's not restricted to acalabrutinib. It can go with other BTK inhibitors. Okay. Why don't we mix it up a bit then and have some questions from the online guys whilst the other team sitting here is thinking about what you want to ask. See if the tech team are ready for that. Happy to shoot one in between if that's okay. Please. Thank you. Yeah. Perhaps a question for Guilherme then. I was just curious sort of how you see BI-1206 fitting into this expanding palette of options that you have. Safety is obviously a key benefit. ORR seems to be within range of what's been reported with bispecifics and CAR Ts, CRRs are a bit lower. How does that guide you? Do you see BI-1206 primarily as a treatment for the sort of more older and frail patient that wouldn't be able to tolerate the more aggressive options? How big would that share of patients be in the clinic of the patients you see today? Yeah. Well, I'll tell you, I'm an investigator on the trial, so I have a lot of experience with the drug, and I would say that I was personally very impressed with that. Not only the response rates were very good, and it's very easy to deliver. I also participate in a lot of other trials, including surovatamig and epcoritamab and everything. It's a different game. For surovatamig, you have to have the patient as an inpatient to do the ramp-up and everything. It's a little bit more complicated. I think this is probably going to be for all comers. You can, of course, niche it to the elderly or the frail, but I think it's really easy on the patients. You just go there and take two shots and go home. I think this is very good. For me, the most important thing in follicular nowadays is not only the response rates, it's the safety, because these patients can have 20, 30 years long journey. I think that's probably going to be for everybody. In Brazil, Epco is approved only in third-line therapy, so outside of clinical trials, I would not be able to do it. I think it's a very good first salvage for a patient who has failed. Of course, the rate of POD24 in the initial data is very high. It's 41%. It's usually higher than what we see in other trials. I think it can be for everybody, but for the frail and with comorbidities, of course, I would go with this combination. Okay. Thank you. We have Richard Ramanius calling in from the outside. Richard, are you ready to ask your question? Yeah. Yes, hello. Also a question for Guilherme Perini. You mentioned a lot of clinical studies. How translatable do you think these are to the real world, considering you mentioned patients are a lot younger and so on, while in the real world, most people are older and could perhaps not even tolerate those treatments? Well, I have a saying to all my fellows that I say, "The first thing you have to do with a follicular lymphoma patient is not to kill him with toxicity." For example, EPCORE + R-squared is a very good and active regimen, but it can be very toxic. We're still in the first patients with surovatamig, the anti-CD19. I really think that there's going to be a lot of these agents, but we're probably going to lean on more on the safer ones. For example, what happened in the U.S. with mozu. Mozu as single agent is very used in the U.S. because it's very soft on the patient. I think what we're seeing here now is a change between we're more focusing on PFS, but we're slowly putting into account that toxicity, especially with these new agents, can be very challenging. I don't know if I answered your question, the whole. I think that's- Yeah. Thank you Good answer. It's good. Do you have more questions, Richard? That's all from me. Thank you. Great. We'll then move on to Dan Akschuti. Do you want to introduce yourself a bit? Here is Dan Akschuti from Pareto Securities, biotech analyst covering BioInvent. Thank you for taking my questions. Just a question to Dr. Perini, but also the team is, obviously the data is really strong so far, but it's I think now 23 patients, and the data from epcoritamab that you've mentioned has 488 patients in the phase III trial. How do you compare the side effect profile between such very different data sets and what gives you confidence that this side effect profile will hold up even in a larger trial, both scientifically and also comparing to earlier data sets from these other drugs? Thank you. That's a very good question. We know that every time that we move from a phase I/II to a phase III trial, where we have a lot of sites and different profile of patients and investigators, you can see some change on that. I think what's the main thing that we have to see is that the toxicity in the EPCORE + R-squared, it was not unexpected. For us physicians that work with a lot of combination with lenalidomide can be very challenging for some patients. Diarrhea, neutropenia, it can be a little bit tricky. Of course, epcoritamab can also be a little bit tricky in some patients. When we did the combination, it was kind of expected to see that. The initial data that we have on the combination from BioInvent, it's a little bit different. We really didn't see a lot of toxicity. The toxicity that you see here, it was kind of expected as well for rituximab and for acalabrutinib. You see the second most adverse event was a headache that's probably 100% related to acalabrutinib. Of course, it might change a little bit, but I don't think it's something that it was unexpected for both the EPCORE + R-squared and also for the BI and then the whole combination. I'd like to add something actually to that. That we have 23 patients in this data set, but we have a lot more patients that have been treated actually with BI-1206 across the different trials that we're running. There's a much larger set of patients in which we've observed a very safe profile. Maybe I can comment on that. Yeah. Yeah. BI-1206 has been administered in different contexts to a number of different patients, different indications. I don't know the exact number, but we're well over 150 patients. The safety, we pretty much understand where the issues were. Thanks to the development of the subcutaneous formulation, we got rid of the large majority of those issues. I feel quite confident that you're not going to see big deviations from what you see here. The other important part of this triplet is that it's associated with rituximab. Clinicians, you don't need to explain anything about rituximab. They know exactly what it is. Acalabrutinib is also a very safe drug. Both of those drugs are really well-tolerated, well understood from clinicians, and we're not adding very much to that. I think we, yeah, you can always see something unexpected, but it will not be dramatically different from what we have