Nykode Therapeutics AS (NYKD) Earnings Call Transcript & Summary

Good morning, and a very warm welcome to Nykode's Capital Markets Day 2023. I just need to see that my slides move. It do, not that efficiently. Yes -- so my name is Michael Engsig. I'm the CEO of Nykode. And on behalf of the Nykode team, I want to bid you very welcome. Those of you who have defied the terrible traffic in New York caused by the UN General Assembly. That's a note to self next time we plan a Capital Markets Day in New York. Also, a very welcome to those of you who have come over from Oslo, Norway. And of course, not least, a very welcome to all of you who have not defied the traffic in New York, but decided to call into this one here via the online webcast, both here in New York, U.S. as well as back in Europe. A very welcome to all of you. So we are really excited to host this Capital Market Day today. And with all the stuff that we'll be showing you today, which I'll come back to. But before I do that, I just want to introduce you to the team, if I can have the next slide. So with me today, it's my pleasure to have Agnete Fredriksen, our Co-Founder and Chief Business Officer, sitting down there. We also have Mikkel Pedersen, our Chief Scientific Officer. We have Klaus Edvardsen, our Chief Development Officer; and we have Harald Gurvin, our Chief Financial Officer. So also a great pleasure to introduce and have with us here today, Bradley Monk, Professor and Director of GOG, who will give you a special outside in perspective on the treatment landscape of cervical cancer as well as perspective on our pipeline of products. So a quick introduction to those of you who are new to Nykode. Nykode is a clinical-stage immunotherapy company, entirely dedicated to exploiting our unique and proprietary immunotherapy, which uniquely targets the antigen presenting cells, which in turn generates a tailor-made strong T-cell response, particularly strong CD8 T-cell response. Nykode as a company today is validated and derisked through 2 strategic partnerships with top tier U.S. biopharma companies, Genentech and Regeneron. It's further validated and derisked through clinical data showing strong durability and survival. And we have a cash position that allows us to execute our growth strategy. So as we look at it today, we are looking at a company that is on a basis of a strong validation and derisking from an investment point of view, but with a host of opportunities in front of us. So we have a focused strategy to take our products forward to the market, including our lead assets towards -- into head and neck and cervical cancer, including a fast-to-market opportunity in advanced cervical cancer. We also see, I was supported by the data that we will show you today a significant upside and unmet need in the early-stage cancer setting, not least for our wholly-owned lead asset VB10.16 but across our oncology platform. And with the data that we'll show you today, we also have a stronger than ever confidence in our tolerance platform and the autoimmune disease, which constitutes a potential entirely new therapeutic vertical for Nykode with an opportunity that as big as our oncology platform. Quick look at our pipeline, which shows the versatility and the flexibility of our technology platform with programs spanning 3 different therapeutic areas: oncology, infectious diseases and now also opening up into the autoimmune field. And the 2 lead assets in clinical stage, our wholly-owned VB10.16 and our partner program, the personalized cancer vaccine, VB10.NEO that we developed together with Genentech together span a range of different solid tumors with corresponding huge commercial upside. Mikkel is going to take you into a deep dive on the technology and the beauties of the technology. This is the [indiscernible] version of the introduction to the technology. What you see here in the middle of this slide here is the core of our platform. Every product we develop is centered around this molecule. It's a protein in its pharmacological form, but we had produced it and administered as a DNA plasmid. And this is really the second generation version of targeted vaccines. The beauties of formulating it and administering as a DNA plasmid includes easy manufacturing and handling of the product. It also includes a long durable expression of the vaccine, which probably can contribute to the long durable responses we see and avoid exhaustion of the immune response. It also allows us to incorporate costimulants into the construct that will further drive or amplify the signal as you will see later today. The construct, if you take a quick look at that one, consists of 3 different modules. In the bottom of this figure here, you have the antigen. That's where we incorporate the targets that we want to increase or decrease an immune response against, middle you have the dimerization unit and on top is where it gets exciting. This is what we call the secret sauce of our technology. It's the targeting unit. Basically, what it does, it ensures that the molecule attacks or attaches to the antigen presenting cells. And this is, in essence, what drives the unique properties of our platform. Can I have the next slide? So why is it important to target antigen presenting cells? Because whether you want to drive a humoral immune response or T cell response, whether you want to see an upregulation or down regulation, the antigen presenting cells are the gateway to that immune response. So that's why -- how we can effectively tailor-made the immune response according to the disease that we are trying to address. Can I have the next slide? So this slide here shows you how we apply our technology in the oncology space. So on the left, you see a representation of the DNA plasmid being injected through a needle-free injector into the shoulder muscles of the patients. The DNA gets into the muscle set. It gets translated at the active molecule and the protein form gets secreted into the surroundings. where it attracts the antigen presenting cells via its targeting unit. It binds to the antigen presenting cells. It gets internalized. And again, because we use this particular targeting unit, we see an activation not only of the classical pathway, but also the cross-presentation pathway, which is, in essence, what drives a very strong CD8 T-cell response in our technology. That is specifically what you want to see in a cancer vaccine. Briefly on our partnerships, we entered to, as I said, sizable partnerships with top-tier U.S. biopharma companies, Genentech centered around our personalized cancer vaccine entered in 2020. And Regeneron [indiscernible] multiprogram deal spanning both oncology and infectious diseases. So 3 in oncology, 2 in infectious diseases. Together, they gave us not only the validation of the technology, but also the cash, so USD 250 million in upfront that allows us to transform the company and fully pursue the growth strategy aimed at maximizing the shareholder value of the company. So before I hand over the word what are we going to review today. So I'm going to, in a minute, I hand over the word to Klaus, our Chief Development Officer, who will take you through an update on our VB10.16 program, that's our lead and wholly-owned asset. He will show you additional not before presented immune response data that further supports our development strategy of VB10.16 and he'll lay out our strategy for developing VB10.16, bringing it forward towards the market, both in head and neck and cervical cancer, but also give you a perspective on how we look at the early-stage cancer opportunities. We're then going to bring -- hand over the word to Brad, who will give you a perspective on the evolving treatment paradigm for advanced cervical cancer. And Brad will also, for the first time ever introduce the design of our C-04 trial, which is our potential registrational trial and potential fast-to-market opportunity in the recurrent cervical cancer setting. Klaus is then going to follow up with a review of our VB10.NEO program, the fully -- the personalized cancer vaccine that we developed together with Genentech and also here show never before, shown data from that trial. that also supports not only the perspective of VB10.NEO in the future, but really with the spillover effect for our entire oncology platform. Then we'll provide for Q&A to Klaus and Brad. Before Mikkel takes over and take you into a deep dive on the research platform, both showing the latest from our focus on optimizing the platform, and give you a perspective on the strength of the platform, the competitiveness. We will then also -- and we're very excited to do that, give you an update from our autoimmune disease programs before we close on with a -- close off with an update from our collaboration with Genentech, also here showing data that have not been shown before. I'm going to hand over to Agnete, who's going to take us through the business model and hopefully wrap everything up. So you'll see how we intend to and this company leverage our platform and our opportunities in front of us to build further shareholder value for the future. So without further ado, Klaus, I'll hand over to you.

