BioInvent International AB (publ) (BINV) Earnings Call Transcript & Summary

Good morning, and welcome to the BioInvent KOL Event. [Operator Instructions] As a reminder, this event is being recorded and a replay will be made available on the BioInvent website following the conclusion of the event. I'd now like to turn the call over to Dr. Martin Welschof, Chief Executive Officer of BioInvent. Please go ahead, Martin.

Thank you, Tara, and welcome, everybody, to our today's virtual KOL event. Today, we have a guest, as you can see, Professor Alexander Eggermont, but I will come back to that in a minute. So what I would like to do is briefly introduce you first to the agenda of our call, and that will be on the next -- on the third slide actually. So if you can go to the third slide, please. Yes. Thank you very much. So this is the agenda for today. Actually, quite packed. I will start the presentation with a brief introduction and then Björn Frendéus, who's our CSO, will follow with some general comments regarding our development strategy which is actually quite unique. And then we dive right into our first STAR program which is actually BI-1808, which is our lead program targeting TNF receptor 2. And Bjorn will introduce the TNF receptor 2 biology which is a potential new checkpoint and has a very interesting mode of action biology. And then Andres will follow and present the first clinical data set of today which will be then the efficacy and safety data for our lead BI-1808, targeting antibody of TNF receptor 2. And that data was also just recently presented at ASCO. Then we switch gears and come to our second platform, which is around a very interesting target called Fc gamma receptor IIB, which is another promising target in immuno-oncology and Bjorn will introduce you to the biology. And then Andres will present 2 data sets: first, the Phase I/IIa data for 1206 in non-Hodgkin's lymphoma and that was just presented actually at the EHA last week. And then the data in solid cancer that was presented at ASCO set in combination with pembrolizumab. And that is also, I think, a super interesting program and making quite some progress. Then we come to our guest, Professor Alexander Eggermont. So he will basically talk about what is going next within immuno-oncology. And hopefully, we'll position 1808 and 1206 in this scenary. Now we have 20 minutes for Q&A, as already was announced by Tara at the beginning, and then I will end the meeting with some final remarks. So just a brief intro to the company. So the next slide, please. And before I come to that, the next one, please. Just very briefly on today's speaker. So obviously, would be me, Martin Welschof, the CEO, but then also we have Björn Frendéus, CSO; and Andres McAllister, Chief Medical Officer. Those are the 2 anchor persons in the studio that you can see. And they work very closely together. And I think this very close collaboration has been instrumental to really move forward this very interesting biology and mode of action into the clinic. And we see the first exciting data sets coming out which actually has raised quite some eyebrows and I think will drive further quite some value for the company. Then obviously, Professor Alexander Eggermont, who is an internationally recognized expert for many things, and he is currently the CSO at the Princess Maxima Center for pediatric oncology. He is also Professor of Immunotherapy at the University Medical Center in Utrecht and a Professor of Oncology in Paris. And last but not least, also a coordinator for the Comprehensive Cancer Center Program for the Deutsche KrebsHilfe and a strategic advisor for the DKFZ. So super busy man. So that's why we are very, very happy to have him here with us. And obviously, he is super well connected to the topics that we want to discuss today. The next slide, please. So very briefly, a snapshot of the company. So we're really focusing on BioInvent translating complex cancer biology into innovative antibody therapeutics. And you will see that's also the play that we have today. So Björn will always introduce to the science, the biology and then Andres covers the translation. We are in immuno-oncology, as already mentioned, but we're really focusing on the tumor microenvironment. This is our main domain, which I think is also very critical for immunotherapy of cancer. The company is based in Lund, Sweden. We are currently around 110 people, fully integrated. In that sense, we're not only doing antibody discovery, target discovery, we also do manufacturing, we do our own formulation and we do clinical development. So everything under one roof, which is super powerful and competitive. We, as a company, we are pushing ahead with a broad portfolio that I will briefly introduce to you. So currently, we have 6 programs, 5 different compounds. We are listed in Stockholm on the OMX Stock Exchange, currently well funded. We have liquid funds of still around USD 112 million, which gives us a good, enough power to go through multiple value inflection points that we already will hit this year and obviously also next year. And even though we are listed in Sweden, we have a very strong international shareholder base that we're very proud of. So the major owners are Redmile, Van Herk Investments, Forbion, HPM, Omega, AP4, Invus, Swedbank Robur, Handelsbanken and those names control roughly 65% of the company. Next slide, please. So very briefly, the remaining milestones for this year, which are actually quite interesting. So we expect further update on BI-1808 in solid tumors as a single agent, so that will be towards the year end. And then we also expect the first data set for the first handful of patients for BI-1206 in non-Hodgkin's lymphoma in the triplet combination, which means in combination with rituximab and acalabrutinib. And then during the second half of this year, we'll have the first data set around of 1910, which is our second TNF-receptor 2 program, and this will be single agent data, dose escalation data in solid tumors. And then also, last but not least, we will have an update around BT-001 in solid tumors in combination with pembrolizumab. So lots to look forward to. And on the next slide, I'll give you a quick introduction to our platform. The next slide, please. Yes. Thank you. So at the floor of the company, we have, first, and this is a very interesting platform that has been developed by Bjorn and his team. And this is basically a reverse functional screening, phenotypic screening platform. Reverse in that sense, we start from patient material, select specific binders, characterize them for function in vivo and in vitro. When we see that they have strong therapeutic effects in those models, then we identify the targets. So the target comes at the end. So the function first is actually the main criteria to pick first the antibodies and afterwards the targets. And this platform has been actually quite significantly tested also at number of international collaborations that was part of my first slide. And this is a platform that we have used to build the portfolio that I want to briefly introduce to you on the next slide, please. So you see the very broad platform that we have, broad and deep, at least for a company of our size. So I mentioned 6 clinical programs, 5 different compounds. But you can see that all those programs are really focused in the sense we are focusing on 3 targets that play a major role in the tumor microenvironment in modulating and changing the tumor microenvironment. And a very interesting target number one is TNF receptor 2, and I will not discuss here much about the biology because that will be done by Bjorn. And as you can see, we have 2 compounds, 1808. This is the one that we will discuss today, this is our lead. 1910, we will not talk about today. And then our second platform and I call our target programs platforms because we normally have more than one program attacking those interesting targets is Fc gamma IIB. And there, we also have 2 compounds, 12 or 6, which is the lead that we will discuss today is currently developed in non-Hodgkin's lymphoma as well as in solid tumors in combination with pembro and then non-Hodgkin's lymphoma in combination with rituximab and acalabrutinib. 1607 our second Fc gamma IIB program, we will also not discuss today. We will also not talk about our CTLA-4 program which is basically our proprietary anti-CTLA-4 antibody in combination with oncolytic virus platform, which will run in a joint venture with Transgene. So this is basically the quick intro. And in order to have as much time as we need for Bjorn, Andres and later also Alex. I will hand over to you, Bjorn. Go ahead.

