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

Good afternoon, and a warm welcome to all of you who have joined us here in Stockholm in site as well as those of you who have decided to join us online. My name is Lars Frick and I'm very happy to be the moderator today at the BioInvent R&D Day 2022. First off, I would like to start with a little warning. Today's presentations will contain forward-looking statements. So beware. There are also clinical cooperations involving funding for some of the research that we'll hear about later on. But enough about that because the focus today is to give an in-depth view and review of the pipeline. So first off, soon, we will have Martin Welschof, CEO, who, together with other members of management will present the pipeline. We're very, very happy to also have a key opinion leader with us today, Dr. Lim, who will talk more about the clinical aspects of research. So we will start off with -1206 and -1607. We will break at 3:00 p.m. for those of us of you who are here physically, Coffee will be served us back, and there are restrooms at the entrants. So take that opportunity. Then moving on in the pipeline. We will have Björn Frendéus, Chief Science Officer; and Andres McAllister, who is Chief Medical Officer, talking about that. Rounding off the event will be a chat with all the presenters, and that's also an opportunity for you to ask questions. So when we reach the end, please save your questions for the end, and we will have management as well as Dr. Lim here to answer those questions. And for those of you joining on the website, there is a box underneath the presentation where you can write and then they will be forwarded to me. And I, in turn, will ask, repeat them for management. So please ask questions. Use the text box underneath the presentation online. Well, enough about me and please let's welcome Martin, CEO of BioInvent.

Thank you very much, Lars, and welcome, everybody. And I would like to start off with a quick introduction of our speaker panel. So Lars mentioned already, Dr. Lim, we're very grateful that you could join today. She comes from South Hampton and is a clinician specializing in lymph node cancers, as is mentioned here on the slide, and she does a lot of research around new antibodies that could be used for the treatment of such cancers. And then, of course, we have Andres, our Chief Medical Officer, who is with the company since now 5 years, and he will give a detailed background on the various clinical programs that we're running. And then Björn Frendéus, our long-term CSO and actually, one of the inventors behind first that I will announce later a little bit more in detail, and he will always give a short introduction to the mode of action of the various programs and it's obviously instrumental to the whole operation. So before we go to the core, which obviously is the R&D, just a couple of general remarks. Obviously, to -- well-known to everybody from here in the audience is that checkpoint inhibitors, they was the last advancement in cancer therapy when they were implemented and developed. And that's actually a citation from Nature Reviews in oncology. So that has changed a lot of things. So they have become the standard of care. For several types of solid cancers, you can see that there are a lot of patients which are eligible. And they're now 8 approved agents of those checkpoint inhibitors. And currently, that's actually quite interesting. More than 5,000 trials running just with PD-1, anti-PD-1 and anti-PD-L1 alone. So a big step forward, which obviously was very important for cancer therapy, one of the hallmarks or the latest hallmark in cancer therapy. But there's still a very high unmet medical need. So when you look at the numbers, so roughly 15% of the patients would respond. The rest are not responding. And there are a couple of reasons for that. First of all, number one, and that's something that we're addressing also by BioInvent, the number of targets which are available for cancer therapies is still limited. So you can see most of the companies working on a handful of targets. And then also, most of the new targets have failed. So that did not really bring what you wanted to see. You saw maybe some early responses, but no long-lasting complete responses as we see with -1206, and we'll come back to that later. And then as I already mentioned, the majority even doesn't respond at all. So it's this 15% that's really responding very nicely and 85% not really responding to the new checkpoints. So a huge unmet medical need that we're trying to address with our programs and with our technology platform. So what you normally would see in drug development is that you select a target by a means of functional genomics and other technologies you characterize it, you make a compound against it. And then at the end, you hope that you see a function, which means therapeutic effects. And by and then, actually, we have turned that around, and we put function first. And you see this very simple cartoon on the right-hand side. So what we have established is a technology platform that starts from patients. So we're in very close collaboration with the local hospital in Lund. Such that we receive fresh patient material on a regular basis. And this is used in the screening process. So we have a high-quality antibody library that we use for screening. And once we have then specific antibodies binding to those materials of interest, then we go for the function first. So we have a very strong phenotypic screening approach which means we check in a number of preclinical models for therapeutic effects. And once we see that, then we go after the target. So basically, at the beginning, we are so-called target agnostic, so we don't care what the target is. As long as we see a strong function, that means a strong therapeutic effects in a number of animal cells. That's our screening technology, and that's what we use and that's what also differentiates us from other approaches. So in addition to the very smart powerful screening technology, we are also a very integrated company. So we have various pillars. So you can see in the middle, we have a strong team with unique antibody experience. So BioInvent's been around for quite some time. It's probably one of the teams internationally with very strong antibody discovery, antibody development, antibody production capabilities. But then we also have cutting-edge science. So Björn is running a team that's not only developing interesting platforms, screening platforms, but also doing forefront immunology, which is quite important to really understand what is the right approach or what is the right target for the treatment. In addition, we can produce the stuff in-house ourselves. So Christopher is here also with us and later maybe during the fireside chat, he will join us here on stage. That is quite important because we don't have to go outside, which takes a lot of time and money. And then obviously, as Andres will show you, we have smart translation into the clinic, which, of course, is also quite important. And Andres is one of those rare species where it's combined science and medical development expertise. And I think that's exactly what we need at the moment. Just to illustrate what that means, this competitive advantage. It means really speed. So 2018, we had one program in the clinic. By second half of next year, we'll have 6 programs in the clinic. And this you can only achieve when you have all these elements that I have outlined here under one roof. So with these capabilities as well as the platform that I have mentioned, we have generated this portfolio, and I will not go through this in detail that will be done by Björn and Andres in a minute. But just to mention, so we are focusing on immunomodulation. And in that context, we are focusing on currently three targets. So one is FCGR2B, which is a very interesting receptor on sales of the innate immune system. And there, we currently have, as you can see, three programs. Two different compounds and the details will be discussed later. And then we're also trying to target the adaptive arm of the immune system. And there, we're focusing on TNF-receptor 2 and CTLA-4. Those are targets which are expressed on T-regulatory cells. And those are also programs that we will discuss later. So the only program that we are not going to discuss today is 1910, which is our second TNF receptor 2 program, which is currently still in preclinical development, but should go into the clinic second half of next year. But I will come back later to the key milestones for next year, and then we'll go through all those elements. I think I will stop here and hand over to you, Björn. So the stage is yours and take us on the journey. Thank you.