Thank you. Michael. Yes, hello. My name is Klaus Edvardsen. I'm the Chief Development Officer of Nykode and pleased to see all of you today. Let me jump straight into an update on the VB10.16, which is our HPV16 vaccine that is wholly owned by Nykode. I'm not going to go into any description about the platform as such, just alluding to the fact that this construct is the whole antigen E6 and E7 of HPV16 that has been put into the Vaccibody platform. Just let me remind you that HPV-driven cancers is significant proportion of cervical cancer, head and neck cancer, anal cancer, penile cancer and a number of other smaller indications. It is for cervical cancer the fourth most common cancer among women and it is still a disease, especially when you get into the recurrent setting, a disease setting with significant unmet medical need. It's obviously an obvious question to address, and that is on the prophylactic HPV vaccine would the HPV-driven cancer segment be diminishing over time, doesn't appear to be the case. It is actually expected to increase in incidents in years to come, likely because of not full uptake of the prophylactic vaccine and of course, also not any prophylactic vaccine will guarantee you 100% effect. So we are looking into a segment in cervical cancer and for that matter, also in head and neck cancer that is going to increase in years to come. Just a few step back on what are the foundation for the immunogenicity data that you will be updated on that is the C-02 trial that is the multicenter single-arm trial that tested out the vaccine HPV16 vaccine in combination with atezolizumab in patients with advanced or recurrent metastatic cervical cancer. It was a trial that had a number of objectives: safety, one of them, response rate, but also duration endpoint and I will touch on all of that during the presentation. It was a strict European trial, patients from 6 European countries and the total number of patients that were enrolled were 52 patients. We did report outcome of that trial some months ago. So it will not be a surprise for you, what you are going to see subsequently. But let me just remind you what would constitute a useful resort in this setting where this trial was actually conducted. It's a bit of a complex conversation and Dr. Monk will take you through more detail on that aspect because the treatment paradigm for second-line recurrent cervical cancer has changed when pembrolizumab moved up to being a part of the first-line treatment paradigm. But irrespectively, what you're looking into of options that would generally be available for patients that are in the second-line recurrent cervical cancer would be chemotherapy with a median overall survival of around 8 months, median PFS at around 3 months. It will be pembrolizumab, KEYTRUDA, and you can read, obviously, the median overall survival and median PFS. That would also be Libtayo, cemiplimab, the Regeneron PD-L1 antibody that is approved in Europe. And then finally, the new guy on the block, which is TIVDAK, which is also called tisotumab vedotin and it is an anti-tissue factor antibody with a payload in reality. And if you see the median overall survival is 12.1 months and median PFS of 4.2 months. That is kind of the single trial experience that we will have to be matched again on the C-02 data. As I said, Dr. Monk will get into much more detail on that treatment paradigm, but I think it's important to have that framed when we go through the clinical data for the C-02 trial once again. Just a few words on the patient disposition in that trial. I'm not going to go over all of the numbers. I'm just paying or ask you to pay attention to the PD-L1 expression level in that trial. It is less than half of the patient at the ones where we knew the PD-L1 stage that actually were positive, which is obviously in a situation where you have a checkpoint inhibitor in the equation not stacking the cut in our favor. Just again, very briefly, what we were seeing in the trial, obviously, a single-arm trial was that in the PD-L1 positive patient, we had a median overall survival 25 months or above 25 months, it was actually not reached at the time. There will be an update on the overall survival figures in the beginning of next year. Looking at all the patients, we had an overall response rate of 19%. And as you can see a disease control rate of 60% as well as a median duration of response on 17.1 months, and median PFS of 4.1 months and median overall survival of 16.9 months. If you look specifically in the part of the patients that were actually PD-L1 positive, then the numbers are increasing to 29% in overall response rate, a disease control rate of 75%, duration of response stay the same because the responders are primarily driven by the PD-L1 positive patients, median PFS of 6.3 months. And as I said, median overall survival not reach at this stage for at least 25 months. So if you contextualize that back to what does good look like, you are in a single trial experience, not looking bad, let me put it in this way, you're actually stacking up reasonably well to what would be available treatment paradigms for patients in this segment. A few words on safety. I'm not going to -- have time to go over it in detail, I think it's fair to say that if you look at the safety profile in the trial with the vaccine on top of atezolizumab, it was very difficult to see that the vaccine actually attributed any additional side effects to what you would already expect from a checkpoint inhibitor in this case, atezolizumab alone. So conclusion, it is a very well-tolerated vaccine that can easily be combined with a checkpoint inhibitor without advancing any of the immune toxicity. A few words on this spider plot, and there are a number of things that are important to take out of this information here. We have broken down the responders and the nonresponders, the responders are the red one and the nonresponders are the blue one. What I want you to take into account on this slide, and that's the reason I show it again is that no big surprise that if you are a responder, you can keep that response for a significant period of time, at least for the time that we at that time had followed up the patients for an effect of the vaccine. But what is equally interesting is that if you look at the blue part, the far left of the curve, you would see that also patients that obtain some kind of a clinical benefit as stabilization of their disease, you can maintain that stabilization for the duration of the vaccine and obviously beyond the vaccine. I think that's an important element to bear in mind when we go over the ideas about what would be a next step moving this vaccine up to earlier lines of therapy, especially in locally advanced cervical cancer for that matter, locally advanced head and neck cancer in an adjuvant or concurrent setting, and I will come back to that later in the presentation. Just again, it is a single-arm trial. We have discussed it many times, how do you in a single arm trial qualify whether you have a vaccine effect on top of what you would expect to have of a checkpoint inhibitor effect. As I think I have alluded to, if you look in the PD-L1 positive patient segment, which would be the most fair compare to a pembrolizumab monotherapy single-arm trial or for that matter, cemiplimab monotherapy checkpoint inhibitor trial, you see that the overall response rate in our trial was 29% compared to 17% and 18%, respectively, for pembrolizumab and cemiplimab. And again, you look at the median PFS with a significant increase to what you would expect from a monotherapy checkpoint inhibitor alone and the same goes for overall survival median. Again, TIVDAK is obviously not relevant to compare for PD-L1 positive -- negative idea because it is a different mode of action. But irrespectively, that will be an alternative treatment that is already available and Dr. Monk will come back to that, had a response rate in what they obtained accelerated approval on 24 months and a median PFS of 4.2 months at a median overall survival of 12.1 months. So again, just emphasizing that from a single trial experience, we are stacking up very well in comparison to what would be available treatment in this patient segment. If you even go one step further and look into a subgroup that is PD-L1 positive patients that have only obtained one prior therapy because what I did not mention when I showed you the trial design for C-02, the criteria to get into this trial was that you at least had 1 prior therapy, but a significant proportion of patients had 2 or 3 prior therapies. But if you look at the ones with only 1 prior therapy and PD-L1 positivity, you see that the overall response rate goes to 40% with a disease control rate of 80%, meaning that 4 out of 5 women actually had some kind of a clinical effect in this trial, which is important when you look at the duration of that stabilization, if you wish. And then again, the duration stays the same, median PFS 16.9 months. And again, median overall survival at this stage, not reached, but at the time, the analysis was conducted 25 months. Why is this patient population of importance to tell because that is the patient population that will come closest to the patient population that will be enrolled into the C-04 trial with that only caveat that the C-04 trial will enroll patients that do have been exposed to a checkpoint inhibitor. The patients in C-02 were checkpoint inhibitor naive. But anyway, at a reasonable comparison for what effect you could expect to see in a patient population provided that the vaccine effect on C-04 can kick in, in due time. Just a few words on something that you have not been seeing before. Part of C-02 was also an exploratory attempt to understand whether circulating tumor DNA, obviously specific for HPV16 could be a marker of response. And as you can see that all of the patients that had a RECIST criteria response actually had more than a 50% decrease in circulating tumor DNA specific to HPV16. And more importantly, if you look at the right side of the slide, it looks very much that it's an early predictor of response. You may actually be capable of using that detection of circulating tumor DNA to see if you have a treatment effect or if you're losing the treatment effect, which would also become critically important when you move it into a locally advanced setting. Now a few words -- now it's getting aggressive A few words on the immune responses and the correlation to the clinical endpoint in C-02. You have seen this slide before, so I'm not going to spend a lot of time on it. it just indicates that you actually have a higher peak T cell response in patients that are having disease control, meaning clinical effect compared to the one that do not have any clinical effect. And it also go to the fold increase in total T cell responses. Same thing, you're seeing a significant difference in the one with a clinical benefit compared to the ones that are not having any clinical benefit. The new data that we are showing you is that instead of using a functional assay as ELISpot, this asset is actually quantifying T cell responses by doing immune sequencing of the T cell receptor B locus, and it is very clearly indicating here that you are seeing an increase in T cell responses with that technology also, and you are also seeing that there is an increase of those responses that are increasing over time and obviously followed up to the time of stop of vaccination in this situation up to 1 year. So another technology that's actually quantifying that we have a correlation between the T cell responses that we are seeing and the clinical outcome, which I think is something that significantly differentiate us to some of the competitors in this arena that they have not yet shown us any data as to whether there is correlation between the immune responses and the clinical outcome. Just a single patient case that and I'm not having time to go into details here, what it is showing is that over time, you are seeing an expansion of already existing clones and they can expand at various time point of treatment and the same goes for the de novo. So you have a dynamic increase of new T cell responses over treatment time, which is also an important thing in understanding how the duration of that vaccination can maintain an effect for a prolonged period of time. Just the summation of it. I think that I will just leave you with the bold one at the bottom. I think that as we have seen before that it is very clear in a single-arm trial that I think we have shown beyond reasonable doubt that there is a vaccine effect that, that vaccine effect can be attributed to what it needs to be attributed to, to specific T cell responses against the antigens that you are actually vaccinated the patient with and then finally the subgroup analysis is indicating that especially if you look at the PD-L1 positive patient segment, you are seeing some significant treatment effect again from single trial experiences. Now to what will the future bring? And as Michael already alluded to, the C-04 trial, which is our potential registration trial that has obtained clearance from the FDA. We are ready to go with that trial. Dr. Monk will give you the design as it is a collaboration with the Gynecological Oncology Group, GOG. And we are still on track to expect that we will be capable of dosing the first patient in that trial before end of this year. more details by Dr. Monk. This is the attempt for the fastest to market strategy obviously provided that we get positive results, which I cannot guarantee you, but I hope that at least I have been giving you a flavor by going over the C-02 data once again that there is a likelihood that, that could happen. We are also moving into head and neck cancer that is the C-03 trial. We are doing that in the first-line recurrent head and neck cancer setting, and we are doing that in a dose escalation trial starting out with 3 milligram, which is our standard dose for HPV16 vaccine, moving up to 9 milligrams. And that obviously is with the attempt to understand in more detail what is the dose relationship between concentration of what you vaccinate with. Can you get earlier responses? Can you get deeper and more broad responses from a T cell perspective? Those are the endpoint from that trial, but obviously, also a starting point to get safety data in a different segment driven by HPV head and neck cancer. We are clear to go. It is a European trial. We have the approval from the U.K. authorities and from the European authorities. And we are expecting patients to be dosed at any time purpose and available patients at the sites that we are working on. And then finally, that I alluded to, based on the results that we have been seeing with the maintenance of a clinical benefit, it would actually be almost no brainer to look into what's going on in what's called locally advanced disease because in locally advanced disease, what you do, you give patients definitive treatment and then obviously, you will have patients that are having a response. So you kind of preselect patients for clinical benefit and if you can translate the C-02 data into that, you are almost having a guarantee that you can maintain that provided, obviously, the mechanism is the same, which is the case in cervical cancer and head and neck cancer also in locally advanced setting. The reason that we have not been talking to you so much about that setting is in reality that we are waiting eagerly to understand a Merck trial called KEYNOTE-A18 that was actually testing out the concept of adding pembrolizumab on top of chemoradiation in a concurrent locally advanced setting. It was with some expectation whether this would come out positive because there was another trial almost similar with druvalumab, the AstraZeneca PD-L1 antibody that did not turn out to become positive. But in July, Merck announced that the trial KEYNOTE-A18 had met its primary endpoint, which, in reality, opened the gate for us to start speculating would it be of value to do a design where you added the vaccine on top of chemoradiation plus the checkpoint inhibitor, we just say checkpoint inhibitor here. But obviously, if you want to mimic the KEYNOTE-A18 it will have to be pembrolizumab and test that out against chemoradiation plus pembrolizumab or you could even consider moving it into an adjuvant -- strictly adjuvant setting, which is maintenance where you follow up with pembrolizumab plus vaccine and only pembrolizumab. That decision will not be made as of today, that decision will be made as soon as we have seen the outcome of the KEYNOTE-A18. We only know that it has met its primary endpoint. Dr. Monk told us yesterday that there's an expectation of a press release as to where the KEYNOTE-A18 will get priority review. I do not know whether that press release is out. But the more important element for us is obviously to understand what are the actual data because that could drive a potential design for adding the vaccine on top of this pembrolizumab in locally advanced and as I said, all most intuitively be the right thing to do based on the maintenance of the effect. So by that, I will stop my first fast speed run through the VB10.16 and be happy to invite Dr. Monk, who is a Professor of Gynecological Oncology at University of Arizona Division -- College of Medicine, it's called as well as the Director of the Gynecological Oncology Group, which is our partner for the fast-to-market strategy, the C-04 in recurrent cervical cancer, please, Dr. Monk.