Thank you, Martin. So at BioInvent, we're a company dedicated to the discovery and development of antibody-based drugs for cancer immunotherapy. The background is, of course, the therapeutic antibodies have transformed cancer outcome, and they're continuing to transform cancer outcome. This is true both for tumor-targeting antibodies like those specific to CD20, which when used in combination with targeted therapy BTK inhibitors here, induce impressive responses safely in patients with advanced stage and difficult to treat B-cell cancer. The same is true for immunomodulatory antibodies like anti-PD-1, which when used in early lines of treatment here in the neoadjuvant setting, induce long-lasting responses and cures in a majority of patients with advanced-stage melanoma. These are patients that prior to the introduction of antibody-based immunotherapy had very slim chances of surviving their disease. So despite these tremendous successes of antibody-based therapy, fact remains that many patients don't benefit from the currently available therapies. They can either not respond or if they respond, they may acquire resistence, meaning that they can no longer benefit from retreatment. So we know that responses to immunotherapy largely correlate with the level of immune infiltration into tumors and specifically CD8-positive T cell infiltration. And that cancers that are highly infiltrated by CD8 T cells respond more frequently to antibody immunotherapy compared with those cancers that are poorly infiltrated such as pancreatic or colorectal cancer, especially one of microsatellite stable characterization -- characteristics, whatever. The patients that initially respond, some of those will progress and discontinue treatment. We know that such patients are unlikely to respond to retreatment with the currently available immunotherapies. In fact, response rates in this patient population may be very similar to those that are most resistant to immunotherapy to begin with. So there's, of course, a great need to come up with strategies that enhance the activity and overcome resistance to the existing safe and effective drugs. There's, of course, also a need to come up with new powerful and safe immunotherapies that can be combined with existing drugs to induce powerful and robust responses and survival in a majority of cancers, hopefully. So these are not trivial tasks despite thousands of clinical trials that have been ongoing with multiple antibodies to a multiple different targets illustrated by the bubbly illustration here. There's only been a single antibody approved to a new immune checkpoint in the last decade by the Food and Drug Administration. So in light of this, we're, of course, super excited at BioInvent to be pioneering the clinical translation and translation in general, I guess, of antibodies to TNFR2 which is emerging as a new Indian checkpoint. And that we, with our 1808 antibody have absorbed already evidence of single-agent activity by a differentiated mechanism that at least in preclinical model systems seems to synergize with PD-1. We're equally excited about having identified and characterized FCR2B, that's a receptor that controls a resistance to tumor targeting antibodies and limits efficacy of immune modulatory antibodies. So starting with BI-1808, our ligand-blocking Fcy receptor engaging anti-TINAFR2 antibody. This was isolated as part of a bigger effort where we wanted to discover new targets and antibody mechanisms of action that would allow the deletion of intratumoral CD4 positive T regulatory cells and at the same time, expand the critical CD8 positive effector T cells in that same compartment. Using our carefully characterized and mechanistically matched surrogate antibody, and using animal models with different clinically relevant tumor microenvironments, ranging from those that would be highly infiltrated by those same CD8 positive T cells I told you about, and therefore, responsive to the currently available immune checkpoint blockers, 2 models that are very poorly infiltrated by CD8 positive T cells and resistant to that same state-of-the-art immune checkpoint inhibitor. We were able to demonstrate that our antibody and this regression of large inflamed tumors curing a majority of CT26 tumor-bearing animals, where treatment with anti-PD-1 had no meaningful activity. If we move to the EMT6 model, which is slightly less infiltrated by CD8 positive T cells, we still retain a very significant portion of antitumor activity. If we move to the MC38 model, which in our hands, is where anti-PD-1 achieves approximately 50% cures when dosed at full therapeutic efficacy, we were able to demonstrate that a subtherapeutic dose of our antibody added to PD-1, synergized with PD-1 to induce cures across the board. Perhaps most impressively, in the B16 model, which in our hands is completely resistant to both anti-PD-1 and CTLA-4 therapy. We found that when combined with PD-1 or antibody-induced cures in a meaningful fraction of animals. So how are these impressive effects achieved, what's different about our mechanism of action in TNFR2? Well, one of the first things we wanted to ask was, does our antibody confer Fcy receptor dependent antitumor activity. We'll get back to Fcy receptors later in our call, but really these receptors have been shown to be instrumental for many different types of antibodies activity. And so what we did was we generated antibody variants that preferentially would engage activating Fcy receptors on the one hand. These receptors are known to be critical for the activity of Treg deleting antibodies. We also generated variants that speak preferentially with the inhibitory Fcy receptor. And those types of antibodies are known to be critical for immune agonist types of antibodies like anti-CD40. We, of course, also generated antibody variants that didn't engage Fcy receptors. And what we found was really surprising. And in fact, we hadn't seen this in more than 10 years' worth of studying the in vivo mechanism of action on multiple different immunomodulatory antibodies to different targets. Once that antibodies that both spoke with the activating and the inhibitory receptor had a very powerful and similar antitumor activity. Remember those 2 formats would be an associate to T-reg deletion and co-stimulation of receptor expressing cells. Of course, indicating that maybe that's what's going on with this antibody, both that leads to regulatory cells and it provides some sort of co-stimulatory activity. So when we then opened up tumors of animals that have been treated, this is exactly what we saw. And it didn't really matter if we used the mouse surrogate antibody and study in wild-type animals, or if we use the human lead clinical candidate antibody study in the human TNFR2 transgenic animals that we have access to. In both cases, we found that very acutely after treatment, there was a reduction in T regulatory cells followed by, but already at this stage, perhaps a trend towards expansion of CD8 positive T cell effectors. This trend was then enhanced up until day 8 when tumors started regressing. So having access to these great mouse and human reagents and different types of antibodies to TNFR2 puts us in a unique position at BioInvent to identify biomarkers and different kinds of biomarkers in a hypothesis-driven manner. And so we have not only found that our antibody induces T-reg deletion and CD8 expansion, we've also demonstrated that the antibody induces CD8 positive T-cell antitumor immunity and that this has been demonstrated for validated immune checkpoint modulators coincides with the appearance of certain types of CD8-positive effector memory cells in blood. Okay, you say maybe who cares. Well, we think this is really important because if we then -- when we see responses in human subjects can observe a similar expansion of these cells in blood, that really reinforces our belief that whatever observations were made related to our drug. And so we've been super excited to see that in the 3 different subjects where we have observed evidence of tumor regression. We see that same expansion of those same cells in the human subjects. And also to the extent we've been able to look at this and infiltration of CD8 positive T cells into tumors, supporting, of course, not only the mechanism that we've characterized in the preclinical model systems but importantly, we are actively inducing an immune response against cancer. So our emerging translational observations while it's super early days and all of that are consistent with TNFR2 being a new type of immune checkpoint, which is clinically and therapeutically relevant to different cancers. And of course, BI-1808 allowing it safe and effective targeting. So just taking a step back here and looking at the state-of-the-art, our antibody like anti-PD-1 and CTLA-4 has single-agent activity in different cancers, including interestingly, those that are not known to respond to either PD-1 or CTLA-4. It correlates with induction of an antitumor memory response. The antibody, again, as far as we know today, appears to be very safe and well tolerated. And I'm sure Andres will elaborate on this. At least in preclinical model systems, it synergizes with anti-PD-1, which by itself being safe and synergizing with PD-1 is a rather fantastic combination. It has a differentiated mechanism of action, like the validated immune checkpoint modulators, it engages CD8, like CTLA-4, it reduces Tregs. It has uniquely broad engagement of C receptors and in contrast to all of the other receptors, TNFR2 is a co-stimulatory kind. So that too is super interesting. So with that, I want to leave the words to you, Andres, to take us through our clinical developments.

Super. Thanks very much. Thank you, Bjorn. So interestingly, this great characterization that we have done preclinically at BioInvent, it is super exciting to see that we're actually seeing that in human subjects. I will basically provide an update of the recent data that we published or disclosed at ASCO recently a couple of weeks ago. And so BI-1808, this is a Phase I/IIa use of BI-1808 as single agent and in combination with pembro. The most important take-home message you've already said, Bjorn, is that this agent has shown single-agent activity which is something extremely exciting in tumor types that are usually not responsive. So it's also very exciting because we are changing what happens inside the tumor microenvironment. And the second most important message, as I'll show you is that this drug was extremely well tolerated, perhaps because it's acting precisely inside the tumor, which is very exciting, which is not only important from a mechanistic standpoint, but also important from the combination standpoint. If we aim to combine this drugs, BI-1808 with pembrolizumab with potentially chemotherapy or other types of agents, the safety issue is of primary importance. So this is the study that we started some time ago. So we basically started with BI-1808 as a single agent. We're starting -- we're dosing this every 3 weeks. We used an adaptive design. We started at 25 milligrams flat dosing and then went up -- stepped up to 1,000 milligrams, where we were able to assess that we have full receptor occupancy over 3 weeks, so the entire treatment interval and beyond actually. We're able to assess what happens to the immune system at those different doses and decided to treat a few more patients at 1,000 milligrams to make sure that the dose was safe, well tolerated and we could use that for subsequent treatment of patients. And subsequently, we opened the cohorts depicted here. So we're actually treating patients with ovarian cancer, melanoma. We have a cohort with all tumor types that allows us to treat patients that -- where we feel there may be a signal. And last but not least, patients with T-cell lymphomas and in particular, CTCL. In parallel to that, we have been escalating. This takes a little bit of extra time because of regulatory requirements, but we are -- we have already pretty much finished the dose escalation. And the dose -- the combo of BI-1808 with 1,000 milligrams in combination with pembrolizumab has been well tolerated, and we're posed to begin exploratory work in the same indications this time with the combination. It's important -- this is basically to show you the waterfall plot, the swimmers plots that we've seen in this heavily pretreated population. But again, the most important message here is that BI-1808 was extremely well tolerated. We saw no serious adverse events related to BI-1808, and we saw no organ type specific toxicities, so very well tolerated and the combination with pembrolizumab also really well tolerated [indiscernible] high doses. Again, very exciting. But importantly, when we see what happened to animals and when we now look at what happens in human subjects, we see [indiscernible] we see regulatory T cell decrease. This is all the patients that we've been able to test and you see that in all the patients, there is a significant drop in Tregs that every time you administer a dose you see the drop. Here is independent patients. And just keep in mind, these red dots. These are the patients that we will discuss in a minute. And very, very interestingly, if you look at what happens inside the tumor, these are 2 different patients, you see that, that ratio between Tregs and CD8 positive cells is increasing when you compare prior to treatment. Five weeks after treatment, you see that, that ratio has increased inside the tumor, which is really most exciting because that's exactly what we wanted to achieve with BI-1808. Here is -- I'm going to show you what we showed at ASCO. So a couple of patients. This is a patient with ovarian cancer, a 63-year-old patient that enters study, that was diagnosed with Stage IIIA and entered the study after receiving previous lines of treatment depicted here, so paclitaxel/carboplatin, carboplatin and doxorubicin, olaparib and finally, bevacizumab and topotecan. So heavily pretreated patient with progressive disease when entering the study. The patient had a very large lesion of 25 millimeters and 2 other cystic lesions. And basically, what you can see here is disappearance of the lesions and the patient developed a quite rapid complete response, which was, of course, very exciting. And here, you see the Treg drop in that specific patient. And this is -- remember, we spoke about GISTs. So this is a patient that entered the study after receiving 12 previous lines of tyrosine kinase inhibitors, often combined with mTOR inhibitors and basically soon after at the first scan, we thought that this patient had progressive disease, but then eventually at the next scan, we started seeing that the lesions were decreasing and this patient has been already in treatment for about 13 months, and the patients still on treatment, a very nice partial response. What you can see here is that metastatic lesions have disappeared. Again, bear in mind that this is single-agent activity of BI-1808, something that you don't normally see with all the other immune checkpoint inhibitors that have been invested quite substantially in clinical development. And here is a Treg drop and very substantial, very significant and very interesting and really proving the BI-1808 is really doing what it's supposed to do. And here is an example in a different patient where you see a pre-dosing of the infiltration of CD8+ T cells in the tumor. And 5 weeks after you see how the CD8+ T cells have now infiltrated the tumor. So very interesting and very compelling data that poses us to be in a situation where we believe that BI-1808 has every possibility of moving forward and being another treatment option for patients with difficult to treat solid tumors.