Thank you, Martin, for that nice introduction Feels good to be talking about clinical pipeline for a change. So obviously, this is going to be Andres' main piece, and I will sell the introductory scientific background to all of you, hopefully. Right. So Martin had mentioned BioInvent is a company dedicated to developing antibody-based drugs for cancer immunotherapy. And of course, the background is that antibodies to immune inhibitory receptors such as CTLA-4 and PD-1 have really transformed not only how cancers are being treated, but also cancer outcome and survival. Now despite these remarkable effects with inductions of cure and long-lasting responses in patients for which there was previously in the home, these are patients that have metastatic disease. And really, again, didn't really have anything to turn to now effectively can get very good treatment and even cures. So still, of course, as Martin had introduced, the majority of cancer patients cannot benefit from these currently available treatments, which, of course, puts a lot of -- well, stress, but also excitement in the rest of the field in companies like BioInvent to help develop new drugs and mechanisms of action that can help themselves or by complementing the currently available great drugs that are out there, induce robust antitumor responses in -- hopefully, the remainder of cancer patients. So while much remains to be learned about why certain patients respond and others do not respond to the currently available therapies, we have some important clues as to what it is we will need to achieve to get effects in these currently non-responding patients. And I'm not going to dwell on it, but one very important finding that has been made is that -- those patients whose tumor cells don't contain inflammatory immune cells and specifically CD8 positive T cells rarely, if ever, respond to the currently available therapies. On the other hand, if you look to those patients that have immune inflammatory cells in the tumors and yet do not respond, they often have tumors that are additionally containing and where the CD8-positive T cells are surrounded by powerful suppressive cells that keep the CD8-positive T cell from doing their job. They're suppressing their activity. So of course, some guiding lights in the research department and environment and actually the whole of our business is to help identify mechanisms and antibodies that can overcome these resistance mechanisms in the tumor microenvironment. And specifically, we're looking for antibodies that can help ignite inflammation in these cold types of tumor. In mechanisms that can help bring the CD8 positive T cells that in many cancers are tracked outside in fibrotic tissue outside of the tumor where they're not doing their job to identify mechanisms that can recruit these into the tumor, such if they can activate antitumor immune responses. And of course, in this mixed bag of immune cells, to find antibodies targets and mechanisms that can reeducate those suppressor cells to become e-factor cells to unleash antitumor immunity. Okay. So Martin had mentioned that a key cornerstone in our efforts to identify such antibodies and targets is our function first discovery platform. That actually allows discovery, not only of antibodies, but also of the targets that these antibodies bind to. So just giving a bit of more detail to what Martin had already disclosed to you. What this process is about is it allows us to use human primary tissues, freshly isolated from, again, the patients, the real deal. We can then use these primary cells to screen our huge antibody library for those antibodies that bind to structures, which are regulated on the cells whose activity we'd like to manipulate. So this could be both intra-tumoral T-regulatory suppressor cells or the tumor-associated myeloid cells. And coming out of these first few circles here, we'll have hundreds to thousands of antibodies that we can screen for functional activity against that same human primary patient materials. And the questions we are asking are, of course, by adding these antibodies, can we then reeducate these suppressor cells and can we help expand and activate the CD8-positive effector cells and so on and so forth. To the extent that the antibodies cross track with mouse target proteins, this is not a given, human and mice are different. As we know that in some cases, they're close enough. Meaning that you can actually test an antibody also in the mouse. We can screen for the ability of the antibodies to actually cure mouse cancer. And of course, if we find that we can cure mouse cancer and that we can reeducate the human cells the way we'd like, then we feel that we're pretty much confident that this is perhaps something we should move forward. And having done and identified the most functional antibodies, we then determine what they bind to, okay? So the pipeline that Martin has shown you, actually, all the programs have emanated from this type of approach, and by this approach, we had identified those targets as being particularly promising with respect to efficacy in our available models. Right, okay? So obviously, if we find interesting antibodies, targets and epitopes, we then characterize what their mechanism is, and we can put them in preclinical or clinical development. So with that said, we've identified a number of what we believe to be very powerful, both targets and mechanisms of action that Andres and myself will cover in our clinical update today. So without further ado, I think we should get into that. Actually, I think there's one more slide just for me to mention better on FcyRllB. So the first couple of programs we'll be discussing are BI-1206, our clinically most advanced antibody and its sibling -1607. Both of these antibodies are exquisitely specific, the other antigen-specific arms for the FcyRIIB receptor. This is a receptor that belongs to the Fcgamma receptor superfamily. And these receptors do exactly what their name implies. They regulate the activity of gamma globulins, IgG antibodies. And in fact, most antibodies that are used for cancer immunotherapy are IgGs. So there's a great potential, of course, in manipulating the activity of this receptor. FcyRllB is the only inhibitory Fc gamma receptor, meaning that in concert with the activatory Fc receptors. This is the 1 that puts the brake to the floor and then slows down immune activation. So we can take our foot away from that break we may be in a very interesting position to help sort of supercharge the antibodies that depend on these types of biologies. Okay. So -1206, that's our first-in-class antibody. It is Fc competent human IgG1. Meaning it can interact with Fc receptors through its tail. And this renders it able to enhance both on anti-CD20 antibodies and on anti-PD-1 antibodies, albeit by different mechanisms. So in Non-Hodgkin's Lymphoma, this is a B-cell type of cancer, where the FcyRllB receptor is also expressed beyond on the macrophage factors. Our antibody will block rituximab internalization. And then consequently, as I show in the next slide, help overcome rituximab resistance. In solid cancers, which in general, don't express the inhibitory FcyRllB on the cancer cells, the mechanism is different, and I'll get back to that later on. But it still allows us to enhance on the activity of these very different antibodies to one of the key or the key checkpoint inhibitor receptor. -1607 differentiated in the sense that this tail of -1607 cannot speak with the activating Fc receptors, and as a consequence, although being equally specific to these antigen-specific arms, renders it to have a very different mechanism of action and allows us to combine it with other clinically relevant cancer targeting antibodies. Okay. So yes, this is just a little cartoon to help illustrate what -1206 does in Non-Hodgkin's Lymphoma. So this is then a tumor cell. It expresses CD20, which is the target of the rituximab antibody. Rituximab will bind via its antigen-specific arms to the CD20 molecule. But then at the tail we'll be able to interact with a habit of receptors expressed on this tumor cell. And in fact, Sean who's here with us today helped demonstrate that by a mechanism whereby the tail binds to the inhibitory receptor, this causes the internalization into the tumor cell and removal of rituximab molecules. And this is bad news because rituximab needs to stay here on the tumor cell surface to engage Fc receptors on those killer effector cells that are going to dock on to rituximab and phagocytose the rituximab coated tumor cell. So if we block rituximab binding to the inhibitory receptor, as is shown here to the right, we will prevent internalization of rituximab molecules and leaving in effect, greater rituximab molecules to engage the macrophages that will gobble up the antibody-coated tumor cell. So we've actually published quite a bit on this receptor and our -1206 block in antibody. Two pieces of evidence that really supported what this antibody is doing are shown here. To the left is a model where the animals are double transgenic. They're expressing both the receptor, the human relevant receptor for rituximab and our antibody. In this model, we find that both of the antibodies have a certain level of antitumor activity or actually B-cell deleting activity. But if we combine them, taking half of those -- each of the two antibodies. So there's the same number of antibody molecules, but we've now mixed the two qualities. We're seeing synergistically enhanced deletion of the B cells, which is then consistent with that sort of prevention of [indiscernible], building on rituximab activity and perhaps bring a little bit of deleting activity itself on -1206. What was a bit more surprising, I guess, is when we developed a humanized mouse model for relapsed/refractory B cell cancer. In this case, it was chronic lymphocytic leukemia. Here, we had taken tumor cells from patients that had received multiple different courses of rituximab. And as a consequence of that, and this is typically what happens if you have that type of B cell cancer. They have become completely resistant and refractory to the CD20 antibody component of those therapies. If we took such cells from those patients and grafted them in this humanized model, we would see no effect following rituximab treatment whatsoever, very limited effect of our -1206 antibody alone. But when we combine the two, we would see objective responses in like 1/3 of the animals. Now for reasons I'm not going to get into. There's some limitations in how long you can run this model. So if we then look to other models, this actually does translate into significantly induced survival. So what does this mean? Well, if true also in human subjects, this would indicate that by blocking the inhibitor FcyRllB receptor, we would be able to reinvigorate responsiveness to one of the world's best characterized antibodies, which is rituximab, which has been exhaustively used across different lines of therapy. That Andres will tell you more about now. So this is what we're testing in the clinic. And word over to you, Andres.

Thank you. So we will be presenting a little bit between Björn and I, the full pipeline. So bear with us. This is just a very important clinical data actually again, Dr. Lim, who is here part of her work, but basically shows you that patients who are high expressers in three different important indications in Non-Hodgkin's Lymphoma actually have -- if they have a high expression of FcyRllB, they have more aggressive disease. And of course, the prognosis is not as good. So what we would like to do is transform that. And again, I think Björn was saying something that is very important, which is the resistance to rituximab. If we can combat resistance to rituximab, we can recover what is already a great drug, and that's part of our endeavor. This is the clinical study that we started about 4 years ago. It's a very classical dose escalation study of BI-1206 in combination with rituximab in patients with indolent forms of Non-Hodgkin's Lymphoma. This study is recruiting patients in the indications depicted here. So mantle cell lymphoma, follicular lymphoma and marginal zone lymphoma. The very classical and then with an expansion cohort in the same patients, same types of patients. We -- very typical exploring safety, tolerability, trying to understand the pharmacokinetic, pharmacodynamics, receptor occupancy, et cetera. Important to note that all patients must have relapsed after previous rituximab therapy. And that's basically the study. We have gone through the first part of the study, and we had some very interesting results depicted in this swimmers plot, where basically, we have seen three complete responses that actually those patients finished their participation in the study and the patients have remained in complete response for over -- actually, this patient has been in complete response for 3 years. This one over 2 years. So that's very interesting. Unfortunately, we lost the information about these patients, so we just basically don't know. We also had some very interesting partial responses, in particular, one patient with mantle cell lymphoma who had complete depletion of circulating. It was a blastoid form, meaning that sales are circulating, and we saw complete depletion of those circulating tumor cells. So that was very interesting. I will come back to what we have done. But basically, the study has continued. We implemented a split dosing, and I'll come back to that in a minute. And actually, we have one patient already still on treatment who is -- who has a partial response. This is the data subset for follicular lymphoma. Again, bear in mind that this is early days. and with a nonoptimal dose, but basically, you can see the waterfall plot, which looks very nice. And the top part is our participation duration in the study. So there again, we see something that is very positive with this. Again, non-optimized dose, so very exciting. So I'll tell you what -- how this played out. So basically, we started at 30 milligrams flat dose. We went up to 100 milligrams. And fortunately, we had infusion-related reactions that were associated with liver enzyme elevations and platelet drops. We decreased the dose to about half, and then we were able to treat 5 patients, but there again, we saw the same issues. Fortunately, this is a very short life and all the patients have recovered within the next few days. So that's really hasn't really been a problem, but we did want to escalate more through discussing with our investigators and through the fact that at BioInvent, we were able to react very quickly. We developed a mouse model that recapitulated completely what we were seeing in humans. And we were able to test just about every regimen of steroid, antihistamines, et cetera. Came up with an interesting regimen of steroids that we implemented in the clinical study and we were able to continue escalating. That allowed us to go up to 100 million. Since we were still seeing infusion-related reactions, we implemented split dosing that turned out to be in this particular setting difficult for patients because of the number of the stay at the hospital, et cetera. So didn't turn out to be a great idea. So we decided to continue with IV infusions of 100 milligrams, which is currently ongoing and the patient that I mentioned before is actually a patient that is receiving that regimen. Yes. So I think -- so we were -- as part of the work that we were doing, we decided to explore different ways of administering the drug. And of course, I have to give credit to our CMC team at BioInvent who were able to turn around very quickly and produce a new strength that will allow us to treat patients subcutaneously. So we're able to concentrate a drug very quickly produce clinical batches and actually the protocol has now been approved in all the geographies that we are conducting this study. So that's very exciting. This is just some predictive work. So basically, we think that the infusion-related reactions that we see are associated to a very high concentration of antibody in the blood at the very beginning. So basically, if you stop or slow the infusion at the beginning, the infusion subsides. Even though the receptor occupancy is high, the infusion actually subsides. So that really indicates that this is a -- the question here is that you're having too much antibody at the very beginning of the infusion. So subcutaneous seems to be the right solution. Of course, we tested this in a number of models preclinically and everything, the animals tolerated the drug as if they had not seen the drug. So that's very, very encouraging. So basically, what I want to show you here is that if you -- the infusion-related reaction, we think it's associated to this peak, the subcutaneous will produce this sort of profile. So same area under the curve, but very slow absorption into the blood stream, which is, of course, what we want. We think that this will allow us to go higher in doses. And so what we actually did was we were able to implement this in the same study. So it's a new arm in the study. This time, we will -- given that we already know quite a bit, we will do an adaptive design, which will allow us to escalate very rapidly. Again, this has been approved in every country that we have, where we have submitted, including the U.S. and other countries. We will begin with 150 milligrams subcutaneous inoculation and then 1 patient expandable to 3. So 1 patient dose escalation. So basically to reach to 600, we need 2 patients. And as I mentioned, we're already looking for those 2 patients. And I think we can expect the first patient to be recruited really any day. Again, just to go back to talk about the interesting responses that we've seen. And I think I have commented on this information. Just wanted to slow down here for a minute and think about the competitive landscape. And of course, the first thing that we have to note here is that this is a very competitive area, where there is -- despite all the competitive environment is mostly concentrated on just a few mechanisms of action and actually depicted here. All of those have a positioning. But I think what's super important and really differentiating from the rest is that we believe that rituximab will remain for years the backbone of therapy, and I will come back to that in a minute. And maybe we can discuss this with Dr. Lim later. But with every physician that we've discussed. This clearly is important. Rituximab is a drug that is highly appreciated in the hematological arena. And we believe that if we can recover that loss activity as you treat during several lines with rituximab. I think this will be great. And in particular, for those -- for the community hospitals for places where were rituximab and perhaps more sophisticated like CAR-T treatments are more difficult to get to. I also think that -- okay, I think I've commented on this. And I also wanted to show you this, which is basically the treatment algorithm for mantle cell lymphoma. And you can see that rituximab-based therapies, you start using them in first line, but second line, third line, you're always using rituximab-based therapy. So basically, BI-1206 could go in any of these lines. Of course, we will -- we are beginning here, but the potential to go into earlier lines is obviously there. One important thing is these treatments such as rituximab and lenalidomide and rituximab plus ibrutinib, who have produced some very interesting results. Those drugs are either already a generic or will become generic very soon. So the triplets will be very affordable and doable. So again, I think our positioning is that the expanded use of biosimilars. I think it's like 70% already in Europe, and this is likely to go in that sense in the U.S. as well. especially with recent new legislation, et cetera. There is an increase in the prevalence of Non-Hodgkin's Lymphoma, increased use of rituximab actually. When you look at the sales of rituximab even though there may be a slight decline in the sales that actually reflects the more availability of biosimilars rather than less usage. Actually, if you consider the number of days of usage of rituximab, it's actually growing very much. So we're very confident that our positioning is a very strong one, very different and very interesting and appreciated by the community. So I think this is just a very short summary. We have a very compelling scientific rationale. Again, pursuing something that no one else is pursuing, which is resistance to rituximab. I think that's a very important point. This is a first-in-class and actually only in class. There's no one else who is doing this. I think that is very important for BioInvent. I think it's also important, and we have data that has been published already. It's very important to think about these patients that are often times elderly who have been through several rounds of chemotherapy, et cetera. If you can come up with a regimen that is safe, well-tolerated and is chemo-free, I think that will be very much highly appreciated by the community. Okay. And last and definitely not least, is that the quality of the responses that we've observed in our short clinical development program are very impressive. So we're very happy about that. Okay. So we'll shift over to your presentation for a minute.