today. Thanks, everyone. Thanks for the great questions and for the team addressing that. Anything left? Yeah. Maybe just one more from me, if I may. For you, Björn, and whoever feels inclined. A lot is happening in the frontline setting now with all the different combos, and despite the limitations, I think it's fair to assume that slightly fewer patients will transition to later lines of treatment. I'm just curious, with you sort of characterizing the dominant mechanism of action as counteracting the rituximab resistance, is there a case for the frontline setting as well? Scientifically, there's certainly, I would say it's not much of a limit to combining with rituximab, be it different regimens or being in different lines. I would leave the practical perspectives of this to my clinical colleagues. Mechanistically, certainly, it's super safe. It does enhance rituximab. Preclinically, we have tested a number of different combinations, and there's actually no magic to this. What it does is it enhances rituximab. Okay? If you use rituximab with drug A, B, or C on top of that, it still seems to work better. I think there's indicated great utility, and then the question is, of course, what's the medical need and those sorts of things. Maybe one additional comment. A lot of these patients, and maybe we can redirect the question to Dr. Perini. When indolent disease presents, some patients are treated only with rituximab. If you treat those patients with the combination of rituximab plus BI-1206, that would be super interesting, probably a lot more long-lasting situation. Very difficult to do the clinical study in the current context. Once the drug gets approved, it's something that you could imagine doing and positioning yourself in those early-stage patients that are longing for a good life without toxicity. You would just give them rituximab in combination with BI-1206, and that can be a huge expansion on the usage, which will make Sylvie very happy. I think that's definitely something that you can have in mind. We couldn't do a study like that today, it's definitely something that once the drug gets approved, is something that can be done. Maybe your thoughts on that. I think the backbone of treatment of follicular lymphoma still remains on anti-CD20 axis. You can do it by monoclonal antibody, you can do it by bispecifics. Moving away from CD20 is a long way. I think that we have trials on that, real-world data setting, I think that 98%, 99% of our patients will be treated with an anti-CD20. If you have a way to make it stronger, for me, makes total sense. I don't think we're ready in a global perspective to move already to bispecifics in first-line therapy. This is very challenging operationally and everything. I think I don't see a lot of change. I think we can add something on the anti-CD20, the anti-CD20 will remain the backbone of indolent lymphoma treatment. Thank you. I think that's a great way to end this session. It's been really good. Again, thanks to all of my colleagues that have presented, Thank you guys for asking some really good questions that I feel have been pretty comprehensively addressed. Without further chats from my side, I think it's time for a coffee break, and we'll reconvene at 1:00 P.M. sharp. Yeah. Thank you. Thank you. Thank you. Thank you. Thank you. Okay. It's time for the second session of this key opinion leader hematology event that BioInvent and then management are hosting. It's now time for us to welcome Dr. Stefan Barta of Abramson Cancer Center at UPenn. Thank you for being with us. Stefan, can you hear us? Yes, I can hear you very well. Wonderful. Thank you. You're all right. Dr. Barta, he leads the T-cell lymphoma program at UPenn and has a lot of experience in treating these types of diseases. You have a special interest in immunotherapy, cell therapy, different kinds of biomarkers to help identify what patients are going to be treated with what drugs. In other words, very important knowledge about our game. Without further ado, I will give the word to you, Stefan, to walk us through the treatment landscape in T-cell lymphomas, in particular cutaneous T-cell lymphomas. Thank you. Glad to join you virtually. Would be great if I would be there in person, that would have been a lot of travel for 15 minutes. I do not see my slides up as yet. You say, "Next slide," I will advance them for you. All right. Well, I see right now coffee break until 1:00 P.M. I do need the next slide. Yeah, it's coming up. Just a second. All right, no worries. Thank you. I think we need a different set of slides there, yeah. Next one, please. Okay, that's me. Okay. All right. Here we go. Okay. Thanks again. Thanks for having me here. While Pittsburgh is also in Pennsylvania, I'm from Philadelphia, the University of Pennsylvania in Philadelphia. These are my disclosures. All right. Very good. Today, I'll be focusing on cutaneous T-cell lymphoma, given that this is where we have had most of the experience with BI-1808, especially here at UPenn. As many of you may know, T-cell lymphomas are a very heterogeneous group of diseases, and that includes also the cutaneous T-cell lymphomas. Those are T-cell lymphomas that mainly involve, as the primary site of disease, the skin. It's only less than 4% of all non-Hodgkin lymphoma diagnoses. There are about 9.6 new cases per million in the U.S. The majority of these are mycosis fungoides, there is a small animation. If you want to click next slide, it should come up. Very good. Mycosis fungoides itself has several variants. If it involves the blood, it's called Sézary syndrome, we'll get to that in a minute. It's a disease that has a very chronic course and often has very debilitating symptoms such as pruritus. At the bottom, you see that the main involvement of the skin is through patches and plaques. On the panel A is a patient who has erythroderma, where nearly all of the skin is involved by the disease. This erythroderma, the erythema, the red skin, involves most of the patient's body surface area. Next slide. The disease is a disease of older patients, 55 to 60 is the median age of onset, with a slight male predominance. Many of the patients are Caucasian. It can be sometimes very difficult to diagnose and require multiple biopsies and actually multiple years. The average time from first symptom to diagnosis is 3 to 5 years. We have criteria here that you can see in the table because the skin biopsies can be sometimes very confusing for the pathologist to come up with a diagnosis, and that takes into account clinical features, histopathological features, molecular features such as T-cell receptor rearrangement, and immunohistochemical features. Sézary syndrome is the cells in mycosis fungoides and Sézary syndrome look the same. They're usually CD4 positive, CD7 negative, CD26 negative T-cells. In Sézary syndrome, patients need to have not only biopsy-proven skin involvement, but also erythroderma, as I had shown you before, and leukemic blood involvement, where the Sézary cells make up more than 1,000 cells per microliter. Next slide, please. The staging gets somewhat complicated. We don't use the Ann Arbor staging as for other non-Hodgkin lymphomas, we use a staging that assigns extent of disease to each compartment, mycosis fungoides and Sézary syndrome are multi-compartment diseases. They originate in the skin in nearly all patients with very few exceptions, the way we assess the skin is by percent body surface area involved. 