Thank you, Andres. Okay. So we'll now switch gears a bit and talk about -- next slide, tailored Fcy receptor blockade as a strategy to enhance cancer immunotherapy. Okay. So what I'll do is I will tell you a little bit about how Fc gamma receptors work, then take you through how BI-1206 enhances on rituximab in the context of lymphoma and end off by saying a few words on our current belief of what's going on when we enhance on PD-1 in solid cancers. And then that will be followed by an update by you, Andres, on clinical status. So the Fc gamma receptors, as their name implies, they regulate the activity of gamma globulin or IgG antibodies. They do this through low affinity, high avidity interactions, meaning that therapeutic antibodies will only engage Fcy receptors once they formed the immune complex following binding to the targeted receptors on target receptor expressing cells. The functional consequences of Fcy receptor engagement include, of course, targeted deletion of the antibody-coated cell by, for example, ADCP or ADCC, but can also importantly include reprogramming of the Fcy receptor expressing macrophage to increase its antigen presentation or result in pro-inflammatory cytokine release. The Fc gamma receptors just like the T-cell checkpoints come in different flavors, those that activate immune effector cell responses and those that inhibit immune effector responses. Unlike the T cell checkpoints of which there are many inhibitory variants, including, of course, CTLA-4, PD-1, LAG-3 and the list goes on, there is only a single inhibitory Fc receptor. That's our target. And the Holy Grail of this would, of course, be that if you can neutralize this receptor's activity, we may be in a very interesting position to enhance the activity of multiple different IgG types of antibodies with Fc gamma receptor dependent mechanisms. So it was early shown that activating an inhibitory Fcy receptors jointly and can certainly control the tumor targeting antibodies efficacy. This was first demonstrated by Jeff Ravetch and team at the Rockefeller in New York. And what the team did was they injected black melanoma cells into the tail means of immune competent mice. What would then happen is the melanoma cells will migrate to the lungs, causing black abscesses. The team then treated these animals that were tumor bearing, of course, with an antibody that's similar to human therapeutic IgG antibodies can engage both activating and inhibitory receptors. And remember, these were wild-type animals, so the effector cells expressed in both of those 2 types of receptors, they would get very significant but incomplete deletion of the black melanoma cells. They repeated the experiment in animals that have been genetically ablated, meaning they had no activating Fcy receptors. The tumor targeting antibody lost all of its activity, demonstrating, of course, that activating Fcy receptors are really important to engage tumoricidal activity of tumor targeting antibodies. Finally and very interestingly and importantly, when they repeated the experiment in animals that lack the inhibitory Fcy receptor, the tumor-targeting antibody was supercharged and deleted all of the melanoma abscesses effectively curing animals, illustrating, of course, the great therapeutic potential of blocking FCR2B inhibitory function. So there's no magic to this biology. It doesn't apply only to tumorcidal antibodies, but it also applies to Treg deleting antibodies, for example, and actually other kinds of immunomodulatory antibodies. So I apologize for the very busy nature of this slide, but I'll make my key points to the headings. One being that the Fc gamma receptors control not only antibody targeted cell deletion. But in recent years, have been shown to promote immune effector cell APC synapse function and very importantly, reprogramming of tumor-associated macrophages or improved ability to support CD8 positive T cell function. Such qualities would again include increased MEC Class II presentation, but also improved type 1 interferon types of responses, again, to support CD8 positive T cell function. So these mechanisms appear to be clinically relevant. This is a recent paper from a team at Genentech. They demonstrated that an Fc gamma receptor engaging anti-TIGIT antibody, when combined with PD-L1 immune checkpoint blockade, conferred superior survival compared to treatment with the PD-L1 checkpoint inhibitor alone. This improved efficacy provided by the Fc gamma receptor engaging and the TIGIT combination, correlated very interestingly with an increased presence of Fc high-expressing effector cells in the tumors, suggesting of course, that Fc gamma receptor dependent Treg deletion and myeloid reprogramming at least co-determined survival. So if you want to enhance Fc gamma receptor dependent function and efficacy of antibodies that engage in that type of biology, you can do it in 2 different ways. You can enhance binding and activation of all of the different activating Fcy receptors or you can inhibit, of course, the function of the inhibitor. In this respect, it's interesting to learn what the expression are of these different receptors inside of tumors, where as Andres had already pointed out, is typically a very important compartment where we want the activity to be and in blood, which actually with respect to Fcy receptors and also other antibodies, in many cases, may be untoward. And if anything, perhaps relating to tolerability issues. So if you then look to the activating Fcy receptors, this is, of course, one example, it's melanoma from [indiscernible] and team. But actually, similar data has been absorbed for different groups and different types of cancer. In many cases, the activating Fcy receptors are similarly expressed in blood and in tumor whereas actually in all of the cases that we had looked up until now, we see a very strong upregulation of the inhibitory Fc receptor in the intratumoral compartment compared with blood. Actually, this is true also in the mouse model, which is convenient from a modeling perspective. So based on that critical role of the inhibitor receptor and its association of tumor as compared with other compartments, we have, at BioInvent pursued the strategy of blocking FCGR2B to enhance on antibody-based cancer immunotherapeutics. We've generated 2 different antibodies, both of which are equally specific for the inhibitory Fcy receptor. They don't bind to the closely homologous FCR2A via its high-affinity antigen-specific arms. The only difference between the 2 antibodies is 1206 is an IgG1 and therefore, can and will engage in Fcy receptor-mediated or Fcy-mediated binding or Fcy receptors. 1607 has been engineered for impaired Fc gamma receptor binding, meaning this will only bind to Fc gamma R2B and nothing else. 1206 will be the topic of today. So we have proof of concept that enhances on CD20 and PD-1. So starting with CD20 and rituximab, in lymphoma, FCR2B is not only expressed on the immune receptor cells, everything I told you up until now are related to immune effector cell expression. So now we're switching gears a bit. It's also expressed on the tumor cells. And actually, our data demonstrate that it's really the tumor cell expressed FCR2B in this context that promotes resistance. So here, what will happen is rituximab will bind to CD20 molecules via its high-affinity arms, detail will dock on to the inhibitor receptor which is co-expressed on those tumor cells resulting in the internalization and removal of rituximab from the tumor cell surface. This is, of course, bad news. So clinically, this has been shown to result then in tumor-expressed FCR2B correlating with poor prognosis to rituximab or rituximab-containing therapy treatment. It's been shown to be true in mantle cell lymphoma, high expressers of FCR2B do worse. These are survival curves than those patients whose tumors are negative for FCR2B, same is true in follicular lymphoma and most recently and in the largest study, in diffuse large B-cell lymphoma. So when we add our 1206 antibody, we block rituximab internalization, and we've shown in preclinical model systems that are sensitive to rituximab that we can enhance on rituximab activity. We've shown in models that we had invented at BioInvent actually, that rituximab has no activity. If we come in with the 2 antibodies, we start seeing objective responses in a good fraction of the animals, forming the basis for testing this, of course, in human clinical studies. So with that, I will not give it to you, Andres, yet because I will first discuss 1206 in the context of solid cancers and anti-PD-1. So in this context, solid cancers don't generally express FCGR2B. So the actions that we will be targeting relate to the immune effector cells. And with particular reference to PD-1, actually, it's been shown that not only the inhibitory Fcy receptor, but also the activating Fcy receptors compromise anti-PD-1 antibodies activity. So again, this was actually first demonstrated by Jeff Ravetch at the Rockefeller and his team, and they used a similar approach to what we had done in the TNFR2 program. They generated variance of anti-PD-1 that were either unable to speak with Fcy receptors or that spoke preferentially with activating or inhibitory Fcy receptors. So you will appreciate that this is a tumor growth curve, that the antibody variants that didn't engage Fcy receptors did the best and that actually both variants that engage the inhibitors or the [activities] seem to do worse. These findings were then recapitulated by Mikael Pittet at Mass General in Boston and in Harvard using a slightly different approach. So he used a pan Fcy receptor blocking antibody called 2.4G2. He added it to anti-PD-1 and found that, indeed, it enhanced antitumor activity and resulted in tumor regression. Finally, at BioInvent, we've then repeated these types of experiments adding our Fc competent anti-FCR2B antibody to PD-1 and seeing the same thing. We are then enhancing antitumor activity. So this is still work in progress, characterizing the in vivo mechanism of action of this combination. What we think is going on is the following. In the absence of our antibody, anti-PD-1 antibodies will, of course, bind to the CD8 positive T cells, but Fcy receptors expressed by macrophages in the tumor can then engage and bind these anti-PD-1 antibodies and actually remove them from the tumor cell surface. This was first demonstrated by the Pittet team to actually happen in the in vivo setting. The other mechanism that has been proposed is that the Fcy receptors, although anti-PD-1 antibodies are IgG4 isotype, if anti-PD-1 is sufficiently highly expressed, they can and will engage in phagocytosis and deletion of the targeted cells, and it's something we had repeated actually at BioInvent. It's true. It's true with the real deal in the human clinically relevant reagents. And there's additional mechanisms actually by which these receptors may promote resistance. In either case, when we come in with our 1206 antibody, it will localize and bind to the FCGR2B expressing TAMs because it's a human Ig1 competent antibody, it will bind to and block activating Fcy receptors and compete out the binding of the IG4 anti-PD-1s. So as much as I'd like to say that this is something we had thought out, it's completely serendipitous, but it really seems to be important and something that is well worth clinical pursuit. So with that, I'll leave it to you, Andres.