He's a bit silly, but there you go. Okay. So I will shift gears a bit and talk about -1206 in solid cancer. And well, how can it be that we can use -1206 also in a very different setting of solid cancers and with a completely different type of antibody. I'll try to convey that and convince you about why in the next few slides. So in solid cancer patients that are being treated with anti-PD-1 antibodies, the PD-1 antibodies are thought to work by binding to -- well, of course, by binding to PD-1 molecules on these good effector cells. Now the clinically relevant anti-PD-1 antibodies are the IgG4 isotype and what does that mean? It means that they can speak, but typically weak speak with these immune Fc gamma receptors. And when the antibodies were developed, people actually, I think, did not fully appreciate that even this type of isotype can have meaningful engagement and biological function by interacting with these Fc receptors. So what we and others have found, and I'll show you the data in the next slide, is that when the anti-P1 antibodies have coated on to the CD8-positive T cells, if there's sufficiently great numbers of P1 molecules, which will often happen as you treat these patients for prolonged periods of time, the tails of the antibodies can engage with the macrophage Fc receptors, and that has two detrimental consequences. One of them being that the Fc receptors can grab hold of the tails of the PD-1s and just pull them off of the CD8 positive T-cells. Then, of course, you don't have that blockade of this inhibitor and you lose a bit of efficacy. The other thing that can happen if you have sufficiently high expression of PD-1 molecules, is that the Fc receptors engage in that same type of deletion mechanism that we had just discussed for rituximab, meaning that the PD-1 coated CD8 positive T cells can be deleted or phagocytose. So this is a data set that really is underlying what I had just told you. The first group in the world to sort of describe a compromising role for Fc receptors in relation to anti-PD-1 therapy, was the Jeff Ravetch lab at MSKCC in New York. So they used an approach where they simply swapped the tails of the PD-1 antibodies to make those that couldn't speak with Fc receptors as the green line here. And you can see this is a very efficacious and controlling tumor growth. They also use the variants that engage strongly in Fc receptor binding in which case, they would see reduced antitumor activity showing that FC receptors are not a good thing to engage with anti-PD-1 antibody-based treatment. Then came along a group from Mass General like Harvard in Boston, led by Mikael Pittet. He demonstrated using a separate strategy where he would use pan-Fc-receptor blocking antibodies. So these are -- this is an antibody that blocks all of the Fc receptors in the animal. Shown the same thing that if you add this in red on to the blue anti-PD-1, you can actually get better anti-PD-1 therapy and survival. And then, of course, the third set is asset bindment, which we've demonstrated that if we take our FcyRllB antibody that has a tail that can speak with the Fc receptors, we get the very same effect. So here, we're actually targeting FcyRllB, which is again up regulated in the tumor microenvironment. So we get more antibody to the tumor, and we're still able to get the same effect as this pan-FC receptor blocking antibody. So that's really exciting and really important, I think, that whenever you are seeing the same results that other knowledgeable people are seeing in the world, that's a signal of strength, right?

So basically, this is the study that we're doing with BI-1206 in combination with pembrolizumab. Again, very classical dose escalation study. Here, we're using a an adaptive design, which has been very much used in recent years by companies. We are in the dose escalation part of the study. And it's important to say perhaps that, of course, all the patients that entered the study have relapsed after previous anti-PD-1 or anti-PD-L1 containing therapies. So we're really testing the idea whether these patients would respond to therapy. This is the dose escalation that we started and basically we are escalating. We're still escalating the dose. I think in this context, we also saw the infusion late reactions that I mentioned before. So for this particular study, it is important that we will also implement the subcutaneous. I think that will allow us to escalate much further and something that we believe is important is to maintain a full receptor occupancy over the treatment interval. So that's where we're currently working. I'm not going to say very much about this study. Basically, what we are thinking is by -- during the first half of this year, we will have a larger disclosure of the -- what we've already observed. We have seen the same data that we had already disclosed. So basically, a very interesting partial response in a patient with uveal melanoma that. Patient is still on treatment. So that's very interesting. And one patient who had a very typical case of pseudo-progression, who is actually still doing really well. Fortunately, because it was pseudo progression, the patient had to come off study, but we opened a personalized patient protocol and that patient is still -- his disease is still under control. So again, we will have a further disclosure of this. But importantly, we are working very hard on implementing the subcutaneous formulation, which I think -- if for the other study, it's important for this study will become much more important. Should we continue now or Fc gamma RII, 1607 or I think...

I think 1607 should be now before the break, please, Andres.

Okay. Okay. So Fc gamma RIIB is also being targeted by 1607. You want to give the introduction, Björn, and...

Right. So 1607, that's the 1206 sibling, which differs from 1206 only in the sense again that its tail cannot speak with these Fc gamma receptors. So here, we are combining with different types of antibodies. One, mentioned by you Andres, is the anti-HER2 antibody trastuzumab. So what's going on in the tumors with this type of biology is in the absence of our 1607 antibody, the -- in this case, HER2 antibody will bind to HER2 receptors expressed on the tumor cell. And the tail can then engage either activating or inhibitory receptors on macrophages in a balanced manner. And this will result in some level of phagocytosis, but not ideal phagocytosis. And what you really want to do is to sort of remove the ability of the anti-HER2 antibody to interact with the inhibitory receptors. And that's, of course, exactly what we're doing with the 1607 antibody. We're blocking this. And now the HER2 can only speak with the activating Fc receptors, and you get stronger activation of the macrophage, which is a good thing because then you can get rid of the HER2-positive breast tumor cells more efficaciously. So I think it's important. I just like to come back to the fact that the -- that there is no magic to these Fc receptor biologies, they're really simple. All they do is they regulate the activity of IgG antibodies. And there's a lot of IgG antibodies, trastuzumab being one. But actually, the CTLA-4 antibody has been approved in the clinic, or actually both of them. But this one in particular, ipilimumab, strongly engages Fc receptors. And so it's known that actually anti-CTLA-4 can act and exert its antitumor activity with -- by many different mechanisms, blocking CTLA-4 interactions with B7 family molecules will result in sort of [ relievel ] of the brakes of the factor T cells. But anti-CTLA-4 antibodies can also work by deleting T regulatory cells, which expresses much stronger -- the CTLA-4 antibodies compared with the effector cells. And there's some emerging data to suggest that actually this Fc interaction, the tail interaction of ipilimumab with Fc receptors, may be very important in sort of reprogramming the myeloid effectors that are in the tumor. This is a bit early, but still, I think very interesting data. So in other words, even for this antibody, which is not even binding to a tumor cell, you really may want to exquisitely engage the activating Fc receptors. And there would be an indication that 1607 could be sensible to use as well. So we've, of course, modeled this in preclinical tumor models using our 1607 surrogate antibodies and have demonstrated that indeed, we can enhance on the activity or anti-HER2 antibodies. In particular, it seems if there's low levels of HER2 receptors being expressed, and that's, of course, really interesting from the clinical perspective because those are the most difficult to treat with the currently available reagents. For CTLA-4, the same thing. We can actually take a lower dose of CTLA-4 antibody molecules and by combining with our 1607 blocking antibody type, enhance activity to full dose levels. This third data piece that's been included is not human relevant. It's just to show that, well, it seems that you can well, I shouldn't say any target, but this is a very different type of solar cancer express targets, gp75 expressed on a mouse melanoma tumor cell line. And if you take an antibody to that specific melanoma tumor cell, a receptor, this biology too is sensitive to FcRIIB blockade because you can much more efficaciously delete those melanoma tumor cells if you block the inhibitory FcRIIB receptor. So these are 3 very different cases where targeting FcRIIB with 1607 could be helpful.