1% body surface area involved is the palm of each patient. That gets staged as T1, 2, 3, or 4. T4 is erythroderma. T3 is actually tumors because we also take into account how thick the involvement is, whether it's a patch, plaque, or tumor. Tumor is T3. We look at the lymph nodes, and there they can just be enlarged as a reactive cause to the disease, but they can also be involved and look the same as a peripheral T-cell lymphoma to the pathologist under the microscope when a biopsy is being done. There it gets staged N1, 2, 3, and 3 is the lymph node's replaced by malignant T-cells. We also have blood involvement, and here it's the amount of Sézary cells. More than 1,000 is B2, less than 200 is B0. Everything in between is B1. We take this all together with a T and MB staging. M stage stands for visceral disease, and we get to stages 1A, B, et cetera, to 4B. The ones that are considered advanced disease are 2B to 4B in red, and they usually have either significant skin involvement, nodal involvement, or blood involvement. Next slide. Staging is usually done to tell us about the prognosis of the patients, but it does differentiate between prognosis, but it's not that good. As you can see, stage III, for example, does better than stage 2B. Those are the patients with tumor stage. Next slide, please. You can see that again here. You can see on the x-axis you have time, on the y-axis you have the risk for disease progression. In T3, that's the patients with tumor stage have the highest risk of progression. Next slide. It's not a static disease. It's a dynamic disease where patients can move from stage to stage, and the probability of that depends on how advanced their stage is. It's the lowest for stage 1A, gets high for stage 1B where we have more skin involvement. In stage 2B, again, that's the stage where we have tumor involvement. Nearly half of them progress to a more advanced stage even over the course of time. Next slide, please. In order to account for the lack of the prognostic implications of staging, people have come up with other ways to prognosticate patients. This is a study published just recently in "Blood" from the PROCLIPI registry, which is a prospective registry for patients with cutaneous T-cell lymphomas that is including 20+ worldwide sites. They came up with other factors such as age over 60, a raised lactate dehydrogenase level, N3 nodal status, that's the nodal status where the lymph node is replaced by malignant T-cells, large cell transformation. Sometimes these skin patches or plaques can transform to large cell and have a more aggressive course. These factors have prognostic significance. You can see that the low risk, intermediate risk, high risk separates much more clearly than patients if they are prognosticated using stage. What I want to draw your attention to is patients with a high-risk stage at five years have a probability to be alive in less than 20%, the median overall survival for those patients is only 25 months. Next slide. In general, again, we have some guidelines giving guardrails of how we treat the disease, the early stages are usually treated with what's called skin-directed or topical therapies. That includes steroids, light therapy such as UVB or UVA light therapy directly to the skin, or topical radiation, localized radiation to areas of concern. For more advanced stages, patients usually require systemic therapy, oftentimes we combine systemic therapy and skin-directed therapy, for stage IV particularly, we use extracorporeal photopheresis. Next slide. What we do know, as I mentioned, mycosis fungoides and Sézary disease are multi-compartment diseases. We do know that different drugs have different activity in different compartments. Here again, on the left side of the slides, I kind of point out how early stage and advanced stage is treated. On the right side, you have some of the currently approved and commonly used medications. Dark green indicates that there's very good data supporting its use and its activity in that compartment. For example, brentuximab vedotin, romidepsin, and pralatrexate have data and have reasonable activity in the skin compartment. For example, pralatrexate has very little data supporting its use in blood, and brentuximab has nearly no data for the use in blood. We see that mogamulizumab, for example, can work in the skin, especially in patients with erythroderma, but has the best activity in blood, but not so much activity or limited data for lymph node disease and large cell transformation. It gets very complicated for each patient how you pick your therapy. Next slide. What we also know from quite some time ago, this is a The New England Journal of Medicine paper from 1989, where investigators compared outcomes for patients treated initially with chemotherapy. They actually used CHOP versus sequential other therapies, for example, interferon and radiation. What you can see on the right at the top graph, with chemotherapy, which is marked as combination with hollow dots, you get a significantly higher complete remission rate. However, at one year, the curves end up the same in terms of remission, and disease-free survival is the same whether you approach this disease very aggressively with chemotherapy or conservatively with sequential, usually single agent therapies, which has been the approach since the '90s until now. All right, next slide. This is from a study from Australia, from the Peter MacCallum Cancer Centre, where they looked at different therapies that have been employed, different systemic therapies. As progression is sometimes very difficult to measure in this disease because patients can have a great response and then they come up with a patch, but that doesn't really mean the therapy doesn't work. It's a very heterogeneous disease, even within the patient. Time to next treatment is often a better indicator of how well therapies work. There, interferon and immunotherapy by far outperforms all the other