Thank you. So that press release was announced 4 hours ago, just saying. So you're 4 hours behind Klaus. But otherwise, your talk was amazing. So much fun to be with you today, and I appreciate your time and your commitment to try to help my patients. So I want to talk a little bit about me. and then talk about sort of what we've done in cervical cancer and then what we plan to do in the future. So I'm from Arizona, as I said. I work in a hospital where I was a medical student. I was there Monday. I saw cervical cancer patients on Monday. And as a medical student, I met my first cervical cancer patient who was going to have an operation, and it was exciting for me to see the cervical cancer cut out but it was metastatic in the lymph nodes. And at the end of the operation, and I was planning to be a lung cancer doctor, by the way, because lung cancer was the most common cancer so I'm ambitious. And the oncologist, Jim Freel said, I'm sorry, Brad, that this patient is going to die because it's metastatic. And I thought in my mind sort of my personality, what the hell. Why don't you do something about that? And I'm a nice, less professional then, more professional today. I'd say, well, why don't we give her radiation or chemotherapy, he said it doesn't work. And she died before I graduated from medical school. She was 47-ish, had a couple of kids. So since that time, radiation now would have been given to that patient and radiation and chemotherapy. And even now Klaus may be even radiation chemotherapy and immune therapy. So moving forward, I decided to flip to a gynecologic oncologist. Gynecologic Oncology is the only specialty that specializes in cancer. Every other specialty specializes in a treatment. A medical oncologist specializes in chemotherapy, a radiation oncologist you get it. Patients don't develop a need for treatment, they develop cancer. So I'm specialist in the cancers, it's the only reason that I'm a gynecologic oncologist. So I give chemotherapy, I work with radiation, and that's what we do. And I'm still in Phoenix. And I had the opportunity to co-find -- cofound called GOG Partners in 2010. It's under the foundation. It's called GOG partners. I'm now still the Director of that. And the studies that you know that have changed the standard of care in cervical, endometrial and ovarian cancer are our studies. We're not always right. We don't always win. We hate to lose, but we do win all the time. And the last study that got FDA approval, of course, was July 31 of dostarlimab in endometrial cancer GSK asset. And if you were lucky enough to invest in TESARO, before it was acquired by GSK, you would have done very well. And so we've delivered on that commitment. I hope that we can deliver here. And so I'm here to represent the sort of the GOG Partners under the GOG Foundation. This study, we need to brand, it's called 3091, it has a name. We started in 3,000, so it's the 91st trial in 13 years. So we -- and we are basically every site that does gynecologic cancer research is with us. So this works, I assume. So these are my disclosures. I talk basically to every company. I'm always fair, always balanced, and I'm going to do that for you today. So the first message about cervical cancer, and you said it, Klaus, it's not going away. I helped launch the Gardasil vaccine in 2006, and it has not decreased. We still have about 14,000 cases. We still put about 4,000 women in the ground and it's terrible. And I'm not going to stand for it. And so the next thing is, is that, well, it's caused by a sexually transmitted disease. HPV is sexually -- you must be sexually deviant or promiscuous to get cervical cancer, right? No, you must have had sex. And my mother is the best woman out there, and I'm absolutely certain that my mother's had sex at least once, actually twice because I have a brother. So it's not a sexually deviant situation, [ promiscuous ]. There are some disparities and we're working on those to get by that. So I'm going to now transition to recurrent advanced cervical cancer. I'm just going to tell you a story of sort of what we've done within the GOG. This is really a delayed clicker. Next slide, can we just do next slide? You guys can do it from the back? So we have had multiple GOG studies published in the New England Journal leading to FDA approval. The first one was topotecan, we don't talk about it anymore. But the next targeted therapy, the first targeted therapy is Avastin, bevacizumab. It was so exciting that when we submitted it to ASCO, ASCO said, sorry, we can't keep it embargoed until the meeting. Can you imagine? You send an abstract to American Society of Clinical Oncology and they send it back and say, of course, it's going to get accepted but you need to offer a press release because it's the newest and greatest. So we -- bevacizumab is here. We call it first line. First line is not with chemotherapy and radiation. It's metastatic disease and the study that we're here to talk about is the second line. The first -- second-line treatment was pembrolizumab was approved in 2018, and it was approved on 77 patients. So it doesn't take very many patients to get FDA approved and it was approved on a 14.3% response rate, if you can imagine. So the high unmet medical need here is clear, okay? And this was sensational and it was a no-brainer as far as the FDA was concerned. Now you have to do a confirmatory trial, and I hope to speak with you guys once we do the proof-of-concept and checkpoint failures. But this is the confirmatory trial, this confirmatory trial was presented at ESMO, again published in the New England Journal. If you notice on the last or first author on basically every one of these papers, it's not about me, but I'm not going to give up until we help every woman with cervical cancer. So -- and so that's what I work on. This now pembrolizumab is approved in -- I checked yesterday, 68 countries in 2 years. So if you can get a medication that works, it really sort of sells itself, okay? And then, Klaus, you showed the press release that it's being moved up to chemotherapy and radiation, study you call A18, also a GOG study in the press release today is that there is the PDUFA date now in January. So again, we're not always right, but immune therapy is here, I get it. And so what should we do next? We should study immune therapy failures. It's a difficult situation. And so we need to be focused, and we need to work seamlessly together. We also studied tisotumab vedotin. You guys are going to think, well, this antibody drug conjugate, which also was a GOG study, which also got FDA approved, this is -- how is this going to play in that. Well, the patients that have been treated with tisotumab are not checkpoint exposed, not. So it's there. It will be interesting to see what the FDA says because this trial has taken a long time to get ultimately accelerated approval -- ultimately accelerate approval, which we got, but ultimately, the confirmatory trial, this is the accelerated approval, altered through the GOG. But the confirmatory trial has also been positive. But again, those are -- this is really terrible guys. So the confirmatory trial will be presented at an upcoming meeting. But those are not checkpoint exposed. So we're trying to keep a step ahead. Second line checkpoint was studied in a randomized fashion just to sort of complete the story, cemiplimab versus physician's choice chemotherapy, these medications that really don't work at all. You can see pemetrexed, gemcitabine, topotecan, irinotecan and vinorelbine. I only show you this, this was not approved because pembro beat them, pembro was in the front line. And why would this get approved in the second line and they didn't measure PD-L1 status because that's important, and that's what these guys are doing. But second-line checkpoint works, okay? And you see this in overall survival in all patient population, squamous cell and adenocarcinomas. But here's the point is that the chemotherapy in that control arm is 6%, that's why pembro got approved in 14%, because here in a randomized Phase III trial, 6%. So to your point, this is a high unmet medical need. You have to win and the current landscape is checkpoint failures. And to your point, Klaus, ideally you would do biomarker testing, again, which this trial didn't do. And that's why it's not approved in the U.S. So this is sort of what we've done. We started with chemotherapy, and we were -- patients were living 13 months. Now this is the first line. We're going to do the next line of therapy. And then we added bevacizumab in there, 17.5 months, and I presented at ASCO, there 28.6 months. And when I was in medical school, women were living 7 months. So why the hell don't you do something about it? We did. And we're going to do more if we can find partners like Nykode that are willing. And you, quite frankly, that are willing to believe in this opportunity. So how did I meet Nykode? I don't know if you even remember, Michael. So we had a meeting in Valencia, Spain, nice place, by the way, third largest city other than Barcelona, Madrid, in June of 2022, I never heard of you guys. And we got together, I'm like, that's an interesting platform. DNA vaccine, antigen presentation, adjuvant built into the plasmid, preliminary data, we should think about that. So we introduced them to the GOG partners because that's what we're looking for. We had a second ad board in December of 2022 just with the U.S. investigators. The first one was international ad board and then we met again. And then ultimately, we signed an agreement to work together in January 2023. There's a press release which we show you, and now we're working together with a very efficient internationally agreed upon U.S. focused, opportunity to prove that the combination, okay, of 10, 16 and checkpoint -- works in checkpoint failures. I get it, it's swinging for the fence but it's a level swing in the zone, and we're looking at the picture, right? So it's not, our eyes are not closed and we're not hoping that we run into a fast ball. And again, what's the proof of concept. So, there's a tale here in the single-arm study in our experience. I get it, they're not checkpoint exposed. I get it. But this provides the impetus and the inspiration to study this combination. And if it's even better if we enrich to PD-L1 positive, which is about 80% of the patients. So we're not studying a very rare tumor, sufficiently rare that there's a high unmet need with a proof of concept in checkpoint naive and if we're going to get past this, then we'll be running downhill, so to speak. So we announced this collaboration. The first thing we did is that we met with the FDA because the only reason we're doing this is to help patients. And the only way we can help patients is get FDA approved. That's what the GOG Partners Organization does. And we needed the FDA's buy-in. We received the FDA's buy-in, we have a go-forward, this study, which we need to keep calling 3091, we need to open it. And this is basically to take patients, as I've described, who are 16 positive, which is more than half of the patients that have a PD-L1 positive score that have failed pembrolizumab, okay? And it gotten multiple cycles, none of the early progressors that have measurable disease and then have a blinded independent central review, make sure that there's tumor before and it shrinks. And then what we hope to do is file for breakthrough therapy designation, prove in this sort of go/no-go opportunity that this can work, expand it, have a frontline therapy and Klaus proposed that, that even may be with chemotherapy and radiation. And that's what we do with the life cycle, right? Life cycle management is earlier lines of therapy, combinations and other tumor types, and that's what you're doing with your head and neck program. So it's relatively intense in the beginning, 5 cycles every 3 weeks and then 6 cycles every 6 weeks and then ultimately, follow-up. So the study design is a randomized trial. The FDA is [ look Monk ] and I was part of these discussions. This agent looks so good, it might work on its own. Really? Yes. Didn't you see the data in CIN and they're a platform. So they said, you actually have to do a randomized trial to show that the atezolizumab is actually contributing anything because these patients have already failed generally pembro. Okay, they weren't that excited to do it, but it needed to be done. So this is a randomized trial and atezolizumab 10.16 versus 10.16 placebo, blinded independent central review 30 versus 30. And if it works, we'll enroll another 70. And as Michael said, get accelerated approval, and it doesn't work, I get it. The good news is, is that we're going to call the question quickly, efficiently in a definitive way. I think this is my last slide maybe. So in conclusion, cervical cancer, I spent my career defining it as a chemotherapy-sensitive cancer. It is as sensitive as ovarian cancer, okay? And I'm proud of that. That anti-angiogenics work bevacizumab. We got FDA approval in 2014. The immunotherapy works. We got FDA approval in 2018. And now antibody drug conjugates, we got approved in 2021. And now we're really looking for the next iteration, innovative strategies after post IO. And that's what we're here to do. And we can have plenty of time for your questions, but I really appreciate your time today. Thank you.

Thanks a lot, Brad. Before we open it up for Q&A, let me just give you a fast update on the VB10.NEO, the personalized cancer vaccination program that we do together with Genentech. Yes, it is. Can I have the next slide now? I'm also used -- I'm not going to go over a lot of that. Many of the things that I will show you has already been communicated as part of an interim analysis on the trial that we call N-01. I will report now the full analysis of that trial. As I said, it is on the VB10.NEO which is the fully individualized vaccine, obviously, against a relevant mutation specific for the individual cancer in the individual patient. As I said, this is -- and you know that in partnership with Genentech, we are currently engaged in 2 different trials. It is the N-01 trial, and that's the trial I will show you the final analysis on the immunogenicity data, which that trial was set up to actually give us proof of concept that selecting neoepitope specific for the individual patient that you could raise an immune response against that or those neoepitopes and I will come back to that. And then the N-02 trial that is in reality, a trial that is testing out whether increasing the dose from the 3 milligram of the vaccine to 9 milligram would make the immune responses faster in onset, deeper and broader. And I'm not going to show any data on the N-02 trial today only to indicate that we have cleared the 9 milligram, it is safe to give. We're not seeing any effects that you would not have seen. And by the way, they are very minor. Again, with regards to side effect at 3 milligram, but we are clear to go with 9-milligram and obviously, eventually will report whether that will have an impact on onset of the responses and the depth and the breadth of those responses. I think most of you have seen this before, what we have indicated here is obviously the trial enrolled a number of various advanced solid tumors. They are listed there from urothelial cancer, head and neck cancer, renal cancer, non-small cell lung cancer and melanoma and all patients in those 5 indications actually showed a response to the selected neoepitopes, at least one of them. And you can see, obviously, that a significant proportion of the patient did have a response to more than 1 neoepitope. It was actually sold at an average of 53% of the selected neoepitopes were immunogenic, ranging from 3 to 20. That was the maximum of neoepitopes that was put into the antigen cassette of the VB10.NEO construct. So there is no doubt that our technology is capable of predicting which would be immunogenic neoepitopes and we can actually also show that we can mount relevant immune response against the majority of those neoepitopes. We have also previously shown to you, and it's just an update with the total number of patients that actually the phenotyping of what the neoepitope will activate is predominantly CD8 T cells, which is the cytotoxic killer cells, which are critically important in a cancer vaccine setting. I'm not saying that CD4s are not important, but you do have to have the guys that are going to do the job, and that is the CD8 cells. You can see the percentage of CD8, preferentially CD8 T cells that are coming as basis of the immune response on the top circle diagrams and then you can see what the various epitopes down. We won't have time to go into that but it is a confirmation of what has already been shown on the final analysis. What is new here and which is important, is that if you give multiple vaccination, it's not a surprise that is an element of a vaccination, of course, that if you repeat something, you can boost and that's theoretically, as I said, expected, but it is also good to show it. And what we can very clearly see here is that the more vaccinations you're giving, the breadth of the vaccination, meaning how many of the epitopes will induce a response, but also the magnitude, meaning how deep, how big is that immune response, is increasing over time in the N-01 trial, which is an important element. The analysis has now been done for patients that have been completing 1 full year of treatment, and the conclusion is very clear. You see, as I said, an increase in breadth and depth of those responses. Maybe even more important is that we have also followed up not on all of the patients as of yet, obviously, because what I show you here is a follow-up on the T cells or the T cell clones that are specific to the neoepitope that we have given the patient, they remain functional and immunogenic up to 1 year after last vaccination. You see the proportion of patients that have an immunogenic response kept for more than 50 weeks to the far left, which is half of the neoepitopes that are actually doing that. That is a critically important element of the sleeve because if you stop your vaccination after 1 year, what is the expectation of a patient keeping that response or hopefully clinical effect would obviously have to be driven by a continued T cell response and that T cell response is present. So that is, again, an important element of understanding that we can now show the relevant depth and magnitude of the responses, but we can also show that they have a durability that makes it very, very clinical relevant. I'm not going to give you more right now, except for just kind of an overview slide to touch on a few points that I won't have time to touch on either. It is, as I alluded to, a safe vaccine to give, we knew that from the 3 milligram. We also now know that it's a safe at 6 milligram, and we know that it is safe at 9 milligram, again, with an expectation that we can do an analysis as to whether earlier onset of response, even deeper responses or broader responses can be obtained by increasing the dose of the vaccination. I just wanted to allude then to the competitiveness of the Nykode platform. I think I alluded to it in my introduction by saying that there are many companies that are also in this field that are seeing results. But I have not yet seen any of our competitors actually trying to make a correlation to the immune responses to the clinical outcome that they are obtaining. And in reality, if you believe that you are doing a vaccination without creating an immune response, you can obviously [indiscernible] you have a vaccine. But that's a more theoretical conversation. So I think I stop here with the update of just, again, emphasizing that we now know that the duration of those immune responses at least last for half of the patient tested out here for more than a year after the last vaccination. And by that, I think we open up for Q&A session. Is that with you also, Brad? I think so. So if you want to join me here, then we'll see who will have to address the hopefully many questions?