So here's the study that we are conducting. We entered the -- you might have seen that we started this clinical development relatively recently. Basically, we started at a dose of 75 milligrams, which I think if you compare to the 30 milligrams that we were discussing for BI-1206, this is already super interesting in the sense that we were able to treat the first 3 patients without any issues, any safety concerns, et cetera, really talks about the level of the understanding of the biology at BioInvent, in the sense that this is virtually the same as 1206 only with a mutation in the Fc fragment. So I think understanding the biology is super important. We were able to treat the first 3 patients, and we haven't seen any safety concerns. The study, again, is very similar to the ones that I've shown before. So dose escalation in the doses depicted here in combination with trastuzumab in patients with HER2-positive cancers, breast cancer or gastroesophageal adenocarcinoma. So, so far, lots of excitement about this. And again, I think it's important to understand, as Björn pointed out that this is -- 1607 can enhance the activity of many other -- potentially many other antibodies, in particular, anti-CTLA-4. We are -- currently, we have, in our protocol, these 2 expansion cohorts, but definitely our very important data set is what we have done with anti-CTLA-4 in combination with anti-CTLA-4 anti-PD-1, we're enhancing the activity of those antibodies, again would be super interesting. So I think I've told you most of this. Yes, and importantly, again, no infusion reactions at that dose that I mentioned. Okay. I think that that's...

Thank you very much, Andres. Thank you very much, Björn. It's time for a break. [Operator Instructions] So we'll pick up the thread in about 15 minutes. And for those of you who've joined us online, please stay with us. In 15 minutes, we will continue with the rest of the presentations, including our key opinion leader and the fireside chat. Thank you. [Break]

Welcome back to BioInvent's R&D Day 2022. I hope all of you, those who are here in Stockholm as well as those of you at home, have had time for refreshments because it's time to move on with the presentations. So I'm happy to welcome Björn Frendéus back to the stage. Please tell us more about 1808.

Right. So I actually thought I'd discuss BT-001 for a bit, but anyways. So the previous 2 talks were on how we can -- are thinking we will improve on 2 of the most successful antibody-based drugs used in cancer immunotherapy. Now I'll shift gears a bit and talk about an antibody that had emerged from our efforts to identify targets -- powerful targets and antibodies to delete T regulatory cells. And it is a bit of a special story that Andres often refers to as the beast. So here comes the beast. All right. Okay. So as part of those efforts to identify T reg targeting antibodies, we had a bit unexpectedly identified one that bound to CTLA-4. So -- because in our hands, antibodies to CTLA-4 and that would be ipilimumab, the clinically validated CTLA-4 antibody is not a very efficacious inducer of T reg deletion. So in fact, we originally felt that, well, can this really be true, and we went back and did a number of controls and each time we got the same answer, well, it is indeed specific to CTLA-4. So this would be an example of how we can use our function-first platform, not only to identify targets that have not previously been pursued in cancer immunotherapy, but perhaps finding uniquely functional antibodies that do stuff that other antibodies don't necessarily do. So anyways, what do you do with an antibody that more powerful than the existing one and where the existing one is not being very well tolerated, which is, of course, the case for anti-CTLA-4-based therapy. And then we figured that how about if we try and deliver this intratumorally and if we did that, we would still want the antibody to stick around for a pretty long period of time. So we didn't simply want to inject it in a recombinant form, but we would need to get it produced in the tumor over a longer period of time and then to get sustained occupancy of CTLA-4 receptors. So we felt how about if we encode the antibody into an oncolytic virus, and we then inject the oncolytic virus into the tumor. So this would -- if you read to the right, or if you're like me, you want to look at the figures. This would -- the hypothesis would be the oncolytic virus infects the tumor cell, the tumor cell becomes a factory for producing our therapeutic antibody, so you'll get high concentrations of anti-CTLA-4 antibody in intratumoral compartments. And of course, as this then diffuses into the rest of the body, the hypothesis was we'd get very little, if any, meaningful biological exposure in blood, for example. So this would prevent untoward activation through targeting of CTLA-4 in other nontumoral compartments. All right, so what's the antibody going to do when it's in the tumor? Well, 2 things we gathered. Firstly, to bind to the T regulatory cells, those very immune suppressive cells in the tumor and because these again express high levels of CTLA-4, it's already been demonstrated that when that's the case, you get deletion of the T regs. The antibody produced in the tumor would also bind to CTLA-4, which is lower expressed on the good guys, the CD8 positive T cells and block CTLA-4 suppressive activity, yes, on those cells. Finally, because this is an oncolytic virus, what that means is when it infects a tumor cell, it will lyse the tumor cell. So the virus, as such, could help kill off a sufficient number of tumor cells to actually promote a third type of biological reaction, which is the release of tumor antigens. So when you have release -- increased release of tumor antigens, when you take away these suppressors and when you take away the break on the good guys, then you're in a very interesting position, perhaps of being able to target 1 of very few clinically validated immune checkpoint targets, Martin had mentioned there's 5,000 studies on-going with PD-1 and PD-L1, I guess, because largely, there hasn't been a whole lot of activity on CTLA-4 lately. But there's reinvigorated interest. So anyways, potentially, if this then proved to be safe, again, because we're not targeting extra tumoral CTLA-4, we might be able to combine that with PD-1 for very important, clinically important effects. Okay. So I'm just going to quickly show a couple of slides. The first thing we did with this anti-CTLA-4 encoding antibody virus was to test are we -- will we be achieving local saturation of CTLA-4 receptors when we inject the virus into tumors? And can we get indications that we're not going to be achieving any meaningful exposure in blood? So you see this gray shaded area here. This is indicating saturation of CTLA-4 receptors in tumor or in blood. And you can see the red line, that's our anti-CTLA-4 encoding in virus. Indeed, we're getting saturation of those CTLA-4 receptors over a sustained period of time. If you look in blood, there is no such exposure or saturation. If you then do the same experiment with a recombinantly added, intravenously injected antibody to mimic what's being done in the clinic to get these receptor saturating levels, you need quite high doses and what it will translate into orders of magnitude, greater exposure in blood compared with in the tumor. So indeed, this indicated very much a significantly improved therapeutic window. The next question is then, okay, when we are saturating these CTLA-4 receptors in the tumor? Are we achieving what we like to do, and that would be deleting T regulatory cells. So we counted the number of T regulatory cells and tumors as you can see here, they're virtually down to, well, not being eradicated but very low numbers. And in the peripheral blood, we're seeing no effect. So that's consistent with this preferential tumor targeting of -- the concept. Now whilst we're treating tumors locally, what we're hoping to achieve here is to activate immune system such that you will get a systemic antitumor immunity, meaning you activate the immune response to then go and seek up the tumor cells wherever they may roam and have those tumor cells eradicated. So to get some proof of concept that this is actually what was happening, we turned to a twist of a tumor model, an animal experimental model, where you can graft 2 different tumors to the same animal and you inject the 1 tumor with the oncolytic virus and then you monitor what's happening to both of the tumors. So this one doesn't get any treatment. And this is the model you're seeing down here. So this is an injected tumor. We eradicate all other tumors. This is uninjected tumors. And in 7 out of 9 cases, the flanking uninjected tumor was completely eradicated indicating that this is a systemic activation of antitumor immunity, which is exactly what we had hoped for. So having seen that, the improved indicated therapeutic window and the systemic immune activation. We turn to look at activity in a range of different tumor models that represent these different types of tumor microenvironments that I talked to you about in the beginning, ranging from the coldest of the cold where you don't find any immune cells to those where you sort of have a few immune cells, but maybe in the wrong place to animals or to tumor microenvironments where you have good immune infiltration. And you need to focus then on the red line here. And you can find that actually in all of these cases, where there are any immune inflammatory cells, we have cures across -- well, in essence, the board. So very good, the tumor activity. And when we then turn to the most challenging cold tumor microenvironment, we're seeing a fraction of animals being cured like 20%, 30% or so. So this may not seem so impressive, but in fact, in the clinic, the responses are currently 0 here. So potentially, this could open up for treatment with immune checkpoint blockade to a group that currently cannot benefit from that treatment.

So we started this clinical study and basically, the study is relatively simple, again we are -- dose escalation started at [ 10 to the 6 ] platforming units per patient -- per dose and escalating up to [ 10 to the 8 ]. That is the first part of the study. The study schematic is depicted here, but perhaps I will shift to this one, which is basically where we are right now. We have gone to the highest dose with this intratumoral administration. We have seen no safety and tolerability concerns. So that is very good. Importantly, and going back to the hypothesis here, which has been able to express and to deliver anti-CTLA-4 into the tumor, we were able to do that. And actually, we have been able to detect the antibody presence. So the antibody is being expressed in the tumor, and we were able to detect that at the lowest dose. So actually, we're currently doing that work in higher doses, but basically, we've already have the proof that the antibody is produced. And also, we also have the proof that the antibody is not detectable in blood. So actually, showing that we -- while we are able to deliver the antibody into the tumor, we don't detect it in blood. So we're not exposing regulatory T cells in the periphery. So that's super interesting. And we're basically up to finishing that highest level cohort. As soon as we finish that cohort, we will move into this part of the study, which will be BT-001 in combination with pembro, and that is planned to begin during the first half of this year -- of next year. Yes. So I think I've told you all of the things indicated here. So exciting, we'll see what happens next. But this is very interesting project that we bring along hand-in-hand with our partner, Transgene. Okay. So now we're going to shift gears and talk about 1808.