therapies like HDAC inhibitors, like romidepsin and chemotherapy. Clearly, it's somewhat biased. It's very hard. Why did I use chemotherapy in one patient and interferon in the other patient? Probably because they have features that make them better candidates. That is also the experience that most investigators have, that immunotherapies really do work well, and we'd like to avoid aggressive chemotherapies because many of these patients are very immunosuppressed at the time of therapies, and therapies can lead to significant infections. Next slide. Here is a list of the drugs that have been approved and are commonly used currently. Mycosis fungoides and CTCL, you have the ALCANZA trial looking at brentuximab, I have a slide on that later, and the MAVORIC trial looking at mogamulizumab. Those are probably currently the most active two drugs. There you can see the overall response rate is in the skin, for example, for Brentuximab, relatively high at 65%, but only a low complete response rate, the median progression-free survival is still less than two years, this is only in patients who have CD30-positive disease. Then you look here at the comparator oral methotrexate or oral bexarotene, whereas you see further down for the drugs like bexarotene, a response rate of 54%, in real life here and in this very well-controlled phase III trial, it was only 16%, so a very low response rate. Even mogamulizumab, which we use a lot, particularly for Sézary syndrome, had an overall response rate in the MAVORIC trial of only 28% and a median progression-free survival of less than one year. If you go to the next slide, this is again a slide showing you all the drugs we use based on compartment and what the response is in the compartment. When you look at response, we often use something called global response, that is determined by the compartment in which one has the least response. Meaning, for example, you can have with mogamulizumab 100% clearance of your blood. That would be 100% response in your blood. If you only get 20% or 30% reduction in your skin, that's still only stable disease as a global response. As you can see, drugs have different outcomes in different compartments. The ALCANZA trial is probably No, you can stay at the ALCANZA trial. That's the trial looking at Brentuximab compared to methotrexate in patients with CD30-positive mycosis fungoides. It was a randomized trial. Next slide. There you can see a quite good skin response, particularly compared to methotrexate and bexarotene. The issue with Brentuximab is that unfortunately, it has significant side effects in terms of the neuropathy, its use is often limited to a year or two years due to the side effects, particularly, as I mentioned, the neuropathy. Next slide. Mogamulizumab is the drug we do currently prefer for patients with significant blood involvement, this is the MAVORIC trial, where patients were again randomized to the oral HDAC inhibitor vorinostat. You can see that mogamulizumab had a nearly double progression-free survival improvement compared to that drug. Again, at 12 months, more than half of the patients have relapsed, unfortunately. Next slide. This is a drug as we are talking about future directions that has some interest. It's a KIR3DL2 monoclonal antibody, it has been looked in mycosis fungoides that are positive that express KIR3DL2 or don't. In Sézary syndrome, the activity in mycosis fungoides was relatively low, but there is some activity in Sézary syndrome, which you can see with best global response about 35%-37% in the progression-free survival. Again, unfortunately under one year. This is probably the drug that is closest to embarking on a phase III trial looking for approval in Sézary syndrome. Next slide. In summary, we have mycosis fungoides as a chronic disease that involves multiple different compartments. Patients with early stage have a relatively good prognosis. However, patients with advanced stage have a poor prognosis and have a significant disease burden due to mainly the itching and the skin appearance. Immunotherapeutic options appear to have the most promise, that includes different interferons. Photopheresis, we consider it as an immunotherapy. For example, pembrolizumab is not approved for that setting, but has a response rate of about 30%-40%. You have to pick your patients right, but we feel these are the most promising drugs currently out there as the disease is incurable. Although it's an uncommon disease, patients live for quite some time and go through sequential therapies relatively rapidly. For many patients during their lifetime, you use all of the approved drugs and then some, because unfortunately, the response rate currently remain relatively low. The only curable approach is an allogeneic stem cell transplant. There's a big need for effective and well-tolerated single-agent therapies, such as, for example, as we may have with BI-1808. Thank you so much. Thank you so much, Stefan. There's applause here from the crowd. I think that was a perfect introduction for Andres, again, our Chief Medical Officer, to let you know how our safe immunotherapy actually is indicated to help in several of those instances. Take it away, Andres. Thank you. Thank you, Stefan, for such a great introduction to the topic. If we can get our slides up. All right. I'm going to tell you a little bit of our journey in developing BI-1808 for the treatment of CTCL. Clearly, this is what we have been doing. The idea was to develop, after our phase I, we did expansion cohorts both as monotherapy and in combination with pembrolizumab as part of our ongoing clinical development of BI-1808, that along the solid tumor data that we discussed just a few days ago. Currently, we have pretty much finished the early phase of the study, and right now we are doing what is depicted here as the dose optimization, where we're testing a low dose and a higher dose. We know that the high dose provides full receptor occupancy for the three-week dosing interval. We also know that if you give 250 mg, you provide full receptor occupancy, but it doesn't last for the full time, so it allows a little bit of time for the drug to go down, and then again, you go up. That's basically where we stand, and in parallel to this, we are also running the combination with pembrolizumab. You'll see a little bit of the first shot of the data. Interestingly, what we've seen so far is, well, the first, I won't go through the background, but what is important to note is that TNF receptor two has come up as an interesting targeting this disease, not only from our group, but from others as well. That's already very interesting. Just for you to remember, BI-1808 is an IgG1 monoclonal antibody, fully