Okay. Thank you. So basically, I will update you on the recent data that we have communicated at EHA last week and at ASCO in combination with pembrolizumab. So the first part of it is what we discussed at EHA. So basically, the efficacy and safety, tolerability of BI-1206 in combination with rituximab in patients with non-Hodgkin's lymphoma. And as you might recall, we're basically treating patients with mantle cell lymphoma, with follicular lymphoma and with marginal zone lymphoma. This is little bit of a schematic of the clinical trial design. Basically, as you probably know, we started out with the IV dose escalation, and then we decided to proceed with a dose of 100 milligrams treating patients with this combination of BI-1206 plus rituximab. In the meantime, we as manufacturers of our own drugs, developed a subcutaneous formulation. This, as I mentioned, is very -- it is extremely convenient. So we will -- so we implemented this in our clinical study as an independent arm, which has allowed us to escalate quite quickly. And right now, we are basically treating patients with the subcutaneous formulation. IV formulation is a little bit ahead of the subcutaneous. But already, as I will show you, the subcutaneous formulation has shown some very interesting activity. By the way, some recent data disclosed has showed how much subcutaneous formulation can provide such an improved receptor occupancy profile that even overall survival was improved with a different antibody. In that context, BI-1206 and rituximab have been really well tolerated. And as I will show you, they have provided very interesting results. And that poses us to do a triple combination which will be BI-1206, rituximab and acalabritinib, which here again 2 to 3 days ago, it was disclosed data at EHA, where the potential treatment paradigm were basically acalabrutinib and rituximab combined with bendamustine are posed to become the first treatment option for mantle cell lymphoma in patients who are 65 years and older. So that combination already very interesting, but it shows the potential relevance of our treatment proposal here. Here is a compilation of what we've seen in terms of responses in patients that have been treating with BI-1206 and rituximab. And what you can see here, we have included the patients that have been treated IV or subcutaneously. And what you see already, it's a very interesting response rate of 56% with a complete response rate of 38%. So still very early days because the numbers are low, but this already shows how interesting it can be, especially if now whenever we combine with acalabrutinib which is what we are actually doing as we move forward. And here is just basically showing you what has happened with the subcutaneous formulation. We see -- we have had one complete response and 2 partial responses. We are still in the escalation part of this study. So it's all looking very interesting. The subcutaneous formulation was very well tolerated with no significant -- or we have not observed anything different that we had observed with the IV formulation. There has been some platelet drops and liver enzyme elevations. The infusion-related reactions were basically abolished and the cytokine response is nil when the curves are totally flat. So the rationale for the combination of BTK inhibitor with our combo is particularly interesting, when you look at the studies that were published last year, the Rosewood study where BTK inhibitors, zanubrutinib was combined with obinutuzumab and getting to response rates that were 46% complete response and 69% of overall response rate. So that's very interesting. And I think we will do actually better. We believe that our combo rituximab plus BI-1206 is an enhanced form of obinutuzumab and acalabrutinib is definitely the best in class that has been disclosed recently at EHA there again. So we believe that this combo will put us in a place where we can obtain very similar response rates to what is observed with other agents, but with a very convenient and very safe treatment option, which is something that is very important for these heavily pretreated patient population and often aged. So that's something that we believe will be very important. And the other part that I would like to tell you about is what we disclosed in our poster at ASCO concerning the combination with of BI-1206 with pembrolizumab, where we have seen some very interesting responses in patients with melanoma. So BI-1206 in combination with pembro led to very interesting response rates -- responses in patients who had previously received several previous lines of anti-PD-1, PD-L1 targeting agents. And there, again, the subcutaneous administration showed very promising results. This is the plots, which I will probably not bear very long time. And this is importantly to note, a very heavily pretreated patient population, but you can see already that some of the patients have very nice responses. And I will show you basically here, this is a patient with uveal melanoma that entered the study. And as you can see, these are the lesions that the patient had when entering the study. The lesion started decreasing, and this patient has been actually completed the 2-year treatment and has been off treatment for about 6 months. The patient is doing really well with a very nice partial response. Needless to say, uveal melanoma, it's a very hard disease to treat. So these are very exciting data. Here, you can see the lesions and the decrease in the lesions and so this patient is doing really well, thanks to this combination. This is another patient with a complete response. This is a patient who entered the study after -- there are again several previous lines, 3 previous lines for this particular patient of immune checkpoint inhibitors. And we saw a rapid response and this patient actually has a complete response, still on treatment and doing really well. So this is very, very exciting for showing the activity of BI-1206 in this patient population. Here basically shows you how the subcutaneous formulation is performing so well. We've seen no issues or concerns and the convenience of the subcutaneous administration, this shows you basically the receptor occupancy during the 3-week interval. So basically, what we now can do is we can administer additional doses of BI-1206 to increase receptor occupancy. As I mentioned before, it's a 5-minute injection. So very simple, very convenient, and we're very happy to be able to do this. This is what we intend to do. So basically, we are now opening the cohorts with lung cancer, melanoma and other tumor types in the Phase IIa part of the study. And we are about to finish the subcutaneous dose escalation, which will put us in a very interesting place when pursuing the development. So I will stop there and now Alex will walk you through what's new in the area of immunotherapy for the next years to come. We just went through ASCO and the data is so exciting on this area that I think everyone should be super, super excited. Thank you, Alex.

Yes. Thank you, Andres. And so good afternoon, everybody. It's a pleasure to be with you. And I will address a number of points, which I think are going to be crucial, but can also be addressed in an organized manner. And the role of BioInvent in such programs could be quite significant. Next, so these are the 5 points I want to touch upon. So first of all, it's clear that BioInvent has a highly original program with promising new agents. And that's because the agents have common denominators that are essential in improving immunotherapies. And that essence is provided that we all accept that we always need anti-PD-1 in the optimization of treatment schedules to protect our effector cells that these agents of BioInvent reduce the vast immunosuppressive mechanisms that are the big spoilers in immunotherapy. So what we want is to reduce, to eliminate T-regulatory cells and what we want is to expand cytotoxic and CD4 effector cells. And those effector cells need protection by anti-PD-1 and what we want is to address the vastly immunosuppressive effects of tumor-associated microphages, which are of the wrong macrophage type, M2 macrophage type and that through their interactions with Fc gamma receptors, they are big spoilers. They take off the antibodies from cytotoxic T cells, so they lose their protection. They split out the wrong cytokines like IL-4, IL-10, they spit out [indiscernible]. They are big spoilers and tumor promoters. And so the effects of these BioInvent monoclonal antibodies are that they address this fundamental problem and therefore reduce T regulatory cells, expand T cells and eliminate to some degree, the M2 tumor-associated macrophage roles and break through that immunosuppressive mechanism. And thereby, they are quite unique. So it has all the optimistic elements of building blocks that we need to construct our immunotherapy 2.0. Now point two is that the enhancement of anti-CD20 show the rituximab in the special lymphoma program by BI-1206, already has highly significant clinical data that are encouraging and not just encouraging that are really spectacular. So I'm not going to touch upon that because that's pretty much already pre-sealed. But my comments will be mostly on the problems in solid tumors. And one of the problems in solid tumors is how do we overcome PD-1 resistance problems after initial or response to anti-PD-1. But in most cases, never ever a response to anti-PD-1. And to address that resistance, we've seen a whole series of Phase III trials that have failed. [indiscernible] trial, the MASTERKEY 265 trial, the T-VEC trial in combination with anti-PD-1, the Nektar IL-2, pegylated IL-2 trial in combination with anti-PD-1, all those trials failed. And so we underestimate the basic problems of PD-1 resistance, and it will have a number of consequences in terms of how to move most effectively forward.

Alex, you're mute.