I think there is one there.

Do you have a microphone? Here you go.

I'm Patrick Trucchio, H.C. Wainwright. Thanks so much for these presentations, very interesting. I have a few follow-ups on VB-C-04. First is when would the circulating tumor DNA data be collected in this trial? And what would you want to see in this data to suggest VB10.16 is on track for a positive outcome in the interim analysis?

Yes. I mean, it's an exploratory end point at the moment. You're not in a situation where you, as of today can use circulating DNA as a regulatory biomarker that can tell you that you have a response or not a response, but it can be an important driver, obviously, for you internally to understand whether you are on the right path. If you can reproduce the results that we have seen in the C-02. But in all reality, to make the decision and I guess you referred to, we have 30 plus -- 30 patients in the step 1 of the C-04 trial. And you'll have to make a decision, of course, when you're doing the analysis in all of those 30 patients as to whether you have a path forward for an acceleration and then enroll the 70 patients. We will not let ctDNA dictate that, that will be a traditional clinical endpoint measurement by scan.

Just for Dr. Monk. I'm curious if you can talk a little bit more about what you saw in the data that's been presented to date that suggested to you that VB10.16 has potential in cervical cancer, but as well that it's differentiated versus the number of these other immunotherapy approaches being developed today?

It's a good question. So we have extensive experience of single-agent checkpoint. So it's inferential, meaning that when 10.16 is added to the checkpoint the response rate is 30% even higher when it's PD-L1 positive. So that's sort of the inference that it's doing more than the 14%, 15%, 16% single-agent checkpoint. I get it that the confidence interval around that point estimate is large. But it seems to suggest that the combination is better than checkpoint alone in a single-arm trial admittedly.

And maybe just one last one, if I may. Just on the VB-C-04 trial. Just regarding this go/no-go decision part 1, what dose of VB10.16 is being evaluated? And as well, what is the interim analysis powered to generate and on which endpoints in order to move VB10.16 forward to part 2?

Yes. We have not made public the analysis plan for that but obviously, we know what we're aiming after. That's what I tried to give from response rates from what would be a competitive situation. But I am also happy to disclose here that obviously in the interactions with FDA that Dr. Monk is referring to. We asked the very specific questions to the agency, would you consider only overall response rate as the surrogate endpoint to assess for a potential acceleration of the C-04 trial because in reality, a vaccine concept may not give you the full bang for the money on response rates, but much more on durability endpoint. And the agency has confirmed that, that will be totality of data set. But obviously, you will have to show because that's the fastest way of showing it that the overall response rate is going to give you something meaningful in comparison with what is otherwise available. So you can backtrack, so to speak, for what the decision tree would be with regard to number of responders that you would like to see in the interim analysis. It's not because we want to keep it as a big secret. That reality is that it will, as I said, be a totality of outcome measures and other elements that we didn't touch much upon is that tisotumab vedotin is not an easy drug to administer. It has a side effect profile that is people can go blind, a female can go blind in this setting. So there are many elements that needs to be taken into consideration before we make the decision in discussion with FDA as to whether we would have sufficient data to go for an acceleration.

So it's a sophisticated question, obviously, and that's why you asked it. Questions always get harder as these guys go. So they're getting harder, keep it coming. And what you said is absolutely true the totality of the data. It's not statistically powered. It can't be, right? You can't do a randomized 30 patients versus 30 patients and make a statistical conclusion. But you can -- what he said, look at the totality of the data as defined as ORR, overall response rate, percent of complete responders, duration of the response and then ultimately ctDNA. So the totality, I like what you said, the totality of the data will be investigated. The last one of these studies that we did, if you guys may follow Verastem. We did -- Verastem, we asked some 2 questions. Do you need a biomarker and just the combination of defactinib, is it necessary, and we did 24 versus 24 and it wasn't statistical, but it was pretty clear, and we move forward that, yes, you need the combination for Verastem and it works in KRAS-wild type. So we're trying to do that. We decided to do a few more 30, but that's how the decision. So when he says it's really not a secret because it will be the totality of the data, and it's not a statistically powered analysis. The real question is, I don't mean to create controversy, is that will you give us all the data when it's known. And I would hope that we would be able to present that at a scientific meeting, granularity, not only from an investment perspective, but from a patient perspective. See my goal is to get the study done. And if my investigators say, "Oh, look at that, well, more CRs longer DOR, following ctDNA, a little bit better ORR " I want to put my patient on that. And then we can get to 100 get accelerated approval. So I want to get that out in the public domain if Michael will let me, he's the boss.

[ Luis Santos ] also from H.C. Wainwright. Dr. Monk, you mentioned that you're looking for tumor shrinkage during the blinded part of the study and potentially applying for breakthrough therapy designation. So when can we expect that data? And how fast -- how much faster will that be for the potential accelerated approval?

It's a good question. So again, back to Verastem, something very -- we got breakthrough therapy designation with 24 in the Iovance. We had about this maybe 28. We got breakthrough therapy designation in cervical cancer. And that's part of the information that went into picking 30 is that we wanted -- it's sort of that 25 to 30 that you get breakthrough therapy designation. Now for accelerated approval, you need about 100 patients. And you saw that with SORAYA and ImmunoGen. You saw that with tisotumab vedotin, our 2 most recent accelerated approval. Pembro, which has a long life cycle, we got of 77, but generally need 100 and that's what they picked to do 100. And accelerated approval generally comes when the responders have been followed for 6 months because they want to see duration of response. And generally, we don't make duration of response to them, they say, "Oh, 40% of the patients are still in response at 6 months, okay? So those are the metrics that are common for accelerated approval. And then you say, well, what happens if the responders happen late. You just can't keep this thing going. And so we have as a plan B following at the median for 12 months. So the answer to your question is accelerated approval comes generally in solid tumors with 100 patients when the responders have been followed for 6 months and if responders are happening very late and a median follow-up of 12 months. Now what that means is ultimately, you have to get the study enrolled. Study enrolled is determined by how interested that the investigators are. And we're really investigating because we've got nothing and so we're engaged and also how many sites, right? The more sites you have, the faster the study gets done. So I can tell you that the -- from the GOG Partners, GOG perspective, we're highly engaged. I don't think we've disclosed the number of sites that's very material and how enrollment is going and that sort of thing. I'll leave it to them. But this is on what I would term the fast track because it's so exciting. And we have a whole team that gets these studies done. We met this morning actually. That's why I couldn't come down in slide review because I was on with the cervical cancer team. And we talked about sort of getting this study, the sites selected which is already happening and activated and ultimately enrolled and first patient in, I think, as you said. Sorry for being so long with you.

I think that was very useful. On 10.NEO, Klaus, you mentioned that the 9 milligram dose had been cleared. To go that you didn't see additional side effects. Was that no different side effects than what was already reported or also no additional frequency of those?

It was impossible actually to tell whether you, percentage-wise, would have had a higher frequency of already known side effects by moving from 3 to 9 milligrams. That's why I said, in essence, same level. So it doesn't seem like increasing the dose necessarily increases, at least in a linear fashion, the number of side effects and we were not seeing any side effects that we have not seen before, and that are the traditional immune-mediated side effects.

I don't know if we have the ability to take questions from the virtual audience?

We do. We do. And I can read them to you. I think this is specifically for you, Dr. Monk, and it comes from several people, so [indiscernible] Gonzalo from ABG, and we also have from Sebastian from Kempen asking the same question about what would warrant and clinically meaningful ORR in this patient population after first-line immunocheckpoint inhibitor? So what kind of ORR? And as you say, maybe some other parameters would you find to be clinically meaningful for us to move forward?

Again, another good question. They are getting harder. So the physician's choice chemotherapy is 6%. And you'll see it in the Phase III with tisotumab vedotin. I don't know what it is, but with cemiplimab, it was 6%. You also know that we got tisotumab vedotin approved with the 24%. So that's the information that I have. Now the confidence interval of the point estimate surrounding 24% for tisotumab vedotin excluded even the confidence interval for the 6%. So it's one thing for the confidence interval of the intervention to exclude the point estimate. But when the 2 confidence intervals do not overlap, then it's a definitive result, and that's why we got tisotumab vedotin accelerate approval so easily. And so the short answer is north of 20%. We already did it with 24%. I would be very happy with 25% so that's -- that would be great. But it's going to have to be north of 20%.

Okay. So this is a more technical question about immune responses, I think, also comes from Sebastian from Kempen. Regarding the relevance of the de novo T cell responses that Klaus presented today, I think both from VB10.16 and the C-02 trial, but also from VB10.NEO. So this is a platform feature that we see. Can you have comment -- can you comment on the immunogenicity data from past clinical studies with checkpoint inhibitors? And whether these also indicate the generation of these kind of de novo responses that we see after vaccination?

By the way, you should introduce yourself since you're the founder of the technology. Go ahead. Just say hi.

Hi everyone. I'm Agnete Fredriksen, I'm co-founder of Nykode and CBO.

So if I understand the question, is it really what's the mechanism of resistance to checkpoint inhibitors? Is that the...

Checkpoint Inhibitors also usually elicit T cells with new specificities or whether they allow the pre-existing T cells to expand and be effective without vaccination? Maybe a very technical question.

I'm not -- I'm not sure I understand. So I mean -- so checkpoint inhibitors work and have almost more than 30 indications. I think you all know that. But they don't work in all patients. They work more commonly in patients that have a higher mutational burden, more neoantigens. That's the point. They also work better in patients who have more CD8 positive cells, the immune cells that are doing their job. And so why do they not work in all patients? And why do they not -- why do the patients become resistant? This whole platform is founded on better antigen presentation. So specifically in cervical cancer, that's why Iovance did their TIL breakthrough therapy designation. There are lots of T cells in cervical cancer. So we resected the tumor, isolated the immune cells, reinfuse them and got breakthrough therapy designation. The T cells are there. I think the question is what's happening. I actually don't think they're exhausted either I think that there is a mechanism of resistance of impaired antigen presentation. And with this antigen presentation opportunity which has a built-in adjuvant, which you can show, you showed that just generated immune response that we're hoping that we can overcome checkpoint resistance. Again, that remains to be seen. That's a great theory, Brad, Dr. Monk, Professor Monk, Well, we're going to prove it. And so -- and we think that there's sufficient evidence to justify the trial, and that's what we're doing. And it will be game changing. If we can show this, this platform of second generation, as you said, plasmid DNA vaccination to improve antigen presentation to overcome one of the key mechanisms of checkpoint resistance will be a major breakthrough. Even the small study could probably be in the New England Journal because it is so transformational. I get it -- I'm getting ahead of myself. But that's okay. I can think big. I thought big many times. And look, we've been in the New England Journal, right? March 27, we were there twice for endometrial cancer.

Perfect. Thank you. There's a question of dosing here for the C-04 trial. And this also comes from ABG, from Gonzalo. Is it still part of the plan, the implementation of a 9 mg dose if C-03 suggests potential superior signs of efficacy when we move to 9 mg? I think this is for you to clarify, Klaus?