competent. That means that it can deplete cells that express the receptor. If a tumor cell expresses the receptor, it will help deleting that cell. It also has the immunotherapeutic component, which we feel it's very important. That immunotherapeutic component is basically decreasing Tregs populations. Those Tregs we have looked into what that does to Tregs, and you see that depletion of Tregs. As Björn usually says, CCR8 positive cells, those are the most immunosuppressive Tregs. It also does something that Treg deleters per se do not do, and that is hugely important. It modifies what happens inside of the tumor microenvironment. It makes myeloid cells evolve into a pro-inflammatory type of cell. Those cells are quite plastic. They can change as opposed to other more committed immune cells. That is also very important because it allows what you want to have at the end of the day, which is infiltration of CD8+ T-cells of the tumor by CD8+ T-cells. We achieved that. We have shown that in human beings, and we have shown that in both solid tumors and our cutaneous T-cell lymphoma patients. That's, I think, very exciting. All of that has yielded to what we see here. An objective response rate of 40%. Of course, this is a small data set, but that's where we are right now, with a high disease control rate. Importantly, one of the patients is in complete response after finishing the two-year treatment period, and that's, of course, very exciting. This patient goes to the hospital, gets the infusion. No side effects and goes on with her life very happily. I think that's very important. I'll also show you a little bit of what we have seen in a couple of patients with PTCL. This is the waterfall plot. You can see here what I was talking about. Importantly, for this drug in this page, we obtained first orphan drug designation. We have obtained fast track designation for CTCL. We had a couple of patients with PTCL up until this time. On the right-hand side, you see the combination with pembrolizumab. We are better than the 30-ish something% that has been reported for pembrolizumab. We're seeing half of the patients responding, that's exciting. As we have been discussing during our previous session, and it applies to this as well, all that can come with toxicity, and that is something that one needs to manage, but it is important.zA Important to note that this is a heavily pretreated patient population. The majority of patients here had a large number of previous therapies. 33% had exposure to mogamulizumab. You probably know that mogamulizumab is, as Dr. Barta mentioned, this is a very heterogeneous disease, and what is given to patients is very chosen, very specific according to the disease and how it presents. The fact that this patient population has been exposed to mogamulizumab speaks loudly about how heavily pretreated and how advanced the disease is. This is usually not that exposure. Many places in Europe, you don't get mogamulizumab unless you have really advanced stage Sézary syndrome. In our particular case, 40% half the patients had Sézary syndrome. You probably remember that of CTCL, Sézary syndrome in the general patient population is about between 6% and 8% of the patient population. The fact of having 47% speaks also volumes about how this is an advanced situation. Here is the safety profile. What we have seen is very mild and moderate adverse events. I think the key number here, again, is the discontinuation rate. We've seen 4% discontinuation rate due to adverse events. I think that's a key thing. On the right-hand side, you see what we have seen with the combo. Importantly, is pretty much what you can expect of pembrolizumab. That is already very nice to see because we're not adding a great deal of toxicity to what pembro does by itself. All in all, it's very well managed. I maybe just summarize here that this represents a novel therapeutic strategy for CTCL. This is different. This is a first in class. No competitors as we know for the time being. It generates very good comparing the efficacy of this treatment in the population that we've treated is very comparable and even better to the number of other agents. That looks very good. Very safe profile again, very well tolerated. The responses, and in particular, one thinks about that patient who had a complete response with BI-1808. Yeah, maybe I'll stop there and maybe. Sorry. This is a couple of just anecdotal cases. This on the left-hand side is that patient with PTCL who had a partial response. You see disappearance of. This is baseline versus week 9 scan, and you see the disappearance of the lesions in all of the shoulders, et cetera. Very nice partial response. On the right-hand side, you see healing of those skin lesions in a patient with CTCL. Concerning our timelines, right now we're pretty much finishing this dose optimization. We are comparing two different doses, as I mentioned before, 10 versus 10. Soon as we have that data set and we complete the assessments that are still ongoing in the patients with pembro, we will be able to go to FDA, discuss the dose, discuss a potential pivotal study design, and then request breakthrough therapy designation. We already have fast track, request breakthrough therapy designation, and we would be ready to launch a pivotal study some time in the first half of next year. Thank you, and thanks very much. Thank you, Andres. That was a great walkthrough of BI-1808, another safe drug that seems to have activity in different stages and forms of the disease. Now time for Sylvie to come back and let us know how this is best developed from a commercial and marketing perspective. Thank you, Björn. First of all, rare disease oncology is one of the most capital-efficient routes to the market in our industry. Clinical trials are smaller and faster. Approval can be obtained on the basis of response rate rather than survival. We also have regulatory incentives. We have seven years of market exclusivity in the U.S., 10 in the European Union. We have tax credits. We have fee waivers. It's a good place to start to launch BI-1808. Commercial model is also favorable. I'll show you later on, we did some market research which showed that actually, premium pricing is absolutely supported across all of the markets, across a very concentrated academic base of prescribers. Therefore, you actually have high margins on what is a small commercial effort. This is, of course, a well-established route to value creation. A couple of examples, ADCETRIS or brentuximab vedotin, reached the market on a single-arm study in 2011. Moga followed the same orphan path in CTCL. BI-1808 is already established on this path. We already have fast track and orphan drug