I don't know how that spontaneously happened, but I'm back. So at this particular point in time, the combination of ipilimumab and nivolumab is most used in melanoma, but it has a reduced or limited activity in PD-1 resistance melanoma patients, and the response rate is limited to about 20%, 25%. And then the tumor infiltrating lymphocyte, protocols [indiscernible] may yield a higher response rate. But these are highly selective patients that is actually relatively biased patient population. But the toxicity of [indiscernible] limits its applicability and most patients come off treatment after 2 or 3 cycles and the toxicity of the TIL and the cost of the TIL protocols are totally prohibitive and therefore, I think it's going to have extremely limited uptake and a limited life cycle. So what then is immunotherapy 2.0, it is getting early, go into first line as your goal and develop triplets in immunotherapy in melanoma and actually, all the candidates that we have seen from BioInvent have a good safety profile, which means they are amenable to be explored also in triplet approaches. What do I mean by a triplet approach? I mean there's always anti-PD-1, but there may be also a lower dose ipilimumab, there may be also LAG-3 or there may be a vaccine in a triplet. And the agents of BioInvent actually have all the potential to magnify or to enhance any doublet or triplet combo and would not take too much toxicity space to make the triplet impossible. So this is true for all the candidates of BioInvent. But you must come in even earlier and that's the current neoadjuvant IO revolution. What do I mean by that? I mean by that, that in our development and classic development of immunotherapies, we always started in the last wagon of a train, where everybody is exhausted, where patients have seen multiple lines of treatment and you have very little to work with. And that has led to the underestimation and underappreciation of the potential of a whole number of agents. So now we are moving our immunotherapies upfront prior to surgery for barely resectable tumors or palpable lymph node involvement or for MSI colorectal. So there's been significant developments in lung cancer, melanoma, MSI colorectal, cutaneous squamous cell cancers in the face, bladder carcinomas and so on. And this means that we actually now have discovered that our immunotherapies can be much more effective than we ever thought or could potentially or possibly read out from the wrong paradigm, and that is always to start at the end of the line of treatments. And so a neoadjuvant component in the strategy of an immuno-oncology biotech must be to have a component in IO, neoadjuvant development to better understand how the agents work and not to underestimate the potential of new agents and I will focus also on including thereby primary tumors in the last part of my talk because I think we can crack standard garden variety, colorectal cancers if we work also with the primary tumors, and this is, therefore, not only true for MSI high or DNA repair-deficient... Next, I already address point through, and I would like to go to the next slide. I addressed this. The graveyard of Phase III trials has been significant. And I think it takes, therefore, a novel approach. And if we don't address the tumor-associated macrophage problem. And if we don't address the T regulatory cell program, we are going to always hear the same obstacle. So next slide. Next, so there was one communication at ASCO where a new triplet was in a Phase II trial. I just want to run it by you, also to show that there is potential in triplets, but there are also limitations. So the triplet of the 3 approved agents, anti-PD-1, anti-CTLA-4 and relatlimab anti-LAG-3 was going to happen, of course, in advanced melanoma. Next slide. NIVO AND RELA dosed at the regular way, ipilimumab dosed that the reduced way at 1 milligram per kg. Why? Because otherwise, the toxicity of IPI plus NIVO alone already will make any extension of the combo into a triplet impossible. Next slide. As a reminder, look at these slides, relapse-free survival on the left-hand side, overall survival on the right-hand side of the top curve is the combination of nivolumab plus ipilimumab, the green curve is nivolumab alone and the bottom curve is ipilimumab alone. Now both nivolumab and nivolumab plus ipilimumab were significantly better than ipilimumab alone. But the combination NIVO plus IPI is only numerically better than nivolumab alone and why is that it's completely driven by the PD-L1 negative patient population in the trial? And the difference is only some 6%. Next slide, relatlimab plus NIVO is showing a similar type of overall survival, 6% benefit here at 3 years on your right hand in the slide. So it's only numerically better. It's not significantly better. Next slide. What does the triplet bring you, I show you relapse-free or progression-free survival data, 52% at 3 and 4 years, and those numbers were about 8% lower for the NIVO-IPI prior trials, but this is very early data. Next slide. The overall survival curve at this particular point in time, with very few patients the total patients that is 46 patients shows 72% at 3 years and 4 years overall survival, which would be about 15% or some number like that higher than IPI/NIVO, all this would be only numerically better, but it shows the potential that a triplet would indeed bring something in addition to the most used combination of nivolumab plus ipilimumab. So we'll see how the data will pan out. There is a large randomized phase trial ongoing, and it's not excluded that the triplet in the end will have the best outcome. But 50% of patients discontinued treatment because of toxicity. So it shows the immediate limitations also of this particular triplet and it could well be that the BioInvent molecules because of different mechanisms of action would have a place in triplet development in melanoma because they seem to take little toxicity space. Next slide. So trying to go into first line because the triplet development is going in first line for advanced metastatic melanoma, the deal. But -- if you want to learn additional elements of the function and the mechanism of your agent, a neoadjuvant trial will bring you gold in terms of information, not the true cut biopsies, which are lucky shot out of tumors that are halfway necrotic anyway, but you get the whole tumor to evaluate and see what your agents have done. So let's say something about neoadjuvant immunotherapy revolution 2.0. Next slide. So the standard adjuvant therapy in lymph node-positive melanoma is do the surgery first, lymph node resection and then give 18 doses of pembrolizumab. Here, the blue curve is you first give 3 anti-PD-1 doses, then you do the surgery and then you give the 15 other doses in the adjuvant setting. So 3 doses, neoadjuvant, then surgery, 15 doses adjuvant and see the incredible impact of working with the lymph nodes that are filled with tumor-infiltrating lymphocytes and work with the expansion of those T cell clones by coming in early with your immunotherapy compared to the adjuvant therapy, only the red curve. Next slide. So one of the big presentations at ASCO this year was -- next slide. Yes, was you give 2 cycles, that's the top curve, the blue curve, you give 2 cycles of IPI/NIVO before the lymph node resection and then you give 9 months of nivolumab adjuvant or the bottom curve. You just do the surgery first and then you give one year of adjuvant anti-PD-1 nivolumab. You see the massive impact of first coming in with immunotherapy prior to the surgery, hazard ratio [indiscernible]. Next slide. So very operative adjuvant therapy or the neoadjuvant immunotherapy, triple effect is that you will see more cures, you will see shorter treatments, and you will see less surgery. The more curious point one has been addressed already by the 2 slides that I showed you. But the shorter treatments and the less surgery are 2 other elements of this approach. Next slide. Why is it that neoadjuvant is better than just adjuvant? Look at the randomized patients in red overhead who had surgery first and then adjuvant anti-PD-1 or who had in blue, first 2 cycles of IPI/NIVO and then surgery and then 2 cycles of IPI/NIVO. Look on the right-hand side, what it means in terms of T cell clones. In terms of diversity and in terms of amplitude per T cell clone. On the left side, in red, you see the effective adjuvant IPI/NIVO. On the right-hand side in blue, you see the multiple expansions of -- expansions of present T cell clones in dark blue and newly detected clones in light blue. This actually represents almost a 200-fold expansion of T cell clones against existing antigens and neoantigens. And so this is a recipe for a cure. It means it sends out the rationale to come in with your immunotherapy prior to the surgery to have optimal programming of the immune system and making use of all the T cell clones that already are in place. Next slide. Look at the right-hand -- look at the right-hand side of this slide, you see that patients who had a pathologic complete or near complete response did not relapse anymore. There were 2 patients who relapsed, one died in a traffic accident. That means that you can actually cure 60% of the patient population by 2 cycles of neoadjuvant immunotherapy in lymph node-positive melanoma. Next slide. This is just to show on the left-hand side, the pooled analysis of neoadjuvant anti-PD-1-based immunotherapies in a consortium and on the right-hand side, a similar protocol for lymph node-positive melanoma with targeted therapy, dabrafenib plus trametinib if they were BRAF-mutated melanoma patients. The superiority of immunotherapy, neoadjuvant immunotherapy is such that we don't even talk anymore about neoadjuvant targeted therapy protocols. Next slide. The top curve here in blue on the right-hand side are the patients who had received neoadjuvant IPI plus anti-PD-1, the bottom curve, neoadjuvant anti-PD-1 alone. It shows the role of anti-CTLA-4 in diversifying and expanding T cell clones and therefore, a better outcome. Next slide. This slide shows you the effect that you don't only cure more, but you give also less systemic treatment and you do less surgery, why? Start this slide at the left bottom corner, it says lymph node marker placement. What we do is put a little magnet in the largest lymph node of a melanoma patient with positive lymph nodes. Then we give 2 cycles. You go to the dark blue, square, we give 2 cycles of ipilimumab plus nivolumab. And now just follow the yellow square. If you have a pathologic complete or near complete response, you are a major pathologic responders. That means that occurs in 60% to 70% of patients, you don't do a lymph node dissection anymore because that pathologic evaluation was done on that node where you had put a little marker. And you don't give, next yellow box, follow-up therapy anymore. You just do a CT scan every 3 months. So less surgery and less systemic therapy. And this is the future. It's not only the future for melanoma, but for multiple tumor types. And that's what I briefly will outline now and then we'll go into a discussion. Next slide. Next, squamous cell cancers in the face, head and neck region. Next slide. New England Journal of Medicine publication. This was just 6 weeks of neoadjuvant anti-PD-1, cemiplimab for these kind of tumors. Look in the yellow, uplight pathology complete and near complete responses in 2/3 of patients and look at the bottom, more cures, shorter treatments and less surgery because most patients who were responding refused surgery and waited for the complete response. Next slide. Triple-negative breast cancer. Yes, even there. Next slide, just New England Journal of Medicine publication, neoadjuvant chemo at the bottom, the red curve, neoadjuvant chemo plus anti-PD-1 pembrolizumab, the top curve. Look, on the left side, the pathologic complete response rate was increased by 14%, and it leads to an EFS and an overall survival benefit. Next slide. This is the same trial. Next slide. Lung cancer, neoadjuvant immunochemotherapy in lung cancer already has 3 approvals for resectable Stage III lung cancers. Let's look at some of these trials. Next slide. This is neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. Look at the EFS on the right-hand side, top curve is NIVO plus chemo, bottom curve is just chemo. Top curve in overall survival in green, bottom curve in chemo. Look at the left lower corner, pathological complete response rate goes from 2.2% to 24% that's a tenfold increase. Next slide. Next slide, next slide. The same thing with perioperative chemotherapy with anti-PD-1 pembrolizumab, also New England Journal of Medicine, non-small cell lung cancer, top curve. This is overall survival, the green bottom curve is just the chemo. So this is significant impact on overall survival. Next slide. And this is a similar outcome for durvalumab in chemo. Next slide. So I dealt with lung cancer, head and neck cancer. Next slide. You know anti-PD-1 and had a neck cancer, so, so. Next slide. If you; however, give a neoadjuvant and look at the right-hand side of the corner because most of the patients were done with nivolumab plus ipilimumab. Look, there are major pathologic responses, and partial responses in a majority of patients. So head and neck is accessible, and it would be great, it could reduce the magnitude of surgery in head and neck cancers. Next slide. Bladder cancer. This is a highly promising field for muscular invasive bladder cancer, MIBC. Next slide. Yes, I couldn't download this article, but gemcitabine and cisplatin plus nivolumab as an organ-sparing treatment for muscular invasive bladder cancer Phase II trial with neoadjuvant NIVO plus this chemo, 43% pathologic complete responses, all patients refused cystectomy. Nobody wants to lose his urinary bladder and it will reduce cystectomy significantly. I predict all these indications will get approval over time within the next 3, 4 years. Next slide. Colorectal MSI is the poster child of just anti-PD-1 mediated effects on MSI high. So DNA repair-deficient colorectal cancer, it's about 5% of the colorectal cancers. Next slide, the study from the National Cancer Institute in the Netherlands, basically, they all get a complete pathologic response. And that means they shouldn't be operated anymore because they can be cured by neoadjuvant anti-PD-1, yes or no in combination with ipilimumab. Next slide. This 16 patients, you may have seen the picture standing in front of Memorial Sloan Kettering treated with dostarlimab. It was the new empowered anti-PD-1 of GSK. All 16 patients had rectal cancer. They all had a complete response and nobody was operated. Next slide. Why do I show this poster of ASCO of this year. We're almost done with my talk. This is botensilimab plus balstilimab in microsatellite stable metastatic colorectal cancer. So this is your normal garden-variety colorectal cancer. Interestingly, that combination was given in patients -- in a patient population where there was a large proportion who did not have liver metastasis. They just had lymph node metastases and lung metastases. The response rate in that patient population was 26%. What does it mean? It means that also in colorectal cancer, we have a point of entry. And now we already know from incidental findings that neoadjuvant IPI/NIVO or anti-CTLA4 anti-PD-1 of which sort can lead to complete responses of primary garden variety, colorectal cancer. So I predict the next revolution will be that colorectal cancer will come into immunotherapy share. Why? Because the immuno score system that is of good prognostic value for colorectal cancer and based on an evaluation of the tumor-infiltrating lymphocytes in primary colorectal cancers, garden variety colorectal cancers is more potent than the whole T&M system for colorectal cancer. That means that if you work with the primary tumor and you expand and activate those T cell clones, you can have your role for immunotherapy in standard variety colorectal cancer. Next slide. And so we come to the following opportunities for BioInvent. In melanoma, of course, you will have to do a Phase II in PD-1 refractory melanoma patients to build on the early signals of activity. Then you must get into first line. Triplets in first line, it was going to dominate the next 5 years for advanced melanoma, and there is multiple entry points for BioInvent because they don't take toxicity space and therefore, are highly combinable with the other checkpoint inhibitors, and you must have a neoadjuvant Phase II trial because you must explore and better understand what is the true potential of your agents because you may even be underestimating the true potential of your agents. And then you must go into other tumor types. MSI low, colorectal standard garden variety colorectal cancer is the #1 cancer in the western world, and bladder cancer is my other recommendation. Muscular invasive bladder cancer. Next slide. And that means I thank you for your attention.