Right. Okay. So I guess in the introduction, I had mentioned the 2 types of interesting antibodies that we might expect and generate with our approach. So the previous program was an example of an antibody that bound to a uniquely functional epitope. But of course, what's also very interesting is if we can identify targets that haven't previously been pursued in cancer immunotherapy and represent very powerful biology. So this will be an example of the latter. BI-1808, this is a first-in-class antibody to tumor necrosis factor receptor 2. It has compelling efficacy, both as single agent and in combination across the types of tumor microenvironments, I have shown in the previous program. It has a differentiated and a very interesting mechanism of action compared with other antibodies to tumor necrosis receptor superfamily. It's regressive existing large inflamed tumors, and I'll show you examples of that. And it seems to synergize with PD-1 antibody, the one antibody that generates those 5,000 different clinical trials. So that's very important to build on what's already out there. It has that interesting mechanism of actually deleting and reducing TNFR2 high-expressing T regulatory cells, similar to CTLA-4, TNFR2 is most highly expressed on the T regulatory cells. But it also seems to actually co-stimulate intratumoral CD8-positive effectors, which have much lower, but somewhat elevated expression of TNFR2 compared with those cells that circulates in the blood. So that would be an indication of tumor specificity and dual actions. Interestingly, we need to know -- to learn more about this, the antibody also seems to reprogram the tumor myeloid component of tumors. Here, we've invested quite strongly in having reagents that can help us translate important information on mechanism from the mouse, but also in identifying biomarkers on when -- what can we expect in a patient that responds? Is there something popping up in blood that we can measure? Ultimately, of course, the ideal biomarker is one by which you can take a blood sample or a tumor biopsy and understand that this is a patient that is going to respond to our therapy and I think that's a bit of [ waste ]. But having these reagents in our hands, we're uniquely poised to actually ask those questions in a data-driven and hypothesis-driven manner. Okay. So yes, you recognize the tumor microenvironments. Starting here to the far left is a mouse tumor model, which is known to respond to anti -- well, to T-cell targeting therapies. So maybe here, you can focus on 2 things. Firstly, is -- anti-PD-1 does not always work in such T-cell inflamed tumors. This is admittedly large tumors and unusually large tumors. And here, anti-PD-1 has no single agent activity whatsoever. This is our antibody you've seen cures in more than 50% of the animals. If you move to a slightly less inflamed, has less CD8-positive T-cells model, EMT6. We see a bit less of activity or antibody, we're still pretty good, it's like 50%. In the third model, we're not seeing very good activity with single-agent treatment of our antibody and decent activity with anti-PD-1. Interestingly, when we combine the 2, there's complete cures across the board. So finally, in that super cold tumor microenvironment that we're very interested in bringing clinical benefit to those patients. We are seeing combination effects when we combine our antibody with PD-1. So in summary, I think there's evidence to suggest this antibody may have single-agent activity, to synergize with PD-1 and potentially even could help bring clinical benefit to this patient population.

Yes. So this is the clinical study that we began -- I forgot exactly when, but basically, these -- this has been progressing extremely well. We -- this is, again, an adaptive design in TPI-2 -- adaptive design to dose escalate. We started at 25 milligrams and we went up to 675 milligrams, which is what was in the original protocol. We had a very well-tolerated drug, no safety concerns, no tolerability issues. And for that reason, we decided to escalate 1 dose further, so 1,000 milligrams. When we are at those doses, we are observing a complete receptor occupancy over the period interval. We have already -- we are characterizing the pharmacokinetic profile and everything looks quite well. So again, for that reason, we decided to begin with 1,000 milligrams, which this cohort is currently -- we already have 2 patients that have been treated, and the patients have tolerated the drug really well. And in the meantime, we opened the first combination with pembrolizumab, which is, of course, very exciting times, given this potential synergistic activity that Björn showed in animals. If we were to see that in humans that would, of course, be super interesting and maybe bringing those T cells into and making tumors more inflamed, but that's where we stand right now. The first cohort with pembro has been fulfilled, and those patients are currently in the dose level toxicity observation period but we haven't had any concerns. And as soon as we finish that observation period, we will move into a higher dose in combination. So 675 in combination with pembro that should happen very early next year. And in continuation with the 1,000 milligram, we will treat a few more patients at a dose in these high levels as single agent. And -- so during next year, we will move into the expansions cohorts, which should be a very different, very interesting. Of course, lung cancer is the first choice for immunotherapeutic agent and in particular, in combination, that's why we're doing that as well. There are several paths forward to registration in that setting. Very interestingly, I think we are targeting ovarian cancer. We're doing that as a single agent because if we see single-agent activity, that will be a major driver of value for this project, but also we will be doing it in combination with pembro data, even though immunotherapeutic agents have not made it to treat ovarian cancer. There is some activity. So we push that activity a little bit higher through that potential synergistic activity. I think that will be super interesting and potentially, again, a quick path to registration. And last, but not least, we're also treating patients with T-cell lymphoma. We will hear Dr. Lim talk about T-cell lymphoma. Currently in our study, we're treating CTCL patients, that could potentially be enlarged to other types of T-cell lymphomas, as we will hear next. And activity in that setting would be super interesting, as you will hear. There are very few agents or nothing really that works. There is a huge medical need. And of course, this would open the way for BI-1808 to go into a orphan drug designation and take a regulatory path to quick registration. So that's really our -- the way we're looking at it. There is a recent study that showed that for patients with CTCL have a certain level of response to pembrolizumab. So the combination there is also has become relevant. So we may also explore that combination in that setting. So that's basically where we stand. I think I've mentioned what it is here. Last, but not least, we have observed 3 stable diseases in our single-agent dose escalation. Unfortunately, those patients progressed subsequently. We had 1 patient with lung cancer. That patient was a very -- had a very interesting response. Actually, it was a naive patient who decided to enter the study through his own decision. And that patient had a very interesting response. And during the first cycles had a 20% and plus tumor reduction. Some of the long lesions were decreasing, et cetera, unfortunately, the patient simultaneously was diagnosed with another cancer and had to be taken off study. But the response was very impressive and interesting. As mentioned, that we haven't had any safety or tolerability concerns. So this program is progressing very quickly. And I think we will have very, very interesting results during the course of next year. In terms of -- just a word about the competitive environment, we are -- we -- I think we are frontrunners, BioInvent was the first to enter the clinical exploratory work with this target and antibody. As you have seen, there is -- and if you look into the literature, there is a lot of different possibilities and very intriguing biology in terms of whether you should develop a agonist or what Björn usually calls a blocker depleter. And you see that several companies that are already entering or yes, have already entered or will enter soon potentially clinical development. I think BioInvent is way ahead of anybody else. And I think importantly, I think understanding the biology of this target is of the essence. It is very impressive what the team at BioInvent has done in terms of characterizing the target, and I think for that reason, we are actually developing 2 antibodies. So one is 1808 and the other one is also an agonist antibody, which will enter the clinic next year. I think the understanding of the biology or the role of the Fc fragment in the antibody is of the essence. And we are in a unique situation to really understand where each antibody can be positioned in the clinic, and that's where we are moving forward in that direction. So I think that was all, as mentioned, 1910 will enter the clinic next year, and we're super excited about that as well.

Thank you very much, Andres. Now I'm very happy to present Dr. Sean Lim, who will give us the clinical side of things. Thank you, and welcome, Dr. Lim.