designation secured in the U.S. Therefore, this is a rapid, capital-efficient, and de-risked strategy, providing a foundation for a much broader TNFR2 platform. Of course, rare disease oncology is a great market entry. BI-1808 is a great molecule with which to enter the market. It's the most advanced TNFR2 antibody currently in development. We do have a few Chinese competitors, but they're way behind. We have a clear first-mover position. The mechanism of action is differentiated from that of the established agents in CTCL, as already presented by Dr. Barta. It depletes Tregs, it promotes expansion and filtration of effector CD8 positive T cells into the skin lesion. Of course, this is a novel immunotherapy mechanism with platform potential across multiple tumor types. We're advancing it first in CTCL, which is where we have single-agent activity, as shown by Andres. I won't go through the disease, but just a few salient facts about this disease as Dr. Barta has already described. It's a rare group of lymphomas. About 70% of the patients have mycosis fungoides. Sézary syndrome, as was already mentioned, is a very small fraction. It's typically diagnosed in the late 50s, twice as common in men, as Dr. Barta pointed out. Although early-stage disease may be indolent, about 30% of patients will present with or progress to advanced-stage disease, and those patients will have a three-year median survival. It is a severe disease. Again, it's a disease much like follicular lymphoma as I was describing, where patients get treated for many years, many cycles. From a commercial perspective, unfortunately for the patients, this is quite a large opportunity even though it's a rare disease. 70% mycosis fungoides, that's an important number for our drug. We did primary market research with Eversana Consulting earlier. Well, it was actually last year, I think. We interviewed 30 clinicians across six different countries. This is some of the things that we hear from the clinicians. This is very telling, and the bottom line is that current therapies are failing these patients. First, there's a durability problem. Physicians are cycling through everything available within a few years, and they're running out of options. Second, there's a symptom burden problem. This isn't just a cancer that shortens life, it also destroys life. Patients can't sleep because of the itch. This is what drives the urgency, actually, in the clinic for a lot of these patients. When we look at the specific agents, the picture is equally stark. Moga, which is arguably the best option many of these patients has a 30% discontinuation rate due to severe rash. Brentuximab is constrained by neuropathy and also a CD30 biomarker restriction. The net result is, as the U.K. physician put it, there just aren't enough drugs to play with. There's no standard of care. Clinicians improvise, they try combinations, they recycle agents, they do whatever worked last time. The opportunity here is clear. It's a well-tolerated agent with a new mechanism, meaningful response rate. Wouldn't just add to the armamentarium, it would be transformative for this field. Going through again, as I go last, I have to repeat what some of my predecessors have already said, but maybe in a slightly different light. This is a summary of major treatment classes and their limitations. Skin-directed therapies do not address systemic disease. That tends to be the first line of treatment for most patients. HDAC inhibitors produce modest short-lived responses, and they are poorly tolerated and not very popular either with patients or clinicians. Moga is most effective in Sézary syndrome, again, 6% to 7% of the patients, and the blood compartment is less active in mycosis fungoides. Brentuximab vedotin is effective, but again, restricted by the CD30 biomarker and the neuropathy risk, of course. ZYNLONTA, which is a new product on the market, confined to heavily pretreated patients, and carries a capillary leak warning as well. Dr. Barta mentioned allogeneic transplantation, which is the only curative option and is available to very few patients. The unmet need is really there for a tolerable, durable, systemic therapy, and particularly in mycosis fungoides, which is where these established treatments don't work very well. Turning now to the BI-1808 data. I won't repeat what was already presented by Andres, but in short, BI-1808 as a single agent achieves high efficacy with an impressive safety profile and has early evidence of durability in a disease where durability is a problem because the patients tend to cycle through therapies. This is the core of the competitive case. This chart actually plots responses, OR on the Y-axis, adverse events leading to discontinuation on the X-axis. This is a chart showing mycosis fungoides, again, a majority of the patients. What you can see is brentuximab vedotin is the blue bubble on the top left, so very poorly tolerated. This is a reverse axis. Poor safety is on the left and good safety is on the right. The dark circle around the bubble means black box warning. Okay. Mogamulizumab is the orange bubble you can see here. Again, in mycosis fungoides, doesn't have extraordinary efficacy. You can see BI-1808 with our little bubble. Bubble sizes are linked to the number of patients in the particular trial that was used for these results. Small bubble only means we have a small sample set, but we can see that small sample set, big efficacy, and big safety advantage compared to these other treatments. These are, of course, early small sample cross-trial data, but the direction is nonetheless consistent. Of course, we haven't plotted here yet the combination with pembro. It'll be interesting to see what that looks like. The sample set is really still very small with pembro. It's still very early. Okay. What does the commercial opportunity look like? We did do, as I mentioned, an in-depth market assessment. We have a base case here of SEK 240 million in net sales across U.S. and five major European markets, estimated in this rather conservative, again, estimate done by Eversana. The principal value driver here is price. Our research indicates, the payers that were interviewed indicate that they will tolerate a very high price for this drug because they don't actively manage CTCL. It's too rare. As a benchmark, note that moga already generates SEK 300 million a year and is still growing. That's for a drug that doesn't work very well in mycosis fungoides. There is definitely a significant market opportunity for this orphan drug. We've actually based this market research on the assumption that BI-1808 had approximately comparable efficacy to other drugs on the market. What we're seeing now is that