Thank you, Alex.

All right, Martin are we good to go to Q&A?

Absolutely.

[Operator Instructions] So our first question comes from Dan Akschuti at Pareto.

Congrats on this very interesting -- scientifically interesting call, and it's indeed exciting to hear what Alexander Eggermont had to say in terms of getting early and that as he say, [ BioInvent's ] drugs are taking toxicity space, which is a bit better thinking since we covered the company and it's just a practical question. And also when you went to the ASCO data from other drugs and combos, it's quite evident that -- yes, your message of getting early is important. But how do you do that practically? Because, I mean, we even saw this partial response, I think, our close to partial response in non-small cell lung cancer of BI-1808. So there seems to be, I mean, across tumor types responses, but how do you get -- especially for instance, non-small cell lung cancer, how do you get to these early patients? And do you see -- do you have some practical tips for the company to kind of navigate this patient channel?

Well, so basically, what you do is you develop a triplet as a Phase II. And if the activity level is good, because you can propose a randomized Phase II to patients who are getting the standard chemo immunotherapy regimen. Give the combo with your agent, let's say, the TNFR2 receptor inhibitor. And basically, your first readout would be after 40 versus 40 patients or 60 versus 60. And if that shows an increase in response rate or PFS then you would seamlessly expand into a Phase III. I don't see an easy other way to get in to busy fields like non-small cell lung cancer because we are still hooked, of course, on chemotherapy in those type of tumors. When you look at melanoma, there is multiple entry points because the standard treatment in advanced melanoma is if you are a PD-L1 expressing is basically anti-PD-1. If you are PD-L1 negative, it's basically anti-PD-1 plus either LAG3 or plus anti-CTLA-4. And then the proposition to those patients to receive that, which is standard plus a promising agent. I can tell you what patients will choose. They will gladly participate and it's vastly underestimated how easy it is to get into first line in advanced melanoma. So it's not that hard. All you need to do is want it and organize it.

Very helpful. Just one follow-up, a separate question on -- because it's -- I mean, it's one thing to get in these trials as you described, but then it also still seems to be a bit of a shot into the dark in terms of finding the patients that are most likely going to respond besides the previous lines because of their tumor. And that's maybe also a question to the company. How do you consider this now going forward in both programs discussed today with 1206? We see this signal in metastatic melanoma. Is there a sign on why -- why that is there in some patients and why not? And the same with the TNFR2 where we [indiscernible] responses in gastrointestinal stromal tumors, is there some marker or something that you can kind of increase the number of patients that are going to respond in the subsequent trials besides getting in early, which obviously may be the biggest factor.

So if I may give a first more general answer, then you guys can take the more specific side of your experience in a couple of tumor types because let's not forget the ovarian cancer patient, they were responded. Because the peritoneal cavity is a bag filled with microphage. And that's one of the reasons why everything fails there. So it's highly interesting that there was a complete, if I remember correctly, response in ovarian cancer. But -- so let's take the patient who has a muscular invasive bladder cancer, or let's take the patient who has a rectal cancer, garden variety colorectal cancer. But so there's a urinary bladder, right? So you can do a bladder resection, then only the bottom of your bladder remains, then you put the sigmoid on top of that bladder, you create an artificial bladder, which always will leak. You have to empty it by putting pressure on your bladder, et cetera, et cetera, right? So this is no fun at all. If the proposition to you is to have neoadjuvant prior to the planned surgery, anti-PD-1-based approach and one of the facility molecules would be actually either one of the products of BioInvent. What would you say as a patient? They will stand in line to participate in those types of studies. Why? Because you can easily follow them by endoscopy and by an MRI. And if you see a good regression you can simply follow them by biopsies. And if it's a pathologic complete response, you will not operate on them. Nobody wants to passed by on such an opportunity. Same thing is true for rectal cancers and so on. So you can organize it and from the resections of remaining tumors where you still have to do a resection, but which can be much smaller. So you can say perhaps part of the bladder, you will get all the information, not only on your subsequent biopsies by inspecting the regression of your tumor, but you will also get the eventual resection material. You get a ton of information on the mechanism of action and of the dynamics of your patients, and you can then correlate it to the original biopsy of the primary tumor and see and work out, which tumors will respond and which might not. Because if you don't respond, you will have no chance in the immunotherapy field anymore as the patient because you need something totally different if you are unable to respond in the neoadjuvant immunotherapy setting. And so you would have very early guidance to radically change what your remaining options might be. So in all programs, it would be highly beneficial for quick decision-making for patients.

This is really helpful. One last question is just considering the recent regulatory progress of tislelizumab now isn't in the end, BI-1206 combined with a PD-1 kind of more potent approach of the same since tislelizumab seems to have its extra edge with being -- minimizing the binding to Fc gamma receptor.

So Björn or Andres, you may give an answer to this one.

So can you repeat the tislelizumab, why is it -- can you repeat, Dan?

I mean there has been a bit of progress now regulatory-wise about tislelizumab and there has been kind of the notion that it is a PD-1 targets that arm, but at the same time, it's minimizing binding to Fc gamma receptors.

That's how it was designed, right? It's Fc, you know. So it supports going after Fc receptors. And of course, we are using a slightly different approach. Our approach you could combine with any of the existing anti-PD-1s that are out there, which are, of course, all IgG4 except tislelizumab. Is that your question or...

Yes. I mean, just how do you see the kind of recent progress now with some approval and also...

I think it's similar to the Agenus data that Alex pointed to. Fc receptors are really critical in several different immunomodulatory antibodies, and I show the Genentech paper on TIGIT. It's a similar story, right? You need to understand Fc receptors, and you can then tweak with different reagents and we're in the fortunate position of having 2 types of [ FCRTB ] that are indicated to be able to enhance on PD-1, C20, CTLA-4 and beyond. So I agree with you. I think all of the data, tislelizumab, the [indiscernible] antibody super supportive for -- and demonstrate that that's a kind of biology that we need. We need to actually start really dealing with that.

And you're quite along with this, right? So far not seen any other company now also with TNFR2 that is that advanced or I missed something here.

No, you're right. Andres, you were going to take...

Yes, I think you're correct. I think that BI-1808 is -- that format of antibody is definitely the first-in-class and way ahead of anyone else. We do see some activity of other companies with agonist antibodies. That's -- it's a different concept. It's a different approach. Definitely, BI-1808 is a first-in-class and way ahead of everyone else. I think that we can safely say that in terms of a blocker/depleter, antibody. So aiming to deplete Tregs and modify the tumor microenvironment, the way we showed you that it does.

And Dan obviously, it's right. If you look -- so obviously, what you say, Andres about 1808 at receptor 2, that's one. But on the FC gamma RIIB front, we're actually currently the only one in the clinic.

Since it's a couple of first-in classes, if you like.

Exactly.

And maybe one additional point is the tweaking of the Fc part of the antibody that has shown enhanced activity, et cetera, that's very exciting and proof of concept that Fc gamma receptors are of the essence. But also when you block Fc gamma receptor IIB, you basically are doing like if you were having a knockout. Basically, you're knocking down Fc gamma affinity for Fc gamma receptor IIB or interaction for the Fc gamma receptor IIB. That, when you do it by engineering is not as efficient. And maybe -- maybe you want to add to that, Bjorn?

Yes. Well, I mean, I think -- so in the slides that I had shown, I think I tried to illustrate actually the complexity of targeting with the high-affinity arms of the antibody, the inhibitory receptor alone, which is we like the 1607 agent, we chop off the tail. And then when you come in with an antibody that does that and has an Fc competent tail enabling it to be and it used in the context of PD-1, which is -- which is quite different actually from a mechanism perspective with respect to Fc receptor engagement to CTLA-4 and of course, in lymphoma. So again, I think we're in a unique position where we are able to manipulate the different Fc receptors in the way you can -- well, at least as far as we can tell right now, [indiscernible] with respect to those different types of mechanisms that are out there. Again, where you want to have Fc receptor engagement broadly, if you want more of a selective activator Fc receptor engagement. And even when the Fc receptor is controlled by a different mechanism, internalization of antibodies in all the tumor cells such as in lymphoma. Of course, a lot of this is good. Well, I don't know, a good fortune. I think we made some good bets early on, and now they're really translating that. It really is starting to prove itself to be quite important. So it's super exciting.

Really exciting. And also interesting to see that others didn't go that far. I mean if you just look at tislelizumab, there has been, I mean, much weaker attempts to target Fc gamma receptors. And I guess you see that also quite some barrier in terms of like you need to have quite a sophistication to design all that in the right way.