No, we decided to move a little bit ahead of ourselves by jumping to 9 milligram already in C-04. It can sound maybe a bit counterintuitive when you do a dose escalation in head and neck. But do remember, we do not have any data in the head and neck cancer setting. And we obviously find it important to do a proper scientific experiment to understand what an increased dose will do for efficacy. But we made a bet and decided to go straight to 9 milligram in C-04 because Dr. Monk and myself has alluded to a number of times, we are in a different patient population because they have the C-02 patients had not been exposed to a checkpoint inhibitor ahead of this trial. That's a completely different situation now. And therefore, we want to hit them as hard as we possibly can. But obviously, we didn't jump to 9-milligram before we had cleared that 9-milligram was a safe dose to give not in this HPV construct or in the NEO construct, as I have alluded to, and FDA accepted that rationale. But it's clear that should it turn out that you would be in a situation where 3-milligram will do the same job at 9 milligram, that will have to be a discussion on how do you then approach that because you're not normally treating patients with the dose that they're not in need of.

Good. So we have also a question here from, yes, let me take -- from DNB. When deciding on this study, which means C-04, you have obviously also considered the addressable market size. How many patients do you estimate constitute the addressable market for VB10.16 for the relevant indication?

Yes. Thank you for that. I keep saying that they're getting harder. The only way to really look at that is to look at the earnings statement for Seagen/Genmab. So tisotumab vedotin is the same population. This will probably supplant that, better tolerated. Again, those patients were not checkpoint exposed. Tisotumab vedotin or TIVDAK, as you call it, is marketed in the U.S. under Genmab and Seagen jointly. So -- and again, I always try to speak objectively rather than my opinion, like we got accelerated approval with tisotumab vedotin for 24%. So that's good enough. So you can sit here and go to the earnings statement in the -- of tisotumab vedotin and look at the new starts in the U.S. The other thing that we're doing, as you know, there's a project called Orbis, which you can get accelerated approval beyond the U.S., they did not do it with tisotumab vedotin, but Orbis allows you to get U.S., Canadian, Australia, Singapore, Switzerland and Brazil, maybe I said the U.K. already. So 7 countries. And so it's just -- it's more than just the U.S. population. You have to file for it has to -- and this would sort of qualify -- hopefully qualify for that. So it would be beyond the U.S. We can also get reimbursement in Germany because of their health care model. And so that's what our experience has been for the accelerated approval situation looking at mirvetuximab soravtansine immunogen, tisotumab vedotin, pembrolizumab, our most recent accelerated approval opportunities.

And then following up specifically on TIVDAK. The question is with TIVDAK positive Phase III data in second line assuming forthcoming approval there? What would an approval most likely be in for VB10.16? Is it second line or third line?

So first of all, it doesn't change anything in the U.S. We already have the medication here. It's not the regulatory standard because accelerated approval does not count as full approval regulatory standard. It's an FDA discussion. Again, I don't -- I think I know, but I don't really know how many patients in the Phase III trial, what's called 301 had prior checkpoint. So if they haven't had prior checkpoint, I'm not sure what that has to do at all with our study, which is requiring prior checkpoint because pembro was approved in 68 countries. So I think that is a very interesting question. The FDA may say, "Look, you would have to beat TIVDAK," which we're never going to do, but we might go after tazotumab vedotin, which is what we do in ovarian cancer, we go after bevacizumab. And you remember from SORAYA accelerated approval of immunogen, all of those patients were bevacizumab pretreated but it did not translate into the label. It was just so that they could assess and judge the single-arm activity beyond available therapy. So even if we had to have prior tisotumab vedotin in the available therapy, our experience has been like bevacizumab in ovarian cancer doesn't translate into the indication statement. So that's a long answer for it's an FDA question.

And I mean, again, I can disclose that. Obviously, that's been part of a discussion with the agency when we decide to go forward with C-04 and the fastest possible to-market strategy. And we have asked the question directly. And the agency recognized that there still is an unmet medical need irrespective of whether TIVDAK turns into full approval. It doesn't mean that we can disregard TIVDAK but as Dr. Monk is alluding to, it's not so obvious that those 2 patient populations are exactly the same. But again, it is something that is also available, whether that translates into the TIVDAK label that they are actually checkpoint inhibitor resistant. We do not know as of yet. As we have also communicated, as you know, we talk about a potential registration strategy because and I think Dr. Monk has already said it twice here also you will obviously have to show the agency that you have meaningful clinical data before you can get an acceleration. And that's why C-04 is designed for way C-04 is designed. But obviously, we have an expectation, and that has also been clarified with the agency that if we can meet that then we have passed in front of us. But it will obviously at the end be dependent on whether the interim results for C-04 will give us the data that we will need to do that.

And I like TIVDAK, and I have patients on it because it all I got. 50% adverse reactions. Got to see the eye doctor every week, every cycle, I mean, if you have preexisting neuropathy, which many of these patients have, you're not eligible. So again, I like it. I'm not here to [ denigrate ] sort of what tisotumab vedotin has done to my patients, help them, but it has lots of limitations and ocular adverse events in these antibody drug conjugates can be challenging. And you guys know that.

I don't know if you have the energy. If I -- maybe 3 more questions, 2 for you -- so -- and the one is actually just about TIVDAK, more speculations about TIVDAK. So with everything you said up until now, and the limitations in the different patient populations, and we know they are exploring different ones. In which direction would you speculate that they would move forward with most force in the future? It also includes -- the question also includes whether PD-L1 negative, whether checkpoint inhibitors alone don't work and different lines of therapy.

Again, I only speak with objective information. So as you recall, Merck had made a bid to purchase Seagen, and that did not go through. As you know, Pfizer now is in development to ultimately acquire Seagen. You guys know that. I think maybe $26 billion, a pretty good price. And so what is -- first of all, it's jointly developed. So who's going to take it? Does Pfizer have an interest in tisotumab vedotin, TIVDAK, I don't know, should ask them. And if they don't and they give it back to Genmab and what is Genmab's interest? So what -- and as you know, the assets that Seagen brings to the Pfizer table, which are in the public domain, there are other ADC platforms, there are other vedotin platforms. And as you know also Genmab competitive landscape, they also have other antibody drug conjugates. So they're going to have to integrate that decision into their life cycle. And I don't know, you should ask them.

Speculation...

I can tell you what I told them, but they don't listen to me anyway, so it doesn't matter.

Very good. And this question, I don't know who wants to answer it, but on the overall survival data of VB10.16, this is from the C-02 trial, though, from approximately 10 months, and the overall survival curve starts to flatten and the number of censored patients is increasing considerably. Do you see these as any cause for worry? Or is it in line with what should be expected in a study like this?

It is in line with what you would expect in a study like that. The reason that we have communicated out that we were not reached at the overall survival at the time of the analysis was because we were not there. Then we had said that it was at that time, 25-plus months. And we said that we had an expectation that, that's not going to change. And you can convince yourself of that, if you look at the number of patients that are censored that is still above the 50 percentile. But we will make an update on the overall survival data 1 year after the first analysis, that's the follow-up -- the ultimate follow-up of the patients for overall survival. But the expectation is that we will stand where we are or potentially even become higher.

[ Pradeep Chaudhari ] from [ Larin ] Partners I'll switch gears a little bit and ask about the neoantigen platform. As you know, there's a debate in the field about the best setting to apply these vaccines, adjuvant versus metastatic settings, high tumor burden versus low tumor burden. Could you shed some light on Nykode's position on that debate? And why you're pursuing a metastatic indication going forward?

Yes. I think that I mean if you just theoretically, you can obviously speculate and say the earlier you can go the more likely it is that you would have a better functional immune system. By that notion, you would obviously decide to position yourself as early as you possibly can. But I also think that it is important to bear in mind that the concept of personalized vaccine has been around for a long time and has not really materialized. Now Nykode and Genentech decided to go in a metastatic setting, which the notion that you will obviously have an easier path to get an approval to do a trial in a setting where patients so to speak, have limited options. But that doesn't mean that we are excluding the option or that is a discussion, obviously, that Genentech will have to drive whether one should position it earlier on. There is data out there now indicating that it works in earlier lines of therapy, there's the Moderna and Merck data in melanoma that has shown on a clinical endpoint disease-free survival that doing a personalized vaccine on top of pembrolizumab is beneficial. One of the things that the community is eagerly awaiting is what is driving that disease-free survival increase because they have not given us any immunogenicity data that tells us whether that's the driver. I mean you cannot take away the endpoint, which is obviously fantastic for patients in that setting. But I would not draw the conclusion that doing personalized vaccine should be reserved only for locally advanced or even earlier. I think that if you can get it to work in an advanced setting, and I'm sure you can because we have seen that you can get relevant immune responses. I think maybe one of the issues going into later lines of therapy is not that the immune system cannot do the job. I think I showed you the data here today that it can. It's maybe more that if you have an advanced tumor, you are not having the luxury of waiting, let's say, 6 weeks, 8 weeks, 10 weeks, 12 weeks, until a personalized vaccine can be manufactured. You need the treatment now because otherwise, you're going to lose the possibility of rescuing that patient. And that's maybe the issue. So there are ways to look into that, obviously, by diminishing the time for how you do your biopsies, the sequence of the relevant neoepitopes you would vaccine the patient with. And if you can turn that down to being a matter of fewer weeks, I think you have an equally likelihood to position personalized vaccine in a later space. But maybe getting a proof of concept may be simpler in an earlier line for reasons that I have said, but they are not mutually exclusive in any way.

I have one final comment. I don't want you guys to be concerned about using atezolizumab rather than pembrolizumab, it's obviously atezolizumab as a PD-L1 versus a PD-1. There will be 2 randomized trials presented in upcoming meetings. One is called [ PCC ] which is pembrolizumab bevacizumab and chemotherapy in frontline cervical cancer. And then there will also, in the second line, atezolizumab versus atezolizumab, tiragolumab or TIGIT. So there will be 2 randomized trials at near-term meetings, which will hopefully give you confidence that atezolizumab does have activity in cervical cancer. So I think that's fair and adequately confidential respecting, but you're going to get some information on atezolizumab very soon in cervical cancer.

Dr. Monk. Okay. Thank you much. So we'll now take a break of 20 minutes and assemble here, 10 minutes 2. And hopefully, also those online will tune in again and we'll then do an exciting deep dive into the research update from Mikkel. So thank you very much also for your questions. [ Break ]

So thanks a lot for being back timely, and also welcome to those of you online. Mikkel, we're going to kick off with a deep dive and exciting updates from not least our autoimmune disease area.