we seem to have better efficacy, so there is probably also upside potential for this product. Okay, I can see that my time's nearly up. In summary, BI-1808 is differentiated where it matters in the majority of patients, 70% of mycosis fungoides. We've got best-in-class tolerability across the entire field. Only 4% discontinuation. Long-lasting responses. We've seen a complete response in Sézary syndrome lasting over two years. We are the most advanced TNFR2 antibody. First-in-class advantage with FDA Fast Track and orphan drug. Of course, we have expansion opportunities in many indications because this is an immunotherapy. Thank you very much for your attention. Yeah. Thanks very much, Sylvie. It's now time for the questions and answers session. Again, please invite the speakers and management to come to the stage and we'll take questions from the audience to begin with, if there are any. I could ask you something about- Yeah. I think I heard you, Martin, spoke about BI-1808 with a potential sales of SEK 1.5 billion or what it was. Is that including these figures? No. No, that is ovarian cancer alone. That was only ovarian cancer. It's also a very conservative estimate. What Sylvie presented here today is only CTCL, also a very conservative estimate. Since we talk about BI-1808, there's, of course, upside on top of that because it's a broad, deep immune stimulation in a way. There are also other cold tumors besides ovarian cancer that could play a role. The commercial upside is big. The timeline for BI-1808 in ovarian cancer, what would you prognosis that for? Andres? Yeah. Yeah, I guess the question is how long would it take for the ovarian cancer to be. Potentially on the market? Yeah, maybe in the order of four, five years, something like that. It'd be like 12 or six. Bit like 12 or six. Yeah. I think we've estimated 2031 in our projections for ovarian and 2030 for CTCL. It actually would be good to get the CTCL market first because then you get the high price and you might have to adjust it a bit for the solid tumors, but you still have an advantage going in on the pricing. Any additional questions from the audience? Again, this is your chance to get some live feedback. No? Well, we have Dan Akschuti again, calling in from the outside. Dan, are you ready to fire away? Thank you for taking my questions. Just a few questions to Dr. Barta, if I may. Just a bit about to just put the data from BioInvent into context, your experience with other drugs and also the relapse risk. What's the risk that some of these patients that have now really well responded to BioInvent's drug are going to relapse, and when would you classically see that from your experience? The last question would be on the pivotal study. What would you like to see, and is it possible to just do it in T-cell lymphoma, also include PTCL and other rare forms, or does it have to be focused on CTCL? Thank you. These are excellent questions. Unfortunately, I wish there was a drug that would lead to durable, complete responses in the majority of patients. I think what we have seen so far is that there are some patients who have an excellent response, and this patient in the CR is actually my patient who is now on a maintenance treatment with the drug. As has been pointed out very well, what we see in other cancers is often we like to have a complete response, and we go very much by response rate. What hasn't been really emphasized much, which I think is very important, is the clinical benefit rate. If patients even have stable disease and can be on this for a long time, and we didn't see swim plots, but that is the case for some of my patients, who might not have a complete response or just miss, for example, a partial response, but they get significant benefit by reduction of the itching, by having a drug that really has no significant side effects, given every three weeks, allows them to travel the world. I have one patient on the study, he went to China, went to Australia, went to Sub-Saharan Africa while they were on the study, which is actually amazing. That is really an advantage we see with this drug. Even if the duration of response is a year or two, that's probably what we would expect, that patients who respond will have to go on to another therapy after a year or two. That would be fantastic. I think it also has been pointed out, while we do use single agents, now we have single agents that don't have a lot of side effects. Now we can think about combination with other drugs, and I think that's where also the upside is to a drug like BI-1808, with a mechanism of action that it may lend itself to other combinations with other immune stimulatory drugs like the IMiDs or, for example, JAK inhibitors maybe actually might be there's some synergy with immunotherapies or, for example, even with chemotherapy, with single agent chemotherapy. Thinking outside of CTCL, I think it would be a great drug to have for peripheral T-cell lymphoma. This is another really orphan drug market where you have very heterogeneous group of patients, and we've seen that there is a proof of concept it can work in peripheral T-cell lymphoma. I think that that's another market to explore. I'm sorry, am I missing another part of the question? Thank you very much. Just regarding the pivotal study. I think initially it would be important to get the drug available to patients. I think a single agent initially phase II, and then with plans of doing a phase III. I would suggest to do the same thing as, for example, has been done with brentuximab or mogamulizumab to randomize to either vorinostat or bexarotene or interferon to drugs that are available across the globe, and particularly in Europe. I think that would be a design that I think would be giving you the answers that you need, establishing its single agent efficacy, and then people will start having ideas for combinations and ISTs and excited to see what else can be done with this drug as a backbone. Okay. Thank you very much. Are you happy, Dan? I always have a few more questions, but thank you so much. I'm very happy to have a new drug that has a unique mechanism of action that while it may not lead to a 60%-80% response rate, that's okay. It offers a new weapon in our armamentarium, and I think, as I said, I think the future will be, even for CTCL or PTCL, that we get some rational combinations. It will then bump the response rates to much higher and more durable responses. I'd be excited to have this drug available for my patients because these quotes that you had are exactly what the experience is. It's a lot of symptoms. The responses don't last very long. We run through options very quickly, and many drugs have side effects that then