Our next question comes from Sebastiaan van der Schoot at Kempen.

I wanted to start off with Dr. Eggermont. Yes. Thank you for your valuable insights. I was just wondering whether you can give your vision on what tumor indications are not yet conquered and where you would see 1808 succeed in the future. And then maybe you can also indicate what type of efficacy you would like to see from the current ongoing trial to actually get the confidence to move with 1808 into earlier lines and maybe a randomized study?

Yes. Thank you. So -- in terms of not yet conquered cancers, I think quite interesting targets would be non-MSI colorectal cancer, would be ovarian cancer and would be neoantigen pancreatic cancer exploration because let's face it. In pancreatic cancer, you're always at the end of the line, unless you move up in neoadjuvant. Neoadjuvant protocols in pancreatic cancer are now happening all over the place. And if you want to click an early readout of what your agent might do in tumor microenvironment modulation because there are T cells in pancreatic cancer, but interestingly, this trauma and the stromal compartment of pancreatic cancers is almost impossible. And interestingly, Hopkins pathology demonstrated that most T cells if not all T cells in primary pancreatic cancers are not in contact with the tumor cells. And so it would be highly interesting to add because here you have free access to a number of protocol developments because the situation is totally disastrous. And you can combine it with whatever you want and study the material because you're going to get resection specimens. It would teach you enormously about the potential of tumor microenvironment modulation in just about the hardest type of tumor that you can deal with. So there is an open-door policy for the tumor as dramatic as pancreatic cancer. So I would try to go in there. Currently ongoing study simply needs to make its numbers and get a readout where there are -- because it's a multitumor type program, et cetera. But there you must choose where you can go early in your pre-sure tumor type to get the additional information. But if you're response rates would be really promising. Then of course, you must grasp your positioning in the advanced setting for whether it's in first or in second line. But in general, always think about first-line opportunities to not underestimate the potential of your immunotherapeutic agent.

Got it. That's very clear. And then maybe for the BioInvent team. I think that you started off the presentation mentioning the patients who relapsed or refractory to immune checkpoint inhibition typically do not respond to new therapy against checkpoints. In that context, can you maybe go over how many patients in the current study were previously exposed to checkpoint inhibition? And going forward in the dose expansion phase of the study, how many patients you expect to recruit and have not seen immune checkpoint inhibitor sets?

So are you talking about the BI-1206 or are you talking about BI-1808?

BI-1808.

BI-1808. Yes. So the current patient population is an all-comer population that you usually treat in Phase I. So some patients, for instance, with pancreatic cancer, they will not have received the standard -- or part of their standard of care is not an IO agent. So you may see those patients in your study. Other patients may have received the standard of care and entered the study. So for instance, the ovarian cancer patient that we saw had not received the complete response that we saw with 1808. That patient had not seen IO agents. The patient with GIST had not seen IO agents. Other patients may have seen IO agents. So that's really not a criteria at this stage. This being said, as Bjorn mentioned in his introduction, if you go after several immuno-oncology agents, chances are that -- your chances of responding are going to be very low. And therefore, we want to go as early as possible as also Professor Eggermont has pointed out. So looking forward, we want to be in a situation where we can be the first immuno-oncology agent that is being administered and also as early as possible. So that's -- I think that's -- those are the 2 guiding principles.

Great. And then regarding 1808 still, when can we expect new data on the expansion cohorts? And will it then specifically be also on ovarian cancer patients?

So maybe I address Andres, maybe I do first and then you can have the details. So as you know, Sebastiaan, so we have now those 4 expansion cohorts as presented by Andres, ovarian, melanoma, CTCL and then other solid cancers that will also include GIST, for example. So those we will push ahead with it. So this is already ongoing. And the earliest update that I currently seen, of course, you can be always surprised, but that will be towards the end of this year, that means Q4.

And as we've said, those cohorts are now recruiting. We are also interested in the T-cell lymphoma arm because here, you may have a direct targeting of the tumor cells. That is a very difficult study to be performed because of course, those are very rare types of diseases, yet with the attention of investigators is captured by this potential treatment for their patients. So those patients are being enrolled. So yes, as Martin said, by year-end, we should have some sort of more comprehensive data. And by the way, all of these cohorts are now enrolling, all the sites are enrolling patients simultaneously. It's not like this Phase I where you have to stop and reopen, et cetera, which is a little bit painful for everyone. But now every site that is open is recruiting patients. So it should be a lot more quickly.

That's very clear. And then maybe my final question is on 1206 in combination with rituximab in non-rituximab responding patients? Like I think that the efficacy signal that you see for the subcutaneous formulation is very striking. It's now 100% ORR in follicular lymphoma patients. Can you please indicate when you will be able to show more data from the subcutaneous formulation in non-Hodgkin's lymphoma? And whether the subcutaneous formulation will be prioritized over the intravenous formulation in the triplet with the BTK inhibitor.

Yes. So it's -- as you know, it's a very competitive field. So it's very difficult to do all of this. However, we are acquiring data as we speak. It's looking very promising with respect to the subcutaneous formulation. So we will make that shift as soon as possible if the data is there to support the change. And that's basically the goal that we want to get before we -- based on data and not on assumptions. What we're seeing is very promising. And as I mentioned, there is data out there that was disclosed at ASCO also of another antibody that actually because it was shifted to a subcutaneous formulation. It actually prolonged PFS and prolonged overall survival, which is not -- it's logical because you basically cover the receptor occupancy, the target engagement for a longer period of time with a more sustain form, et cetera, that's where we hope to be able to achieve. And I think that's the way it's looking. So we're just hoping to be able to acquire more data. And at the right time, we will make that shift. In the meantime, because we want to progress quickly with the activity of the triplet and show that as a proof of concept also. We are moving forward with the IV. So the IV will enroll patients. Actually, it's pretty much a very good situation now to be able to start enrolling patients, have received approval already in some countries. That's already very interesting. But as soon as we -- the data allows us to be convinced that the subcutaneous is a good -- is what we hoped it would be, then at that moment, we will make that shift.

Our next question comes from Richard Ramanius at Redeye.

Excuse my voice, because I'm a little bit sick. Well, the first thing that I was curious about is if you, Alexander, have any comments or views about the results [indiscernible] presented at ASCO in solid tumors, both BI-1808 and 1206, there's something that stands out or in the results that is particularly exciting.

Is the question addressed to me?

Yes.

Okay. Well, first of all, the TNFR2 receptor inhibitor is basically unique and shows I would say almost unexpected levels of activity. It's great principal, Treg reduction, T cell expansion and so on. But let's not forget that all these 1206, et cetera, drugs, I mean they may be one of the first macrophage checkpoint inhibitor that we've now been waiting for, for 10 years because we've been talking now for 10 years, all the time of how to break the vastly immunosuppressive environment because of the tumor microenvironment of established metastases also in primary tumors, by the way, but particularly in metastatic disease. And -- this is, therefore, a highly original portfolio and every new data coming out of this program is going to be interesting new data because this is novel. And it addresses one of the big thresholds to finally expand the number of tumors that will respond to T cell immunity because of modulation of the tumor microenvironment by addressing one of the main headaches that we have, it's M2 macrophages. So actually, I think every update of the program will be interesting.

Yes, quite interesting to hear that. I think macrophages are reported live. In my work, I've come across more references to Tregs that they're more problematic. I guess that would be the area of 1808.

Yes, I know, sure. But I mean the data that Bjorn has shown and also out of the clinical patients that [indiscernible] is that while we've seen in the mouse now for once, also we see in patients. So the Tregs reduction, Tregs depletion is obviously of major importance because it's the immediate breakup of an effector cell mechanism that otherwise would be highly effective and now is basically neutralized. So for me, there's -- the 2 components, obviously, that are important. And the 2 components are promisingly addressed in the portfolio. So we need more patient material, but this is highly original, and this is actually a stepping stone to break through immunosuppression mechanisms that up till now, we've been basically powerless against period.

I was thinking about another triplet and this is a perfect question to [indiscernible] especially from [indiscernible] that the CTL-4 is supposed to have also a T regulatory depletion [indiscernible] the literature, you can read that it's -- it's a bit different and it affects the checkpoint on Tregs. So what -- does it make sense to combine CTL-4 plus PD-L1 plus BI-1808 in the triplet...

Yes, it makes sense. This needs to be explored now, and both explorations need to be done, and then we will know. But this is too good a molecule to say I'm not going to explore scenario A and B.

I have a huge set of questions, but we're over time -- and the last question, what positive is to BioInvent, what do you think about going to neoadjuvant treatment?

That is something that we obviously will explore, no doubt. And I think we have to sit together, actually, we discussed it already a little bit. But obviously, currently, we first have to establish or collect more patients as Alex was saying in the current trials and then in parallel, we can prepare for those other scenarios. So maybe, Andres, you want to add some more flavor.

No, yes, I was just going to say exactly that. And then as Alex pointed out, there is incredible opportunities, and he spoke about bladder cancer. I could not agree more with his assessment. And I think it's a perfect opportunity to explore and the amount of data and information that you can get out of that sort of study would be just huge. And also the impact on the quality of life of those patients who would do anything to avoid a cystectomy, it's huge. So I think there are definitely opportunities, and we will try to do that as much as possible, for sure.

All right. So our next question comes from Mayank Mamtani of B. Riley.

Thanks so much for the helpful summary of your recent ASCO presentation and very exciting indeed, and I appreciate you taking our questions. I'll keep it short. So for the company first, about the 1808 Phase I/II data set, just translational data being generated to kind of better characterize the synergy between PD-1 and TNFR1 and then more specifically, have you looked at Treg population in the periphery? And maybe lastly, the road map to getting to RP2D, what sort of questions remain there, knowing project optimists front and center for everyone. So if you could just maybe address that. And then I have one follow-up for Dr. Eggermont.