I failed the first test. Okay. So I'd like to thank BioInvent for inviting me to speak today. It's -- as Andres alluded earlier, I'm going to be talking about peripheral T-cell lymphomas. You have my biography, so I'm a lymphoma doctor, but also I have a research interest in cancer immunology. And as someone who treats patient's lymphoma, I can tell you that we really do need new treatments for patients with this group of diseases. Now I'm going to start right from the basic, so bear with me. So I'm going to start with what are -- how do white blood cells developed and how do lymphomas come about? So all our blood cells come from stem cells. I tell my patients baby cells, they can grow up to become anything. They grow up, they can mature to be different types of white cells and some of these white cells are called lymphocytes, B cells, B lymphocytes or T lymphocytes, and they're really important in fighting infection. B cells produce antibodies, we've heard about them; and T cells kill infected cells. And so when the normal developmental pathway for B cells is disrupted, they can turn into abnormal malignant cells, B-cell lymphoma. And likewise, if the same happens for T cells, then they become T-cell lymphoma. So fairly it's kind of a straightforward concept. So where do lymphomas feature in kind of the grand scheme for all cancers? So this is the number of new cancer diagnoses in 2018 in the U.K. And here, we have the lymphomas at number 5. So kind of reasonably common. We see a lot of them. I'm always very busy. And the distribution between males and females are roughly equal. And it's complicating. It's not on lymphoma. So I mentioned earlier about B-cell lymphomas, but there's also Hodgkin's lymphomas, but I'm going to concentrate on the T-cell lymphomas here. The World Health Organization kind of broadly classifies them into 5 big groups, but there are over 91 types of lymphomas in total. Kind of T-cell lymphomas alone, there are 19 of them. And the commonest lymphomas we see are the B-cell lymphomas, and you heard about it from Andres earlier the follicular lymphomas, the marginal zone lymphomas, they're all B-cell lymphomas, our bread and butter. And then about 10% of cases they're the T-cell lymphomas. And the fact that they are rare means that really we have less opportunity to study them and also makes them, in that respect, are much harder to treat. And so here are some of the commonest subtypes of T-cell lymphomas in Europe and North America. And so PTCL NOS tends for peripheral T-cell lymphoma, not otherwise specified. And not otherwise specified, really just means it's a waste basket category where we don't really know what they are beyond the fact it's a T-cell lymphoma. We can't group them into anything, so we put them in a waste basket category. And they make up the bulk of it. And then the second category is angioimmunoblastic T-cell lymphoma. And this is very -- this distribution is really different from Asia. In Asia, the kind of the commonest lymphomas are the acute T-cell lymphoblastic lymphomas in orange and the NK cell T-cell lymphomas. And we think really this is because there are different incidences, prevalences of viruses. So like Epstein-Barr virus as well as human T-lymphotropic virus which makes this slightly different. And this is -- like all lymphomas are largely a disease that becomes commoner as we get older. Most of my patients, I do see 20-year-olds and 30-year-olds, but with -- they tend to be kind of 50 and above, again, which makes it slightly tricky because it means they are less fit for some of the treatments that we want to give them. And this is the kind of the saddest graph in their specs. So this paper was published by the International T-cell Lymphoma Group, the first kind of collaboration -- international collaboration. It was published in 2008, but I can tell you that -- so this survival curve, there has not been a change in 30 years. We have made no improvements in the treatment of this cancer despite all the advances we've made in B-cell lymphoma, nothing has been made for T-cell lymphomas. And I have here the survival curve of the 2 commonest subgroups I talked about, the peripheral T-cell lymphoma, not otherwise specified, and angioimmunoblastic T-cell lymphoma. And essentially, 1 in 2 persons diagnosed with T-cell lymphoma will die within 2 years of being informed of the diagnosis. And this contrasts for something like B-cell lymphoma, which is usually -- a roughly about a 70% survival rate at 5 years. Okay. So I just want to -- so the patients I see, how do they present? Well, not all of them, but quite a few of them will present with a lump, a painless lump, generally enlarging over weeks and months, depending on where this lump is, it may cause problems due to compression. Say, for instance, they may compress blood vessels that leads to blood clots. This is a scan of one of my patients actually, who is unfortunately no longer with us, and he had a -- so it's a PET scan of the patient's, given intravenous radioactive glucoses, very low radiation and cells that multiply quickly, they take up and they light up for us. And it's a very good way of spotting where the cancer is. So normal organs will light up like the brain as well and the heart and the liver slightly. But you can see where I pointed the red arrow, it's where he had a really large tumor in his neck and the blue arrow points to his airway and it was so big that it was compressing both his voice box and his airway, and he was struggling to breathe. So we had to treat him very rapidly. And kind of apart from this, they may present with fever, they may lose weight with and not realize what the reason for this is and another classic symptom is that they may have drenching night sweats so they'll say, "doctor I'm really hot at night, I have to change my pajamas, I have to change the bed sheets." And there can be other nonspecific symptoms, which can make it quite difficult for us to diagnose sometimes. And to reach a diagnosis, we need to take a piece of tissue. We need a biopsy. And the history pathologists will examine this under microscope and kind of the published slide is what you're looking is as of quite small atypical lymphocytes and some larger ones. And you're absolutely right, they all look the same to me. Sometimes they do. And so -- and sometimes they do to the history pathologists so -- to kind of to help them really decide what this is. They kind of look for what markers are expressed by applying special antibodies. In this case, this is a -- it kind of shows up CD3, which is a T-cell marker, and that helps us come to diagnosis. And then the next stage is really staging. So we need to decide where the lymphoma is, whether it's just in 1 area, it's Stage 1 or Stage 4, meaning it's kind of distributed to multiple areas, both [ start at the ] diaphragm and may affect other organs, which are not only lymph node as well. And a really important part of assessment receipt patient is that we need to assess how fit they are. Are we dealing with marathon runner or are we dealing with someone who's a lot [ LD ] with a lot of medical problems, diabetes, heart attack, et cetera. And so really, if we see a fit patient and they don't all have to be marathon runners, they can just be reasonably fit. Someone who can go for a good few mile walk, then the standard treatment is CHOP chemotherapy, which is 3 types of different chemotherapy drugs combined with steroids. It's outpatient-based. And they -- we give them 6 cycles of it. And the problem with chemotherapy, though, is that it's not targeted treatment like antibody or kind of the new drugs that we have these days, it's not discriminatory nature. It kind of kills cells which rapidly divide, which is why we lose our hair when we have chemotherapy or they might get mouth ulcers because it just does not discriminate between cancer and normal healthy, fast-growing cells. And so if they have a good response, then -- and if they are fit enough, we will try and consolidate this response with a bone marrow transplant from their own self. This means that we essentially collect their bone marrow or their stem cells gives them really strong chemotherapy, hopefully, wipe it out, wipe out the rest and then rescue this bone marrow with stem cells. We monitor them. Unfortunately, from the survival curve, you can see that most of these patients' disease will relapse. And this is where it's really an uncharted territory. There is no other options for these patients, and that's when we look for clinical trials. We can try other drugs, chemotherapy drugs that they've not had before or anything else that might be potentially of use really, and I'll come to that in a bit. For those patients that we can manage to control their disease again. And again, if they're fit enough, then we will consider a second bone marrow transplant, and this is one from a sibling or an unrelated donor, if they have a donor. But this is really a very, very small proportion of patients. And even then it obviously does not represent a cure. And it's also a kind of a procedure that has a very much higher rates of death from side effects from the transplant itself. Unfortunately, if the patients do not respond to frontline CHOP chemotherapy, then again, we come back to the same green box, it's unchartered territory. There's just no other option. And if there's a clinical trial, we will always opt for that because it means the -- giving the patient an opportunity to try a drug that might work. The less fit patients, they will have kind of a dose attenuated CHOP or any other gentle chemotherapy. And unfortunately, they do not respond to that, we're back into the green box. This is another survival curve. So in patients whose disease comes back or if they do not respond to the frontline treatment, the survival curve is even worse in that, on average, most of these patients will essentially die within 6 months of [indiscernible] their T-cell lymphoma has come back and 1 in 3 patients will have died within 12 months. And it's not that we haven't tried to treat this kind of improve our treatment of this disease. The CHOP chemotherapy, which is what we use is clearly not good enough. And we've tried adding antibody -- an antibody called alemtuzumab, which is a targets for monoclonal CD52 and is expressed on lots of cells. But they're in light a problem because it's expressed on lots of cells, there was a lot of toxicity from it and that was added to CHOP. And you can see that the red line is -- the antibody plus CHOP, blue line is CHOP, the survival curve is completely overlapping and really quite dismal. We tried different chemotherapies. We tried replacing CHOP with a completely different chemotherapy regimen called GEM-P, but this is a forest plot and it crosses one, the odds ratio across -- which means it made no difference at all. So we haven't managed to improve on this for the bulk of patients with peripheral T-cell lymphoma. They are caveats, but I will kind of stick to the main T-cell lymphoma subtypes. And there have been other novel drugs, and I won't go into the mechanisms of actions of all these drugs. Most of them have been approved in the U.S. -- by the U.S. FDA and some -- you've seen one in China, one in Japan only. None of these have been fully approved in the Europe or in the U.K. But I just want to draw your attention to the response rates. Now most of them essentially -- the oral response rates are about 20% to 30% apart from one very, very good subtype of T-cell lymphoma called [ AITL ]. Most all of them, the response rate is about roughly 20%, and in all cases, the median duration of remission, meaning the length of time the drug works is about 10 months. And these are all the new drugs that we have managed to kind of produce. So to -- what do we do next? I mean we heard a lot about biology and I think that is really the key to understanding how we can better treat this lymphoma. We need to understand why, how they form. And we know -- we do know some factors. We know that sometimes these malignant T-cells, they form because they have somehow managed to produce their own survival signals. And sometimes, they have mutations, which drives the survival signals or proteins. They produce a lot of proteins that are able to control and kind of improve the gene transcription or how the genes are at. Occasionally, we kind of see kind of metabolic dysregulation, meaning that the -- kind of the chemical reactions that occur are just all misplaced. They're -- but they're all -- not all the patients have every single feature. They're all slightly different. We had viruses. And indeed, like I said, viruses are implicated in some patients, but I should kind of reassure you and say that most patients with that Epstein-Barr virus won't develop T-cell lymphomas, but yet in some T-cell lymphomas, all of them will have Epstein-Barr virus. So it's a bit of a mystery. And finally, all these features may contribute to their invasion of the immune system. And why is the immune system important? We heard about how a lot, and this slide is probably -- I apologize, it's probably simplistic of that what you've heard. But I just want to take us all back to what we think we need to learn about T-cell lymphomas at the basic level. And one is that our bodies are -- ourselves are constantly mutating. There are trillions of mutations developing on a daily basis, but we're not constantly popping up cancer cells. And that's because we have a highly effective immune system. The cancer immunosurveillance comprises of T-cells, B-cells, NK cells, lots of different cells that do a very, very effective job in killing the abnormal cell usually. Cancer escapes when this process balance is disturbed, and the cancer itself may suppress, we heard about regulatory T-cells may suppress the immune system. And so I think -- one means of addressing T-cell lymphoma and a lot of other cancers as well is how can we reengage back the immunosurveillance? How do we bring them back to where they were right at the start? This brings me to my last slide, just some take-home messages. So I just want to stress that peripheral T-cell lymphomas, they are rare, but they're a highly aggressive cancer. 1 in 2 patients will die within 2 years of diagnosis. We have not made any improvement in their treatment in over 30 years despite all that we've learned about new drugs about cancer immunotherapy. And so we really need to focus attention on this disease and design better treatments because in learning how to deal with this, we might also help kind of -- we might also understand the treatment of other rarer, hard to treat cancers better as well. Thank you.

It was a very, very good presentation. And as you could hear, a high unmet medical need and therefore, also a very important target for our BI-1808 program because it could be also a very interesting path forward strategically to a quicker approval because it's a smaller indication. So before we then go to the Q&A, and so-called fireside chat, just a last slide from a corporate perspective, obviously quite important. And based on the excellent presentation by Andres and Bjorn, you could see that we have a full slate of programs, currently 5 clinical programs ongoing. Second half of next year, 6 programs, which will, of course, drive a very interesting news flow going forward. So here, we have listed the expected key catalysts for next year. And you can see on top, the milestones that are expected for the first half of 2023. First, we will hopefully see interesting data for BI-1206 in combination with rituximab, and that will be the preliminary results of the subcutaneous clinical trial that we're starting or about to start. So that would be quite interesting. And obviously, the hope is that we eliminate the infusion-related reactions as well, hopefully see the same kind of efficacy, high quality of responses. Then I think, as Andres demonstrated the positioning, I think that could be a very, very interesting product. And obviously, there, we also have a chance to [ unpivoted ] study, but that will be depending on data. Then as Andres already mentioned, we'll then start also to implement the subcu into the BI-1206 in combination with pembrolizumab, that will also happen during the first half of next year. And at that time, as Andres already mentioned, we'll also update further on the clinical outcome that we have seen so far for the IV. So today, you learned that we still have those 2 patients that are still in response. And I think that is a very first interesting sign of efficacy. But hopefully, there will be more when we come out with further information. Then 1808, the single agent. So as Andres was saying, so we finished the dose escalation as planned. So we did it exactly on time. Actually, we started the trial, Andres, early last year. So not that long ago, actually. And we just put on top the next dose, the 1,000 milligram, which will extend that study a little bit. But I think that's for good reasons. First of all, Project Optimus obviously, everybody has heard about that. When you do test the dose, that's the time point to do it. We have good safety. And I think it would be also quite interesting to see a high dose as a single agent. So cut a long story short, so we'll have the data set, preliminary results, Phase I also during the first half of next year. And then BT-001, as you could see, it was running well. And there, we want to kick off the combination with Keytruda, pembrolizumab. Then at the bottom of the slide, you see the 3 milestones for the second half of next year. So will be the 1808 and pembro combination. And as you could see from Bjorn's presentation, there's really, really strong synergy between anti-PD-1 and 1808. As you could see that we could really get responses in the ice cold animal models regarding tumor inflammation. So that will be quite interesting to see. And then obviously, also 1607, our second [ anti-FcyRIIB ] that will then have the first data set in combination with trastuzumab. And then last but not least, we didn't discuss it today or I just mentioned it. So that's our next candidate, BI-1910, second [ TNFR2 ] program that will then go into the clinic. And there's a lot of work already ongoing because when we talk about implementing subcu running a new program, that means there's a lot of stuff ongoing. And being, yes, a 100-people company, I think this is already a quite impressive portfolio. And also what we didn't mention, and that's something that goes without saying. So we continue the discovery. So there will be other programs eventually at some time point. So we really keep the wheel turning the first screening wheel basically. So I will stop here. And then, [ Lars] if you can maybe then introduce the Q&A.