preclude giving them for a longer period of time, even if patients benefit. I'd love to have this drug available commercially for my patients in the near future. Thank you so much, Stefan. Thank you. I think we will need to move on to Richard Ramanius. You have time for one or two questions, I think. Richard? Yeah. I had two questions. I'll start with the TNF Receptor 2 question, if anyone could explain why it's so important in this disease. Is it because the T-cells from which the disease derives its name are regulatory T-cells? Maybe I can have a shot at that and then leave it to the other guys. I think it's really interesting that TNFR2 is overexpressed on the tumor cells, and as we have previously introduced, that may allow for yet another mechanism by which our antibody, which clearly deletes normal T regulatory cells, deletes also the cancer cells. I think it's not entirely clear yet as of today how is TNFR2 contributing to the disease severity and these sorts of things, and that will need to be understood and studied. Clearly, our mechanism is really powerful. Perhaps what will provide the strongest activity and durability in the end, I think, is kicking in the immune system, that we have some really clear evidence of across the different types of solid cancers and tumors that we have assessed. I think stay tuned for some more on this, clearly a compelling and different mechanism compared to the other stuff that's out there. Do you want to comment, Andres, a bit on this? I think you've summarized it. I think that's our understanding today. Was there another question, Richard? I wonder if you could explain or discuss whether BI-1808 as monotherapy or in combination with pembro is preferable. You, Andres, want to comment? Maybe. Right now, from the drug development standpoint, our life would be a lot easier to develop it as single agent. As Dr. Barta said, that would put the drug in their hand so they can use it. The best people who will use it is the investigators and clinicians because they will have the best ideas. For the purpose of the company, ideally, we would do it as a single agent. We started the development in combination with pembro because as Björn just said, we think the two agents combine extremely well. We've shown that clearly in ovarian cancer. If you were able to, on the one hand, have an early response based on what the drug is doing to the tumor cells, but in the meantime, you have time for the immune system to kick in and develop a strong immune response against, that would be achieved with the combination, that probably would be super useful for clinicians, and maybe we can ask Dr. Barta. I think that from that perspective, that would be ideal. When you do combinations, you have to weigh the safety that comes with the other drugs that you're combining, and pembro comes with toxicity. We would have to think about that. I hope I answered your question. Stefan, what are your thoughts concerning the combo? I entirely agree. I think while you might have a higher response rate, I am not sure that this is the first path I would go to. Pembrolizumab is actually not for every patient with CTCL. There are some concerns. There is a flare reaction, for example, we can see with immunotherapies. I think initially having this available as single agent and then later create data where we can have combinations that may fit a specific patient profile where we really need the high response rates. I would say single agent would be preferable given the safety profile of BI-1808 as opposed to pembrolizumab. Super. Thank you. I think it's actually time to hand off to Martin to say some closing remarks. On my behalf, I'd like to thank everyone that's participated here in person, but also calling in for the great questions. I have a correction to make. Dr. Barta is from University of Pennsylvania and nothing else. Now I tried to correct that at least. Thank you, everyone. I leave it to Martin to close this up. Thank you very much, Björn. First of all, I would like to thank all the participants, presenters, specifically, for excellent presentations. I was at least very happy, I am very happy. I think well done. What I would like to do at the end is to summarize what is coming and what we have achieved. As you can see, again, just to repeat, we have two first-in-class compounds that have shown efficacy in liquid as well as in solid tumors combined. I emphasize again, with good safety, because that's important as we have learned today, hopefully that is kind of lowly getting into the brains. Starting then with BI-1808, we obviously had an update just a little bit more than a week ago on ASCO. That was the first good. Then today, at EHA, the CTCL data. Just focusing now on BI-1808, there will be a further update coming for the combination with KEYTRUDA in recurring ovarian cancer. I think, as far as I remember, we have all 40 patients recruited. Now it's really following up and get the additional data. My expectation is clearly because we have seen now the maturation of that program twice, that it basically will continue at the levels that we see regarding safety and efficacy. Obviously, by end of this year, we would like to start or during the second half, the triplet combination, that basically combination of BI-1808 with the standard of care, which is currently Pembro plus paclitaxel. In case we kick that off, we would have the first data readout during the second half of next year. That this is a very strong value driver. On the CTCL side, I do not repeat again. I think everything has been said. The main thing is now further maturing the trial and being ready or getting ready for potential pivotal study next year as Andres outlined. On the FCγRIIb BI-1206 side, today obviously we had the update on the non-Hodgkin lymphoma data set. That also will be then maturing further such that we are ready for potential pivotal study next year. Something that we did not discuss today at all, but also FCγRIIb is a very interesting target expressed on dendritic cells in the tumor microenvironment. A couple of month ago, we started a first-line non-small cell lung cancer and uveal melanoma trial. There we'll get the first readout during the second half. At the moment obviously, BI-1808 is in the forefront because we have very strong data in a very difficult solid cancer indication. Remains to be seen what we can generate here with BI-1206 because that could be also another very strong value driver. I would say stay tuned. I am very happy with the progress that we have and continue to look forward to second half of this year and also next year. Thank you very much for your attention and happy to have further chats after this. Thank you very much.