Andres and Bjorn first.

Yes. So maybe on the first note of mechanistically what's going on, we're currently writing up a couple of papers actually that discusses, well, I think what you asked for in a bit more. So hopefully, that will be available before too long. The other questions did seem to relate a bit more to the clinical stuff.

Yes. And as Bjorn alluded to, there will be a significant amount of biomarker that thanks to the approach that we've been taking. We see this in preclinical models. We look at that in human subjects and interestingly, we see very similar things happening and major -- very important things happening inside the tumor microenvironment. And I think that's -- and unfortunately, we can't -- there is a lot of the data that is confidential, but we clearly see the signals pointing in the right direction. So that's the one -- the first question, Mayank. So please stay tuned. Regarding the -- I think you're referring to project Optimus. We have already -- we're looking at different signals, in different tissue type specificities, et cetera. And I think that's already very good. I think we will be in a very interesting discussion with FDA because this is a -- this is a very safe drug, as I mentioned. So when you're thinking about therapeutic window here, you're thinking, wow, the whole window is very open. So yes, we have receptor occupancy with 2 different doses. We look at what happens to the immune system with those 2 different doses. We can explore that and we'll explore that. But we are in a very comfortable situation when thinking about 1808 in the context of Project Optimus.

Fantastic. Great. And then for Dr. Eggermont, obviously, the [indiscernible] study was the ASCO headliner and obvious there were other biomarker-specific approach where maybe durability in the metastatic melanoma was sort of the focus I'm thinking frame at ASCO. And then you pointed to the [indiscernible] more sort of in the non-MSI high where maybe garden variety colon cancer may not be as [indiscernible] as we think. So just as you think about some of the regulatory considerations when you think about tumor selection, contribution of components, knowing this could be a combination-based drug. Do you think this is more like [ ORR ] plus PFS plus OS kind of drug? Or do you think this could be more of a sort of PFS, OS and maybe not betting too much on the ORR? Again, I know things can be got tumor-specific, but just Dr. Eggermont, your perspective, as you talked about some of these near-term opportunities for potential [indiscernible] approval. I would love to hear your thoughts.

Well, basically, with immunotherapy, if you have a major pathologic response in the neoadjuvant setting, almost all patients are cured and don't need any further adjuvant therapy anymore. I'm talking melanoma now, but I'm sure it's going to be exactly the same cutaneous squamous cell cancer and it's the same in MSI colorectal cancer and potentially in any MSI tumor. Because that's how transversal this might be. But if you bring into the equation on top of your neoadjuvant approach a tumor microenvironment remodeling agent and you finally address the macrophages, it becomes very interesting. And if you can show your Treg depletion rates to be as significant as they seem to be, it becomes even more interesting. And then you get a multi-component readout of the likelihood to have a major pathologic response on a number of elements that you can detect by peripheral blood sampling. You do not necessarily end by, if accessible biopsy. But if you ensure that your Tregs drop then you're already adding to a gamma interference signature, 2 elements that would be of fundamental importance to say, okay, I got a responder, I got a major responder, prognosis and likelihood of a curative response is so high that -- and so on. I will not only give it, but I will also propose not to do surgery and so on. So I think there will be a couple of readouts that will lead to this in multiple tumor types. And per tumor type, there may be slight differences, but I would say that Treg depletion and gamma interferon signature and CD8 expansion are the 3 top markers that will [indiscernible] cure, not just a major response, cure.

Got it. And lastly, Martin for you for 1206, seems like this is the ideal combination partner of choice to enhance potency of existing drugs, existing standard of care, you win doublet of drugs. So maybe strategically, do you think this might be an agent in hands of maybe a larger strategic so that the full breadth of indications could be explored. Just maybe your latest thinking on corporate strategy.

So obviously, our goal is to prove the activity of our reagents as we are currently doing. If you just go through the list very briefly. So 1808, obviously, the big milestone there is to manifest further the single-agent activity that will be quite important from a strategic perspective. And then so we will continue also with the other compounds and drugs that we really approve and that's why we do Phase I/II that the thing is working and it's safe. From a strategy -- corporate strategy of the company perspective. First of all, keep in mind, we have a very broad portfolio. So we will not be shy in partnering with the right partner. And you're absolutely right. So from that perspective, if you have the right partner with retaining certain rights, you can do, of course, much broader clinical development because I absolutely agree with the outlook of [ LAX. ] But of course, you need also the money to fund all this. So this is actually important to do that together with a strong partner. At least for some of our assets, and we already have some discussions ongoing. And obviously, then having indications such as CTL-4, 1808 in case we see data there, then we could think about doing a pivotal study ourselves at some time point. But this will be, of course, entirely data-driven. But we will have in mind to find right partners in a way that we can also retain rights, co-development, et cetera, in order to really push the broad potential because that's what we have with all the assets that we have, talking about the leads today only 1206 as well as 1808, the potential application is very, very broad. And of course, as a small company, you have to be very smart how you go about it, and that's what we're trying to do.

So that concludes the verbal portion of our Q&A. We have time for one more written question from the audience. So can you please give an update on the business development area? And how do you see the possibilities of achieving value-creating deals?

Yes. So as I'm saying, as I already mentioned briefly when I was asking -- answering Mayank question. So we have a very active business development strategy. And I think we are now at a very interesting time point of the company because now we see that we have not only safe lead compounds but also lead compounds that have shown efficacy and in some cases, even single-agent efficacy. And based on that, we have already interesting discussions ongoing. And of course, I cannot discuss it here in detail. But I would assume that towards the end, maybe early next year, there's definitely potential keeping the current trajectory of data to do a large deal. What I'm thinking there is so upfront at least of high double-digit, low triple-digit USD 100 million, I think should be doable. And that is basically, of course, would be a strong validator and as I said, so have a portfolio. So we're not giving away everything, but we could partner one or the other. And that will be also a strong validator for the overall approach and way how we go about it, as Bjorn mentioned at the beginning, using first, really focusing on the tumor microenvironment and that could give a tremendous boost to the value of the company. As you already could see. So we have doubled the share price over the last couple of weeks just based on the initial data. And I would think that towards the end of the year, we have even more mature data and obviously, we're all hoping that we keep the current trajectory. And that should basically lead to 2 things: number one, to do a larger partnering deal; number two, to do larger financing.

All right. Great. So that concludes Q&A. Martin, do you want to give some closing remarks?

Yes, I can do that since we are already a little bit overtime. So if you just can go maybe to the next slide. Thank you. And before I comment on that, maybe summarize on that. First of all, a big thank you to Professor Alexander Eggermont. So very, very nice presentation, and I especially like that you were really trying to make the connection between what we are trying to do and what the overall feel [indiscernible]. And then, of course, a big thanks also to Andres and Bjorn, very sustained, very precise super presentations. Thank you very much. And then just a few concluding remarks. So here on this slide, success factors, obviously, the platform that I already mentioned and Bjorn had very nice outlines how we use it. And then I think what is also quite important and very often is forgotten, really understanding the science and the biology of the mode of action because I think that has been key here in order really to move successfully a preclinical portfolio into the clinic. So with all the hard scientific work and preclinical work. And I think we could not even go deep into this because besides our first that we used to generate human antibodies. We also have the mouse counterparts that we can really use to fine-tune and analyze and characterize what is happening. And I think this is key -- and that's I think also the comment that I made at the beginning that we closed collaboration between Andres and Bjorn, so chief Medical and Chief Scientific Officer is also super important. Andres is a Chief Medical Officer who understands the science and can translate the science in the best possible way. So I think this is absolutely key. And then, of course, having first in hand, we can be innovative, as Alexander has already mentioned. So what we have is really first-in-class and hopefully, not only first but at the end also best-in-class. And at the end, of course, we want to help patients and I think the outlook that you gave, Alex was very inspiring actually what is there as a potential. Maybe just a last comment on the last slide. Just to remind everybody again what are the remaining milestones of this year. So next slide, please. So this will be then the remaining milestones for this year. And I think it's also important, even with all the prospects, I think we have to conclude successfully those clinical studies that we're currently running. So just to sum it up again so 1808 as a single agent, as I said, so we want to collect further data in ovarian cancer, I think, which is very interesting because there's no IO approved really that works in ovarian cancer. So I think this is also strategically very interesting and falls into the one of the categories that Alex has mentioned. So there, we are already in such a cohort. CTCL is super important because if you see on data over there, it's a small patient population, then we could do a pivotal ourselves basically. And then the other solids, I think there will focus or try to focus as much as we can on GIST since we saw the good response or have the good responder there. And then melanoma as much as we can go early. And all this will be hopefully updated by the end of the year, then by -- with 1206 in non-Hodgkin's lymphoma, we will kick off the triplet. And hopefully, we'll have the first handful of patients by the end of the year, which also will be super, super exciting. And then what we didn't discuss much today is obviously, we, I think, from my perspective, at least, we own the space around TNF receptor 2 because we not only have a blocking deleting antibody with 1808, also an agonist 1910. And when we look at our competitors, they're both, they have one or the other. So we have both which gives us, of course, a very unique positioning in that space. And that data, the first single agent data of the dose escalation 1910 will be available also during the second half of this year and then we didn't discuss at all today, of course, our innovative approach around all our proprietary anti-CTLA combined with operative [indiscernible], but also there, we'll have an update during this year. So I think financially, we're well positioned, and we have already hit quite some interesting milestones [indiscernible] further interesting milestones towards the end of this year. And then, of course, there's even more to come next year. So I think very well positioned and with, of course, supporters such as Alex, I think we can also hope for the best and really try to move the company and the portfolio in the best possible way. So I think I end here and thank everybody again for presenting and of course, also the good questions that we received from the audience and look forward to the next KOL event once we have kicked off or ticked off rather a couple of more milestones. Thank you very much.