Yes, thank you very much, Martin. And a big thanks to Bjorn, Andres and Dr. Lim as well. And I would like to welcome you up back on the stage. We're not done yet, I guess, maybe this is the most interesting part. And this is the Q&A session. [Operator Instructions]. And for you who are following us online, I see we already have a few questions, please write more if you have. Perhaps I could start off by -- since we have the -- we're in presence of Dr. Lim here as an active clinician. And having listened to these presentations, do you think there's 1 or 2 factors that sort of stands out with BioInvent's pipeline? I mean the duration, for instance, of effect is quite impressive in several of the diagrams you showed? Or is there anything else that you think is really popping?

Well, I think -- I can certainly see the application of some of the drugs, I think like BI-1808 for T-cell lymphoma that's certainly an option. I think it's -- yes, it's one of those things we have to try it and then we see, but I certainly see the utility, the combination. So one thing we didn't really discuss this. I think with all these novel drugs, the combination therapy is involved very much like chemotherapy, we are going to need more than one agent. So the more we add to the options, then the more likely we are to succeed in treating these cancers.

Like expanding the toolbox to...

Indeed, yes.

Right. I was quite surprised, Martin. In your starting presentation, you mentioned there were some 5,000-plus candidates globally, all aiming at [ 8 targets. ] Is it lack of imagination? Or is it that these targets are so well validated that success rate is high or perhaps you could expand a bit why there is such a lack of novel targets, something you address, of course, with your own pipeline?

It's a combination of things. First of all, of course, anti-PD-1 and anti-PD-L1 are successful. It's a very interesting target. So that's why once you have a compound that really works, you try to expand. That's why the number that you mentioned, this is only for anti-PD-1 and anti-PD-L1. But then, as I mentioned in the beginning, sorry, it's very apparent, and that's not only just now. This is now for the last 10, maybe actually 20 years. There's a lack of good therapeutic targets. It's just the case because if you look around, biotech companies as well as pharma companies that work maybe on a handful of targets with various variations. And I think in order to expand the toolbox, we need new targets, and there comes something in that we have, first, the function for screening platform. It's a completely different approach. It's a reverse screening approach, which means, first of all, just to mention it again because I think it's quite important. We start from the real thing. So we're not just expressing a protein or a peptide and use that for screening. We really use patient material. That means then potentially interesting targets are presented in the context of the patient in vivo. That's number one. And then we don't bother so much what kind of target it is, also we really look for therapeutic effects first. So we have really strong preclinical validation in the process. And I think through this, you select targets that potentially could make the difference. And one other point to talk to Dr. Lim's point is, yes, it will be a combination because a lot of people are really obsessed by single agent. And there is always good when you see it. So I don't want to discuss it away. But at the end, the end game will be combination. So it's even much more important that you develop early on your product -- your potential product in a combination setting, such that you can combine it because the problem is on combining is safety, right? And if you have something which is already as a single agent, quite toxic, just forget about it because you will kill the patient rather than to cure the patient. So I think that's so important that you early on in your development path you have focused on combination.

That's interesting. And I'm thinking there are some other disease areas, let's say, hepatitis, for instance, where combinations and patients have a very difference in response to different medications. So I guess there is quite a fragmented market if you look at patients, so there will always be patients who might be nonresponders to a certain treatment. So my question is, will there be a room for more drugs? Or I mean, when this 5,000-plus projects come to fruition, competition will be very intense. But do you still see that you have a strong position, strong enough to maintain like a market position in spite of this competitive...

Yes, absolutely. I think...

Like there's room for a lot of drugs in the market?

Yes. So there will be room for a lot of drugs in the market in anyway. And I think at the end, it comes down to unique positioning that you have a certain mode of action that you can provide to the patient, which is unique, and this is what we have in our -- all our programs actually.

Yes. Speaking on patient selection, for instance, Bjorn, in several slides, you mentioned the hot and cold environment. So how do you determine that? Is it through a biopsy? So you see the specifics of the tumors? And is that then used to decide on the best treatment options. Like for instance, if it would be a cold environment, perhaps it wouldn't be relevant for your candidates or...

Yes. Well, thank you for asking the question. We have 2 clinicians with us. So I don't know if I'm the ideally poised to that. Do you want to talk to that?

I think that's a really important observation. I think especially for cancer immunotherapy. It's all about the tumor microenvironment. If you want to engage immune system, it makes sense that if you already -- there's a signal there, give T cells, then you're more likely to engage it. But I think the problem is -- well, rather not -- I wouldn't say the problem. The solution is designing very good clinical trials and making sure we ask those questions because what -- so for instance -- so I can tell you that we are -- Southhampton, we're taking out in the BI-1808 trial. And what we're trying to do is, as part of the protocol to collect biopsies from the patient's tumor before and after treatment because; one, we -- because we're not going to get 100% response rate, no one ever does. And -- but when we have that, yes, those that respond and those who don't, if we have the information in the tumor, then we can work out right, who is responding and those are the patients more likely to benefit from the drug, and those are the ones that we can build on.

Right. And speaking of response rate, I mean, when -- in your slide, Dr. Lim, you showed these sort of various treatment options, which had response rates ranging from, what, 12% to 25%, 26%. And looking at the response rates in by [ invent ] pipeline, which is more like 50%, 60%. It seems very, very good. Or is it comparing apples and pears?

Completely, they are different diseases.

Right. Yes. Just trying to get a sense of what's a good response rate, please, Andres.

Yes. I wanted to come back to the biomarker notion because I think that's something that has been very much in our spirit since in every program. So we're trying to look at biopsies prior disease, and we're looking at the transcriptome. So basically, the proteins that are being expressed or the RNA that has been -- that is present in cells. And we're looking at that, and we're trying to compare that before and after treatment. And importantly, we would like to be able to generate some sort of gene signature that would allow us to say this patient is more likely to respond to that or the patient. So we are -- even though these are very early stages, we are looking carefully into that. And actually, it's implemented in every one of our programs.

Interesting. Maybe it's a bit off topic, but perhaps diagnostics is also a part of the problem here that not only having effective drugs, but sort of, as you've been talking about before to find the proper patients or proper drug for the right patient.

So just building on what Dr. Lim and Dr. McAllister told us. I think like one of the things that you really need is actually have good collaborations between early research, discovery, understanding of mechanism and then the clinic and then collaborators that can do the stuff that Dr. Lim's team is doing in the clinic, because then we can let you guys know, these are the kinds of mechanisms we would expect and if you start seeing signals of that in the patients, and that's not only looking at whether a tumor expands or shrinks, you understand better how to move forward. And so you need that very joint effort moving forward. And I think that's one of the really good things that I'm very proud of BioInvent is doing. We're teamed up with some of the absolute, most knowledgeable people with respect to the different diseases that we're doing. And I think that's a key thing.

That's very interesting. Is there anyone here in the audience who has a question, please raise your hand. Until then, yes, we have a question here. Just a minute, you will get a microphone. It's for the webcast. So apologies for the hassle. But I'll ask EMEA, as we say in Sweden, even the webcast, please.

And congrats on the great progress. Just -- so it was partially touched upon that it's not really the response rate that is really interesting. It's the duration of response. And how are you looking at the 3 complete responders that you have now, do you see any markers, do you have especially high expression of the target receptor or do you see other markers that they share and that others don't, and I assume they are all follicular lymphoma patients.

They are follicular lymphoma patients. We're not looking specifically at those patients. Those patients are off study basically. And we just keep informing ourselves how they stand with respect to the tumor. And basically, they are still in complete response, at least those 2 patients that I mentioned. What we are doing is looking into biopsies pre and post and trying to understand variations they're in. Of course, this is early days, and we need to do a lot more work. But I think, of course, the obvious thing is -- are these patients high expressers of FcyRIIB or not. I mean that's the obvious thing that comes to mind. And of course, that's our highest priority. But then there may be other things around high expression of FcyRIIB that could allow you to be more precise in selecting that patient population. That's what we are trying to do.

Okay. And so far, you are not sure if they have something clear -- clearly?

We don't know yet. It's embryonic data. So we're still looking into it. And I don't know if you want to comment about that, Bjorn.

No. I think, again, very encouraging data, but early days. I mean, of course, if you have 3 responders, the percentage of them doing the same -- the drug achieving the same thing in those 3, if it's 30% is going to be in 1 of those 3. So we need greater numbers to understand on average, what's happening. The one thing I would like to complement is actually, again, coming back to the duality of doing both the clinical analysis and the preclinical, nonclinical analysis because if we can find markers in the animals, that correlate with antitumor activity, then we can set up a hypothesis and say, let's say, CX3CR1 positive T-cells pop up when you treat with your antibody in the mouse. And then you get the response in a patient where the patient seems to be responding and you see that this thing pops up in the blood, right? Then you're in a position which really sort of strengthens my belief in the biology because I picked up something that I might expected to be happening. Of course, that can be complemented by the unexpected and there we also need to do the pure clinical analysis where things are different between mouse and man. But I think we're trying to do all of that. That's what we're trying to say, and we're very encouraged about the data that we already have, but need even more, of course.

Always more data. If you would find biomarkers that are interesting in the form a hypothesis, would that also be included in future study design, like secondary endpoints or measuring this or...

By all means, that's actually what we will try to do is to find a way to be terrific as we say, the patients. And so that would be implemented into the clinical studies.

Are you happy with the answer? Any follow-up questions?

Yes. I would have maybe one more, but time is time, so you're quite dependent on a functioning immune system and you're seeing some signature efficiency for 1808 in a patient with [indiscernible] 2 are pretreated already, not caring too much about [indiscernible] efficacy here, but is there a way that since your drugs seem to be very safe that they we get into earlier lines of treatment that have not been destroyed by these earlier regimen of chemotherapy. So where we have still more immune cells that can actually react to your drugs.