Thank you, Michael, and hi, everyone. My name is Mikkel Pedersen, and I'm the Chief Scientific Officer of Nykode. So today, I'm going to give you an update on our research and innovation activity and has been -- I've been looking very much forward to this because we have some really, really exciting data to share today. But before that, I think we should remind ourselves why is this Vaccibody platform, so unique. And as Michael already mentioned earlier in his presentation, when we're doing vaccinations, the key is to get activation of the adaptive immune system, which are the part of our immune system that is key to obtain effective and also long-term immune responses. And how do we obtain that? The gatekeeper here or the portal to this adaptive immunity are the antigen presenting cells. Antigen presenting cells come in different flavors, you can say, as I tried to illustrate here on the figure to the right, we have CDC1s, CDC2s and also the monocyte-derived disease that are inducing inflammatory responses. Those are the responses that we would like to have when we are trying to treat cancer or when we are trying to treat or prevent infectious diseases. But there are also other types of antigen presenting cells that can do the opposite so that they can induce activation of an expansion of T regulatory cells that are important for suppressing active immune responses. By targeting antigens inhibitor directly to APCs, we get very effective -- highly effective triggering of these adaptive immune responses. And Nykode is a leading, if not the leading company developing antibody -- sorry, vaccines against antigen presenting cells. And we already now have a platform that's proven across infectious disease and cancer. So how do we achieve this? As Michael already mentioned earlier on, we have this modular platform that we call Vaccibodies, which are really proteins -- or fusion proteins that are put together from different modules. So we have the module 1, which are, what we call -- the targeting unit, which are the key module responsible for directing the vaccines towards the antigen presenting cells. And we can use a number of different target units. It can be natural ligands. It can also be part of antibodies, for example. Then we have the module 2 which is -- which we call the dimerization unit. The dimerization unit is important for getting a strong binding and also for inducing a very effective internalization of the Vaccibodies once they bind to the antigen presenting cells. I'll come back to why this is important. And then finally, we have the module 3 which is the antigenic unit. That's where we put on those epitopes that we want to raise an immune response against. It can be either globular antigens or strings of T cell epitopes. As we have already heard today, we are using DNA to deliver these Vaccibodies into our patients. But really, our platform is delivery agnostic. We can use also mRNA to deliver Vaccibodies and we can even purify the Vaccibodies and deliver them directly. Michael already presented this. So when we inject the DNA into the muscle of a patient, the muscle cells will take up the DNA, they will express the Vaccibodies, that would then attract antigen presenting cells to the vaccination site. They will bind to the antigen presenting cells, be internalized and then the epitopes will be presented either by the classical way -- pathway to CD4 or by the cross-presentation pathway to CD8. And with CD8 the ability to get epitope presented through the cross-presentation pathway is really what is unique for our platform. So we get this very strong and broad CD8 responses. And those are the ones that are driving efficacy, in particular, in cancer settings. We have done a lot of experiments to validate these things to show that, that's how it's working. Here is a -- and -- an older experiment where we have compared a peptide vaccine, an mRNA vaccine and our VB10.NEO vaccine in -- you could say, in a model setting. So here are the exact same epitopes that we are comparing across. And as you can probably see here the VB10.NEO, our Vaccibody design provides a broader T cell response in particular, stronger CD8 responses compared to both the peptide vaccine and the mRNA vaccines. And we believe that this is due to the targeting of the antigen presenting cells. We have also, of course, explored what happens when we don't add the antigen unit to the vaccines and compared an APC targeted vaccine to a non-APC targeted vaccine. And here are some of the data that we have generated. This is a vaccine, our VB10.16, HPV16 vaccine, where we have compared it to a vaccine, a DNA-based vaccine, just using the same antigens as we are putting on the Vaccibody. And as you can probably appreciate here when we then vaccinate mice having these TC1 tumors that are HPV16 positive, the Vaccibody will drive -- the only vaccine here that will drive strong antitumor efficacy with regression of large established tumors, whereas the antigen-only vaccine barely does anything in this setting here. And this also correlates, as Klaus also showed on our clinical data with a stronger T cell response both again the E7 peptides and the E6 peptides. We also have demonstrated that the Vaccibodies will induce long-lasting and effective memory responses. So here, we have used another vaccine. This is a SARS-CoV-2 subunit vaccine, and we treated or vaccinated animals with 2 different doses, 25 micrograms and 50-microgram at day 0 and day 21. And then we looked at the T cell responses 2 months after vaccination. And we still see strong -- see if I can get this to -- no, I just wanted to point, but as you can see from day 0 to day 21, we still have large or strong T cell responses, but we can further boost. So if we vaccinate again at day 89, we see a very strong boost in the actual T cell response. So these data show that the responses that we generate are long lasting, but we also generate very strong memory responses that can then be further boosted by additional vaccinations. So just to summarize, the targeted approach are able to induce very strong CD8 responses. We have increased breadth. We have increased, you can say, strength of the actual vaccine response compared to other types of vaccines. They are long lasting, and we get these memory responses. So that was a very brief recap of the strength of our platform. So now let's move into our research and innovation strategy, which is really based on 3 key pillars. The first one is to continue to improve the vaccine platform. This is important to remain a leading APC targeted vaccine company. Then we also want to expand into novel therapeutic areas using novel therapeutic molecules. And this is where I will focus my presentation today because we have some really exciting data to share from experiments or studies that we have been doing for the last half year. And then finally, you want to build a differentiated pipeline of very exciting vaccine candidate across indications. Sorry -- just have to jump one back. Today is not about how we optimize our platform, but I just want to share one slide with what we call the fourth module platform that we have generated. So here, we are using DNA sequences that we can add to our plasmids. Because this is a very flexible platform, we can add what we call a fourth module. So it's a sequence of DNA that are encoding additional polypeptides. So it could be either a cytokine. It could be a ligand, immunomodulatory ligand. It could be an adjuvant, it couldn't even be an antigen. And we are including a ribosome skipping sequence into the DNA plasmids, so that we ensure that we get production of 2 separate proteins. So we generate Vaccibody. And at the same time, we generate these cytokines, adjuvants, antigens, to further boost, stimulate or direct the immune response. So it's a very, very flexible system. And importantly, this fourth module constitute a potential significant extension to the platform's proprietary lifetime. We have filed a number of patent applications using the fourth module approach. Just very quickly, snapshot of some of the data using GM-CSF. This is the cytokine, classical cytokine which we have encoded as a fourth module. This is a [ CT26 ] model new vaccine, you can say. So here, we are encoding different epitopes that are mutated in the [ CT26 ] is a colorectal -- mouse colorectal cancer cell line. When we do these immunizations, what we see is that we very quickly get high infiltration of antigen presenting cells. That's what you can show on the top graphs here, the yellow one are antigen presenting cells that are actually moving into the vaccination site. We also see at the bottom here to the left, that when we have GM-CSF into the construct, the T cell responses are much stronger. And this translates also to superior antitumor immune responses in the [ CT26 ] model. So we believe this is a very, very promising technology that we can use in many situations going forward, both within our oncology projects, but also within our hopefully, future -- sorry, autoimmune disease projects. So now let's move to tolerance, which we believe will be a new therapeutic focus area for us. So tolerance induction by inverse vaccination. What is this? So regular vaccines, they educate the immune system to recognize and attack bacteria, viruses or cancer cells, and at the same time they create immunological memory. That's how we survive every day so that we are protected against pathogens. Inverse vaccinations, they aim at doing the exact opposite. So we want to remove the immune systems memory of antigens that are causing unwanted immune reactions. And that's what we are seeing in autoimmune diseases, for example. So direct targeting of vaccines to specific antigen presenting cell subsets has the potential to dampen these disease-causing antigen-specific effective responses. And importantly, this is without impairing the protective immunity. So when you are treating these diseases, currently, you have broad immunosuppressive treatments. That will prevent you from raising, let's say, an immune response to what, an infection, which will cause serious side effects. Here, we can do it very specifically against those T cells that are driving the disease. So not interfering with any normal immune system function. So this is a highly promising approach for allergies, for example, autoimmune diseases as already mentioned, but also for organ transplant rejection. And we really believe that Nykode platform is uniquely positioned to target antigens to the tolerizing dendritic cells. which are then stimulating antigen-specific T regulatory cells that will dampen in a specific way the T cells that are causing these diseases. How does it work? This works exactly the same way as I've already presented for our cancer vaccines. Here, we are just targeting a different APC. APCs that are doing the tolerization. But it's the same mechanism, but with different targeting units. So we are targeting different receptors on these cells, the vaccine gets internalized and it would trigger expansion of antigen-specific CD4 [indiscernible] , which then in turn dampens the T cell -- the unwanted T cell responses. So we have been working in this area for some time now, and we have worked, of course, with module 1, the targeting. That's the key. We want to direct the vaccines to the tolerogenic DC. So we have identified a number of important targets. On the tolerizing DCs, we have identified both natural ligands but also antibody fragments, for example. We have also identified for the module 3, the antigen unit, autoantigens or allergens known to elicit these unwanted immune responses. The dimerization units is exactly the same as we are using all our other vaccines. So there's no difference. And then also for the fourth module, we have identified cytokines and modulators playing key roles in mediating anti-inflammatory responses. So these are like -- many of these like [ liquor bricks ]. So we can put them these together in all different ways and we have done that. So we have created numerous exploratory vaccines built on these above modules here and evaluated them experimentally. We have filed several patent applications covering these concepts. So does it work? You can ask. Yes, it actually does. So these are our first data. So multiple cirrhosis is an autoimmune disease of the central nervous system, where the immune system attacks nerve cells in the brain and in the spinal cord, a very a, very serious disease, as you probably all know. Experimental Autoimmune Encephalomyelitis, EAE, is a model of this disease. So what we did is that we designed an exploratory vaccine, which we called TV004 which has a unique targeting unit, and then we add on the disease causing antigen at the end. When we treat these mice with these exploratory vaccines, at day minus 7, minus 3 before we induce the disease. We see that the vaccine completely prevents any serious disease in these mice. And this furthermore correlate with a decrease in disease causing cytokines. So these were really, really promising data. And we were very pleased to see -- to see this very, very pronounced effect. The next experiment, we explored the dose. We wanted to see how far down in dose can we get and still see an effect prevention of disease in this model. So we tested [ 35 ]. That was the dose we used in the previous experiment down to 4 micrograms , which is really a very low dose. And what we saw was that all these doses actually prevented the disease. So this seems to be a very, very effective way of treating this disease here with these tolerizing Vaccibodies. And we also saw a dose-dependent decrease in disease-associated cytokines, indicating that they may be still superior to use the high dose. We also wanted to explore what happens if we target a different receptor on tolerizing DCs. Does it still work? So here, an example, the top one here is what I've already shown you, TV004 targeting Target 1 on the tolerizing APCs, works very well. Here is another exploratory vaccine targeting a different receptor on tolerizing DC. This actually also works very nicely. So we can show that we have lots of opportunities here to develop vaccines that can induce antigen-specific tolerance with potential in important diseases such as multiple cirrhosis. So these data here are from the lab. This is a diabetes model. So you all know that type 1 diabetes is also an autoimmune disease where the immune system attacks the insulin-producing cells in the pancreas. So the NOD diabetes model. This is a spontaneous mouse model where these mice will develop diabetes spontaneously. So again, we designed number of different exploratory vaccines where we include the diabetes antigen and then plus/minus fourth module cytokines that further condition the vaccination site towards immune tolerance. So what we see is that if we have -- if you don't treat the mice, they will get diabetes. So we see that mice will get diabetes. We also see an increase in glycose levels. If we treat them with the vaccine, just the vaccine based on the Vaccibody, we see that this will delay onset of diabetes. And probably also you have fewer cases of diabetes and the glycose levels are lower. But if we then add on the fourth module cytokines, we see complete prevention of diabetes onset in these animals. This is an ongoing study. So I would just highlight that, but this is a very, very promising initial data, demonstrating that Vaccibody vaccine work also in this setting, but that fourth module can even further increase the efficacy of our vaccine in this space here. So some of the highlights in the tolerance here. So the opportunity is, of course, autoimmune diseases, allergies, organ transplantation, as I mentioned. There is a high medical need in these diseases. I think we can all agree to that. And existing therapies are really broadly immunosuppressive with all the side effects that you get from those treatments. It's B-cell depletion, where [indiscernible] destroying all the B cells so that you don't get any antibody production with all the side effects. We think there is a perfect platform fit because we have this APC targeted approach. So the only thing we need to target is a different APC. We can add on immune-inhibitory cytokine as forth modules. We have very, very strong initial preclinical data in 2 different models, very different models. One is spontaneous models. The other one is an inducible model. We see strong partner opportunities here for product-specific collaborations, and we already have early interest from potential pharma partners in this area here. Competition is limited, at least for antigen-specific immune tolerance induction. So to summarize and conclude, we have generated numerous exploratory inverse vaccines built on our diversity of modules and evaluate them experimentally. It works with different targeting units, different antigens and different fourth modules. We have filed several patent applications covering these concepts. We have also shown that recombinant Vaccibodies designed to target these cytogenic disease works, prevent disease in this EAE model, resembling multiple cirrhosis. And we have preliminary data also demonstrating that it works in a diabetes model. Furthermore, in the diabetes model, we see that the fourth module technology further improves the efficacy. So what we want to do now based on this data is to build a new therapeutic area focusing on inverse vaccines for the treatment of initially autoimmune diseases. So we are really, really excited with this very promising data in a very, very challenging field with limited progress over the remaining or the last many years. So now let's switch gear moving away from tolerance to our discovery pipeline. So we, of course, want to grow a pipeline of differentiated vaccine candidates. We want to fully exploit the advantages of our platform, the uniqueness and flexibility of the targeted approach and the ability to include additional modules, build different modules together. We have 2 therapeutic growth areas. That's, of course, oncology and now also tolerance. We want to have clear product differentiation. So oncology, we want to push boundaries. We see opportunities both in the early stage, maybe even the premalignant stage, but also in late-stage disease. For tolerance, we want to build first-in-class antigen-specific products, and there is really, really a big opportunity here to be first-in-class. So the status as of now is that all our internal as well as partner discovery projects are progressing according to plans, and we expect to nominate a new oncology development candidate at the end of the year. So we will come back and then we want to initiate tolerance project in 2024 to drive further pipeline growth. I will end by giving you an update on our Regeneron collaboration. This is a very exciting multi-target collaboration with the aim of using Nykode's modular vaccine platform, combined with Regeneron's expertise in selection of the antigens. So there are 2 vaccine programs within infectious diseases and 3 vaccine programs within oncology. This collaboration moving forward according to plans, all 5 programs are now initiated and progressing. We have designed multiple vaccine candidates for each of these programs, and they are now being tested experimentally. And the next step for this program is, of course, to identify the lead candidate that we can bring into development. We cannot many data show from this collaboration, but we have been allowed to show this highlight here, which I really think is strong data showing the ability of our platform. So there are many, many, you can say, antigens that are not mutated in cancer, but they are still highly enriched. If we want to go after such antigens, what we call tumor-associated antigens. We have to break tolerance. So these are normal sequences we all have, and we are typically having tolerance -- central tolerance against these targets. So the platform -- the vaccine platform needs to break tolerate. So Regeneron wanted to model this to show that our platform can do it. Probably they didn't believe that it was possible. So they used animal models. So they selected different types of antigens with somewhat high thymic expression that those that have the highest tolerance. So this is virtually impossible. And we don't really want to have strong T cell responses here because that will lead to autoimmunity. But those with low thymic expression, no thymic expression. That's where we want to show that we can break tolerance. And we really see -- Regeneron demonstrates very clearly that we can get strong T cell responses against these antigens. So this opens up a whole new space of potential targets that we can incorporate into vaccines. So that we not only have to pursue mutations, but also genes or proteins that are enriched in tumors. So we were very, very happy to see these data here. So I will stop by showing this graphic here that really shows that the Nykode platform allow us to tailor the immune response by targeting different APC populations. So you can say this is like the Ying and Yang of the immune system. We have the improved inflammatory here. That's what we are typically doing. We are doing vaccinations. We want to get T cell, many T cells. We want them to be highly active. We can achieve that by targeting certain types of DCs. On the opposite end, we can target the tolerogenic DCs and get Treg responses that will then lead to immunosuppression. So I will leave you with that, and thank you for your attention.

Thank you, Mikkel. That was a lot of data. There's a lot of data going on in Nykode now. And it is across multiple different programs. It's across oncology, and it's across now the new field that we're entering into with autoimmunity. And I hope today that you've seen that we generate very consistent patterns of what we show you across the different programs. Obviously, it's different for oncology and autoimmunity, but they are platforms. And what we see is that the platform is applicable to make multiple products. So we have a very strong vision in Nykode, and that's to unlock unlimited possibilities for the future of medicine. We want to build the leading immunotherapy company. And that we do by developing these game-changing medicines. And now you see we expand them to different range of therapeutic areas. That includes now autoimmunity in addition to oncology. If that's not clear to you, Nykode is really leveraging this unique insight in immunology. So Nykode is based on researchers with deep insight into how the immune system works, how all these molecules, cytokines work, how are all these cells doing their interplay and how can we make something that the body is not able to make by themselves. And that we do by generating new codes. That's the name of Nykode. This means new code in Norwegian. And that's what you've seen today when we say APC targeted vaccine is actually based on our unique ability to take these genes that have certain very interesting features that can do something and manipulate the immune system in the way we want to and we combine them into one new groundbreaking molecule. Important for the business model is that we do that not only on a product-to-product basis, but we do it on a platform basis. So when we make this new code targeting certain antigen presenting cells that gives us the CD8 T cell responses that you've seen. We see it in preclinical studies that we get a broader CD8 response. We see it in clinical studies that we've got a broader T cell response. And we see this long and durable responses that you're now seeing in the clinic with VB10.16 and VB10.NEO. It's a platform, meaning we can see the same pattern. And when we change the antigens we will get the same long durable T cell responses. So it's not just a product. And that's really where we are with the business model. We really want to focus on ensuring that we have a differentiated and proprietary platform IP. That's where we start. That's where we think we can generate the optimal value for U.S. shareholders and also for the patients. We also then design and develop products not only applicable for 1 tiny patient population. But as you see with VB10.16, yes, we start now in cervical cancer. But the same exact product is applicable for multiple patient populations that have the HPV16 driven cancer types. We -- when we work on this platform, we know that we cannot make 100 cancer vaccines ourselves with just changing the antigen and put them into the market as rapid as possible. That's where we can take advantage of partners. Since we have a platform like we do with Regeneron, we can make multiple products and accelerate those through partnerships that don't take away anything from our own pipeline in parallel with us doing our own in-house development of our products. That's really accelerating the value of having a platform. Now I think we are seeing that we really feel we are at the stage where the oncology platform has progressed very well. It's a derisked now through the clinical data and the partnerships that we've seen. You see even more data today. And you see also we progress this very rapidly now forward in all HPV-driven cancer types. So we're really ready now to further accelerate our oncology pipeline. It starts with VB10.16 and it's going to be expanded with other products, both with our partners and in-house. And you've also seen today that Nykode doesn't want to stop there. We want to make a new platforms. And every new platform that we have is built on this new code where we take advantage of how does the immune system work. How can we combine genes that can code for certain properties into 1 new molecule that constitutes a platform for us. You've seen that today starting with autoimmunity, you've also seen it with the fourth module technology. They're all new codes and they're new code platforms, which we believe is the best way for us to build a company that will continue to be the leading immunotherapy company. When it comes to exact -- how to take it from here in our cancer vaccine franchise, we feel that the data today that you've seen with this differentiated long durable T cell responses. Today, you also see T cell responses lasting even up to at least 1 year after the last dose of vaccinations. I don't think you've seen that with other platforms. We also see that we have a very long durable overall survival in our patients. That's derisking us. So now it's about how we can take this forward as a biotech company and generate as much value as possible. And the way we decide to do that is not rocket science, it's first to do the fast-to-market strategy. That's what we're doing today. That's what Bradley Monk is sitting here and talking about. That's our way to get VB10.16 to the market as soon as possible. That's why we start in second-line cervical cancer. But we also know that this, as I said, is applicable in other indications. VB10.16 is now moving also into head and make. We also move it into first line. So this is an earlier lines of treatment. We have data in C-02 in indicating that it's safe but also inducing very relevant responses that we believe has a huge opportunity in early stages. So in addition to that, VB10.16 needs to move into adjuvant settings as well. As you've also seen today with the KEYNOTE-A18 trial reading out, giving us a very nice basis now to move into that segments where immunotherapy start to get some ground and where it's very natural for us to see additional efficacy by adding VB10.16. We're also waiting for IMvoke010 on head and neck, et cetera. So it's really the time for us to explore VB10.16 also in earlier lines, setting up the huge future opportunity for VB10.16. We should not forget the broader populations in other indications and also PD-L1 negative. So it has a lot of potential after starting with the second-line cervical cancer. But you also see Mikkel presenting today and also done by our partners, Regeneron, that when we have this oncology platform, we now have applied it for individualized cancer vaccines. This is what we're moving forward together with Genentech. But there's a lot of different off-the-shelf cancer vaccines we can develop. VB10.16 is one on the viral antigen. There are more viral antigens, so we can use for oncology. There are also tumor-specific off-the-shelf antigens that we can continue to explore with our platform. And today, I think we got a lot of substantiation that tumor-associated antigens that have failed previously with other vaccine technologies in the clinic, we may actually have a platform technology that is able to break tolerance against this, and that will open up a huge opportunity for us because these antigens are expressed in a broad range of patients at high levels. So there's a huge opportunity for us now to exploit the full range of cancer antigens with the vision of having every patient the day you come in and have a cancer diagnosis, there should be a cancer vaccine available for you. As I said, we use these partnerships strategically. And it's always good governance to push your own products forward and generate as much value as possible for your shareholders because as long as your product is efficacious, you should keep it in-house and keep the value of the product. However, when you have a platform, you have the opportunity to also add partnerships on other products that you would not develop yourself anyhow. And that's what we did with Regeneron. Regeneron is fully based on our platform, adds their antigens and then moving that forward. And you can see that has generated a lot of value for Nykode to have a platform and not just products. We also want to develop -- continue to develop products that are differentiated. They are unique to generate the interest from pharma partners like we did with VB10.NEO in our platform. And you can see that that also has provided a lot of value for the company. Now we are actually at the starting point again because here today, I think we feel very confident we are sitting on the new novel and differentiated platform for autoimmune diseases. We have fresh patents covering the entire platform idea with all these different modules that we can make. And we can -- when we find the optimal format and formulation delivery for moving into autoimmune diseases, and if it works clinically with a proof of concept with the first in-house candidate, obviously, we'll follow the path that is we take it to first candidates towards the market. We obviously want to expend this candidate for all addressable patients. I hope you can recognize this from oncology and then in the end, expand into the broad potential of autoimmune diseases and allergies and organ transplantation that also this immune tolerance as of importance. And here, again, we are at the starting point where partnerships, very similar to what we've done on the oncology platform, we have opportunities both from the platform but also at different stages for the products we will take forward ourselves. And this has a huge opportunity for multiple products. So briefly on autoimmune indications, I hope you all know. But scientifically, to be able to direct the immune response into antigen-specific tolerance, you need to be able to manipulate the antigen presenting cells in that direction. And having a basis with a lot of insight and know-how in APC targeted technologies as we have, we believe we have a very sound scientific basis for being the leader in making sure that we can actually achieve these antigen-specific immune tolerance. It is -- has a lot of opportunities and a lot of indications, and there are currently no other technologies that's been able to achieve this. There are no autoimmune vaccines at the moment. So we are breaking new ground here. It has a lot of commercial upside. As you know, it's like every tenth patient people -- person in the world has this. So if you look at the total market for a commercial opportunity in autoimmune drugs, it's huge and at least at the same level as we see in oncology. So if we get this done, I think we have a very unique position to move in this direction. So last, I hope you've seen that we have this ability to generate ground braking platform technologies. We leverage that both in-house and partner products in parallel. It is not the same with all biotech companies out there. We have validated this for oncology, and we are now really ready to further accelerate this in oncology. We reached a stage now where we just want to push the gas and make sure that we can help patients with different cancer indications. And now we really see this opportunity also starting from scratch in autoimmunity. And we have a name that's called Nykode, a new code not to sit and wait and relax after doing this. We will continue to make new codes and try to fill the gap of where the immune system doesn't do what it's supposed to do by itself. Our job is to make sure that we can then take bits and pieces of whatever genes that are involved in the immune system and make sure that we can fill that gap with new codes. And those new codes, in our business model, will be new platforms. You've seen it with the fourth module, and you may see more in the future.