Very good question. So very important. And actually, one of the priorities that we're discussing with Dr. Lim and Dr. Frendeus, is that we are actually trying to find patients that, as I mentioned, for instance, in the case of ovarian cancer that the standard of care for those patients would not include these type of drugs. So those are the kinds of patients that we want to and actually have already included in the study so that they have not been exposed to these sort of therapy. And by providing that therapy, we will be in that specific setting that you're mentioning. So naive to immunotherapeutic agents. So if we have that potent activity that we hope to have, we would be able to see responses in those patients. And that's clearly -- if we were able to accomplish that, I think we would have a very, very quick path to registration to approval, basically. So that's a very important question.

Thank you. We have questions from our online audience. We have, for instance, one question from Sebastian van der Schoot from Kempen. So the question is, roughly, if you're looking at the 3 complete responses and 3 partial responses in the 11 follicular lymphoma patients, this does not appear to differentiate from the 45% to 55% overall response rate seen by using rituximab treatment. So where can we find the comfort that BI-1206 is clinically active. So I guess the question is how does it differentiate from rituximab only?

Yes, yes. Of course, it's a very important question. And you summarized it yourself, more data, right? So -- but this being said, the quality of the responses that we've seen, which have been -- that have lasted for a very long period of time. I think that's very important. We have -- so the first answer to that question is that is a very important question that we will address by the way, in future clinical studies. So that is -- and the only answer to that question is more data. So the answer -- just one if you want to say, where could I find some comfort? The quality of the responses that we've seen, that's one thing. And the other aspect is if you look at the data, the ex vivo data with cell lines derived from patients in mantle cell lymphoma, which by the way, is quite -- can be quite aggressive. So patients become resistant to a number of drugs. And we took cells from those patients and implanted it in animals. And the single best treatment for all those resistant types was the combination of BI-1206 and rituximab. So if we can reproduce some of that data in humans in the ongoing clinical study, I think that will be great. So far, we only have 3 patients with mantle cell lymphoma. One of the patients responded really well. And so more data and clever clinical study.

Dr. Lim, do you want to add...

I was going to ask -- ask a question. And just so I was going to ask a confirmation I thought that the patients in that study were all rituximab refractory. So you would not expect a response rate of 45%. So this is in effect higher than what you would expect.

Excellent point.

Just one caveat. The word refractory is where that has a regulatory meaning. So in this study, patients are -- have relapsed after previous rituximab-containing therapies. So that's just a caveat.

Sebastian had more questions. One of them, I think, is interesting, perhaps something for you, Martin. If you have success in your studies, how can you get good terms in an agreement with the partner totally depending on with regards to rituximab since you do the combination trials? Are you sort of well, perhaps financially dependent on them as well? Or it's a very strong tie. So how do you maintain that relationship?

Yes, not necessarily. First of all, as already mentioned by Andres earlier, so there's a lot of biosimilars already on the way. And obviously, that also has then to be shown in the clinical trial. But we would not be dependent on rituximab, but we're, of course, doing the current clinical development with rituximab because that's the standard of care. That's what we're trying to show. But we are afterwards quite flexible. And I think it could be very, very interesting for companies that want to position themselves that have interesting and good biosimilar to partner with us in order to grab significantly a chunk of the market. So I think in that sense, it's a very interesting positioning that we have.

Yes. Final question from Sebastian. And the waterfall plot on 1206 rituximab combination, who are the 6 additional patients not included in the efficacy analysis. So is the...

So the waterfall plot is basically follicular or just to be sure that, that is clear. So the mantle-cell lymphoma patients or patients who have dropped out of the study because of the DLT, et cetera. They were not included in that. So these are basically evaluable patients. That's why there's a little bit of my lend itself to confusion. So yes.

There's another question from Martin online. He's asking about partnering on a project next year. You have a Keytruda, right in the second half of 2023. Are there any other discussions that you may mention or perhaps it's work in progress?

It's always work in progress. So far, I think we have delivered quite well in partnering regarding 1206. That is already partnered. So I didn't mention it at the beginning with CASI pharmaceuticals for China, Hong Kong, Macau and Taiwan, which is a very well ongoing partnership. There's still rest of the world. And the idea could be to generate really strong data with the subcu, and I think then we probably would have very interesting partnering discussions, but I would not give you any timing because there's always 2 parts that you need there, 2 parts for a successful wedding. And obviously, will be data driven, but we have partnering very high up on our agenda. So probably you will remember that we also did a deal around the platform that was with Exelixis during the summer when other companies are really suffering partnerships, and that brought also nice money into our bank account. So partnering is high up. And obviously, with data points that are getting more and more interesting, absolutely. There's partnering potential.

It's interesting that you mentioned success in subcutaneous at least that's a trigger that would increase the likelihood of potential partnering of subcu going forward.

Subcu 1206 showing the same efficacy and then hopefully abolishing the infusion-related reactions completely, I think, will be a very interesting product.

Do we have any more questions from the audience here in the room? We have a question here, please?

Yes. This is kind of a combination of what you've been talking about so far. So from my perspective, there's huge opportunities still left on the table. If you look at every line of therapy in each B-cell lymphoma and maybe Dr. Lim can come out as well. Most B-cell lymphomas will develop mutations over time, so clonal evolution and all of this. So it's not just biomarkers that we're talking about. It's actual evolution of the disease after relying with treatment. Is there an expectation as to the increased efficacy of 1206 in combination in earlier lines? And is this something that you have in mind when designing future trials?

So absolutely. Of course, as drug developers, we have to start when people have received the standard of care. That's unfortunate. That's the way it goes. But once we have been able to demonstrate and isolate the activity of BI-1206, an absolute key thing will be to try earlier lines of treatment, in particular, more aggressive forms of disease. So you could imagine putting BI-1206 upfront with rituximab in and even chemotherapy in first line or second line of mantle cell lymphoma patients. So I think that's one approach. And obviously, we're also considering triplets. We mentioned here rituximab and lenalinomide, rituximab and a BTK inhibitor. Those have produced already interesting that doublet has already produced interesting results, enhancing the activity of the combination within that -- with that cocktail would be super interesting and something that I think the people that we have discussed with are very interested in trying. I think one important aspect of this, and I think this really differentiates 1206 is that you don't see added toxicity. So you're not seeing -- you're not dealing with a new drug in the sense like with a separate set of toxicity issues. You're basically enhancing the activity of rituximab. And that basically should provide a very interesting positioning even within the triplet, for instance.

No, I agree. I think it is probably go long duration of [Technical Difficulty] The efficacy would last even longer, which would help probably the clinicians to avoid some of these patients that get worse from every line of treatment.

Correct.

Great. Satisfied with the answer? Another question for Martin. Are you in transgene looking to do more together in addition to BT-001 -- [ BI001 ] sorry?

Yes. Currently, the focus clearly on BT-001 only because that's already complex enough. You could envision doing other vectorized antibody work that might not be only including oncolytic viruses, could be also RNA-based technologies, et cetera, et cetera. So I think currently, we're focusing just on this one just to see how we work together and how -- what we can generate in that clinical trial. And then probably would rather look at other potential combination at a later stage.

Are those potential new combinations part of the development process. I mean you started the presentations were talking about your reverse lead generator, the engine so to speak, in BioInvent.

That's one part of it. And of course, it's always driven by the target biology, what you want to use. So currently, we have targets where mainly with the exception of anti-CTLA-4 for the reason of toxicity. We basically put that into an oncolytic virus. But otherwise, the targets that we have are lending to naked antibody treatment, which I think has a lot of advantages regarding toxicity, cost of goods is a very important factor. If you think about more complicated constructs, biospecifics, et cetera, are very, very difficult to produce. So -- but what we are considering, and that's part of the discovery process in that sense. So if we have targets where we feel a vectorized version of an antibody would make more sense, then that's something that we consider absolutely.

Talking about cost and production. I mean it's impressive. We have Marie here, Chief Operating Officer; and generating new targets is, of course, very interesting, but then you have to have the capacity to produce this. And the move to the subcutaneous delivery was quite rapid. So perhaps you could give some flavor on operations and your strategy with regards to the production side of the business. I think that's a key part of business as well, Kristoffer?

My colleagues here [indiscernible]...

We also have Kristoffer, who's running the CMC part.

Yes. Yes. In that way, I would say that we are better standing than many others because we have in-house manufacturing, which means that we could turn around rather fast. We could change our plans rapidly like we have produced materials now will go into the subcutaneous. Originally, that was planned to make productions of IV material. If we were relying on external CMOs, that's most are probably from a decision to start a subcu version and we have developed the formulation, we will need another 1, 1.5 year. And in this case, we actually changed under our already started production, which is rather uncommon.

Yes, it's interesting. How come you decided to have manufacturing in-house? I mean, most biotech and research companies sort of higher CDMO or?

So this is obviously related to the history of BioInvent. And luckily, they developed that capability. Because I think from my perspective, as of today, this makes things so much more efficient and also so much more cheap because it's not only timelines, but it's also costs. So it's -- we do it at much cheaper costs. Obviously, to develop a company like this from scratch, would require a lot of investment, which obviously, BioInvent got over those years. So luckily, we are now at a position where we have R&D of clinical development, and we have CMC and cell and generation capabilities under one roof. And again, so I mentioned it already at the beginning. So the subcu is one good example. The other example is, again, so just think about the numbers, 2018 one clinical program, by the end of next year, 6 clinical programs. All generated in-house, including cell and generation, including manufacturing, and this you only can do when you have everything under one roof. Otherwise, it's impossible. It's not possible. So it has a huge competitive advantage, clearly.

Unfortunately, we will run off the time. So I think our presenters deserve a big round of applause. Thanks to all of you, and thank you to all of us who joined us here today. The webcast will be available for viewing later on if you missed something or want to delve in deeper into the diagrams. I guess there's a lot to absorb here. So thank you again. And now there's time for refreshments. And I believe management will remain for a while. So if you have further questions that you were too shy to ask before, take the opportunity now. Thank you.

Thank you very much.

Thank you.