Thank you very much, Agnete, and I'm just going to try and wrap up in a few minutes before we invite the Nykode team up on stage for a round of Q&A. So we have been busy over the last many years, and we are busy also for the coming period. Klaus' team is not missing a step in making sure that we can get the head and neck trial started, that we can get the potential registrational trial in cervical cancer up and running, together with our partners at GOG. Mikkel's team is not missing a step in making sure that we can put a name to the next project coming out of our internal oncology pipeline in the fourth quarter of this year. And of course, as you've seen today, continue to push the boundaries within this autoimmune disease area that we are very excited about. I will be looking forward to also give you an update from our C-02 when we've been following the patients for another year in the first quarter next year. We're well capitalized with USD 174 million at the end of second quarter. That puts us in a very, very good position to execute our growth strategy with all the initiatives we have in front of us. We've also been very clear on our aspirations on a trajectory to the U.S. market by initiating the process to explore a potential listing on the NASDAQ. We're not able to provide any further guidance on time line or compliance reasons, but this has been an effort we've been undertaking for a couple of years. Nykode is at a pivotal inflection point now. We have, for the last couple of years, been focusing on validating and derisking our unique and proprietary APC targeted platform technology through top-tier U.S. partnerships and through clinical data showing long durability and survival. We've today added further evidence to the validation by showing long immune responses, long sustainable immune responses across both our programs, VB10.16 and VB10.NEO as well as a differentiating post-treatment long-term immune response. All these elements adds up to where we see the platform going in the future. We are also standing in front of a vast range of opportunities in front of us. And that's what we'll be busy on for the future. We have a focused plan to bring VB10.16 forward to the market and the patients including a fast-to-market potential in cervical cancer. We also see early-stage cancer as a significant upside -- to commercial upside, not only for VB10.16, but in general for our entire oncology platform supported by the data that we have been showing, including today. So very well safety -- a well-tolerated safety profile long-lasting immune responses and as you've seen, effect on the durability and the survival. Our data also indicates as Mikkel was showing from our Regeneron program, that we have a broad range of applicability in the type of antigens that we focus on. So we'll not only be focusing on viral antigens or neoantigens from personalized cancer vaccines, we can also go with tumor associated antigens, an area that had previously been very hard to target with vaccine technologies and gives us further range of opportunity to address unmet needs in the future. The data you've seen from Mikkel's departments today, we are taking the next step in unlocking the also unique proprietary autoimmune disease area, which could very well constitute the next therapeutic vertical for Nykode. And as Mikkel and Agnete have been alluding to with a huge potential and a high unmet need. And as I said, still very well capitalized and well positioned to execute our growth strategy. So our conviction in our platform have never been higher, and our outlook for the opportunities in front of us have never been higher. And I can guarantee you our sense of urgency to get started and get this moving have never been higher. So thank you very much for coming here today and listening to us. And now I'll just ask my colleagues from the Nykode team to come up here on stage together with us, and we'll be able to take a couple of questions, both from the room here as well as people online. So thank you very much.

A couple of follow-up questions. That's an interesting question. Can we delay that for a week or 2? Or do you need that now?

So just a couple of follow-ups on the autoimmune platform. So first, what are the targets in the MS models? And how should we think about the translation of what's been demonstrated preclinically in MS and type 1 to humans? And when would you envision being able to name a lead candidate or candidates?

Yes. So maybe I can start on that one. So that was 3 questions. So the first question was related to antigens or targeting units, I think, right, for the MS models. We don't want at this stage to disclose any of our targeting units. We want to keep this proprietary because this is, of course, the key for this whole platform within their tolerance. So I would prefer not to mention any names today on the targets that we are pursuing because these will, of course, be proprietary. Then you -- you asked about the translatability of these models to humans. It's a good question. I think it's -- these are, of course, simpler than the human setting because they are driven by 1 antigen primarily, MS with the MOG peptide and diabetes with PPI, but I still think -- and these are early days, we should remember these early days. But I think that you can say the outlook here, it's so great that we see a lot of promise. What we need to show is that we can get, what you call, epitope expansion. So what you typically see in a human disease is that you have 1 driver antigen and then you will start to have epitopes spreading. So we will spread to additional epitopes. We can easily incorporate more than 1 epitope in our vaccine. As soon as we know what are the drivers of the specific disease. So that's, of course, something that we are going to dig much further into for the specific diseases, what are the key drivers, for example, for MS or for diabetes?

Timing in terms of potential for naming a good candidate?

Yes. No. So it's a good question. We have a very good idea about where we would like to go. We are not yet ready to disclose anything. I think we expect to give some guidance maybe next year on the first potential project.

Great. And then just one last one, if I may. Just on the -- on the fourth module. If you can talk a little bit more how is the fourth module contributing to the efficacy that you've seen?

No. Yes, it's a very good point. So what we know is that the vaccine works very locally. So when you do the vaccination, you will get expression of these fourth module cytokines or whatever it is at -- by the exact same cells that are producing the vaccine. So you will get a very focused conditioning of the microenvironment. And particularly for tolerance, for example, it is key that it stays immune-suppressive that you're not switching it to being proinflammatory because then you will lose the edge. So this -- we believe these cytokines will contribute to that local conditioning, either in tolerance where it needs to be immunosuppressive or in where we're using it for the cancer setting, it needs to be inflammatory. So it works very locally primarily by the cytokines that actually, we are by attracting additional APCs, so you get a stronger response and a broader response potentially.

If I can ask a question on the Regeneron program and the data that you've shown, there was a lot of variability of the thymic expression of those subjects this case, animal. But I assume in humans is going to be similar, high variability in the thymic expression levels. How do you plan to address that variability with external adjuvants with other ways? So the response that is induced by the vaccine might not be the same for everyone based on the baseline thymic expression. How do you address that?

Yes, that's a good point. I think it's again -- these are data that are showing proof of concept that it is possible with the vaccine platform to induce or to break this tolerance against a variety of different antigens, which you remember that these -- there are different antigens for the different levels of thymic expression. So I think for the human setting, of course, every target will be its own, you can see case. So we need to still take it on a case-by-case basis, building up the confidence using animal models, using different models for, you can say, the ability to break this tolerance. But I think it's -- I think this is a very, very promising start that we can break these tolerance against these. And as I mentioned, we don't want to break it against those that have high thymic expression because then you could easily vision you will get autoimmune responses because these have what you call central tolerance and key - which is key to maintaining nonresponsive -- so I think those 2 situations with low and no thymic expression, that's really the area where you want to be to avoid autoimmunity, but at the same time, still getting antitumor immune responses.

I like the answer. And -- but going a little step further is how does the FDA see something like an endpoint on a trial for this? Would you select just like you select for PD-1, which is less than 1% expression of PD-1 or PD-L1 something like that?

Yes. So of course, you need -- if it's a tumor associated, you don't have a clear biomarker. I think that's what -- like you have with a mutant where you can take or certain do you have it or do you not? So I think this will be a case where you need to justify that. There's a high likelihood that you have the target expressed and then you can discuss what does that mean? If it's not amplified, if it's not genetically coded, then it is a very plastic thing. I understand that. But you can develop assays -- biomarker assays that would allow you to at least upfront explore what is the level of expression of these proteins. And how does that correlate to potential efficacy so that you may set a threshold for what is the level of expression you need to get efficacious or vaccine efficacy.

Yes. Okay, maybe just clarify. So when we have those boxes, it's not -- it's different antigens that we're targeting. So in principle, they go in different boxes, it's not the different mice that have very different levels of thymic expression. In principle, we would choose antigens that would go in the medium to low thymic expression in order to make sure. But it's not every different patient has different levels, right? But then again, it's also about finding those actions. But this has been done before. I mean there are many vaccines just [ calculations ] started with tumor associated antigens. So this is not a new principle as such. What's new is that we think our vaccine technology is able to break that tolerance because those data, those studies were not effective enough, and there's been a lot of discussion about these are wild-type antigens and it's difficult to break tolerance, so that's why they didn't work. I think that's what we're trying to show here that the -- this is a nice indication that maybe we can go back to those antigens that has been tested before and make them work, hopefully.

PD-L1 is an example of such a biomarker, right? That's not genetically encoded, but you still were able to use it as a biomarker to direct trials.

Any more questions from the audience? No. So I don't think we need to hear too lot here. So we have one question, which I think I answered 2 to 3 times. I think it was posted before. But -- so today, you have both wholly owned and partnered development programs in oncology. This is from guys from DNB. Can we expect a similar mix within autoimmune diseases or more or less partnering compared to oncology? I think for us, it's the same starting point, right? So it's the same thing for us to now have the autoimmune platform as it was to have the oncology platform. There are always different levels of interest. We are a different company. We have -- we're a more mature company than we were at the same time point as we had just the platform in oncology. Now we have lot of proven things in oncology. And then we also have the autoimmunity platform. So that's a different factor just from where we are. And then there's also the -- when we started with oncology, there's lot of cancer vaccines out there. There's a lot of companies pursuing cancer vaccines, but it hasn't been many successful cancer vaccines. That is a bit different starting point than in autoimmunity, where we feel the entire pharma community is seeking treatments for autoimmune diseases that don't inhibit your entire immune system, with all the side effects that comes with that. So there is a huge interest into platform technologies that has this promise or opportunity. So that makes -- then makes some factors they can decide whether we do exactly the same, not then everything is about the opportunities and when we think a partnering deal makes sense or not. But in principle, it gives us the same opportunities, and then we will take the optimal strategic discussions in order to maximize the value for our patients and shareholders.

Anything else...

Yes. So we have some questions about patents maybe -- our patent strategy. I think we also touched upon it a bit, but more specifically about, for instance, VB10.16, we can use that also as a question to how we think about our IP strategy with the platform IP we have for our oncology and in principle infectious diseases, the first sort of starting point that we have, that is a platform IP that will expire as such in '24 to '27 in different countries. But then again, what we do with that situation is that we then have other platform IPs with certain targeting units, for instance, the CCL3L1 that we have for all our oncology programs, that's the version out of the platform. This is sub-platform for oncology that we apply currently for all our cancer vaccine programs. That is younger. So that gives us into the 30s. So every platform cancer vaccine using this targeting unit gives us protection into the 30s. Then we have product IPs. And this is one of the reasons why Mikkel doesn't want to disclose what's our first autoimmunity program. We cannot do that until we've decided how that vaccine construct will look like. When we have a lead candidate, we will submit a patent application that describes exactly that candidate and that gives us even longer IP protecting that particular candidate. That's what we also have with VB10.16. Then for VB10.16, which is, as we've said a few times, if this study goes in the right direction, we would maybe expect that we could get into the market in -- I think you said like [ '28 strictly ] which is before the patent expires importantly. If it then -- when it comes to the market, you get -- you can both get up to 5 years extended patent terms for the first product you have into the market and then also market exclusivity addition, which is up to 12 years in U.S., 10 years in Europe, et cetera. So there is a buildup with platform IP, sub-platform IP when we have our own tolerance, we've desired exactly which targeting unit with our fourth modules. That's a separate version. And then we have the products when we have that, that's also a separate version. So this is a layered patent strategy that we have that will continue to help us. And the fourth module technology as such is also pretty new. And in principle will protect a new platform for all our cancer vaccines and infection disease and we have it for tolerance. That's why we have a lot of patents. That protects us for another 20 years, and then you will have products, et cetera, in the future. I hope that that was a very long answer guide, but I think we have some patent strategy and long protection.

If nothing else, it has been a long day. Thank you very much for making your way into here. Those of you who made it across New York, but also those of you who came from Norway. It's been a pleasure, and I hope you share our enthusiasm and conviction in the future and the potential going forward for Nykode and our platform and will join us on that journey going forward. So thank you very much.