Evaxion A/S (EVAX) Earnings Call Transcript & Summary

Welcome to this webinar sharing the 2-year readout from our Evaxion Phase II study in advanced melanoma. We are very, very happy with the virtual turnout for this call here. And together with the Professor Adnan Khattak, I look forward to sharing results and discussing data and implications of these data with all of you right from this important Phase II study in high-risk melanoma. So if we look into the next hour or so, we will be covering an exciting agenda. Initially, I will deliver an introduction to Evaxion and introduction to our AI-Immunology platform and briefly cover the data from the Phase I study in advanced melanoma that really paved the way for the Phase II study that Professor Khattak will present. I'll then hand over to Professor Khattak, who will take us through the Phase II design, who will perform a detailed review of the results and also discuss implications of this data. We'll end with a question-and-answer session. And we really encourage that all of you, if you have any questions, please post them. So there will be 2 different ways of posing questions. One is to simply put it into the chat here to type it directly into the chat. Alternatively, feel free to type in queue or question, and we will then ensure when we get to the Q&A session to unmute you, enabling you to post the question directly to myself or to Professor Khattak. So on that, I'm happy to initiate this webinar with an introduction to Evaxion AI-Immunology in the Phase I data, as previously explained. My name is Benjamin Wolthers. I'm a physician, and I serve as the Vice President of Clinical Development here at Evaxion. And it's truly a privilege for me and a great pleasure to be able to present for all of you today. So if we look first at Evaxion, we were founded in 2008 here in Copenhagen, Denmark as a truly AI-first company. We leverage our proprietary AI-Immunology platform for vaccine discovery, for vaccine design and for development. And based on AI-Immunology, we've developed a clinical stage oncology pipeline, out of which EVX-01 that we, of course, are presenting today is by far the most advanced project, but where we had several additional projects in the pipeline. Moreover, we leverage AI-Immunology in our infectious disease pipeline, where we target bacterial, viral diseases with a high unmet medical need. If we look at AI-Immunology and the AI-Immunology platform, this is really at the core of what we do. It's that pumping heart of Evaxion. And AI-Immunology decodes the human system for therapeutic target discovery. AI-Immunology integrates data from the genome, from the transcriptome and from the proteome really to identify optimal targets for our vaccine. As we'll show later in this presentation, AI-Immunology has proven a very, very high success rate in selection of targets inducing potent vaccine-specific T-cell responses and then enabling these vaccines -- sorry, these T-cells to interact with cancer cells and elicit tumor kill. So if we look at our pipeline here, EVX-01 is our lead candidate, really demonstrates the performance of our AI-Immunology platform and is really our proof of principle proof-of-concept. EVX-01 is a personalized anticancer vaccine, really designed to match the heterogeneity and the high number of tumor mutations that we observe in melanoma. When you look here on this slide, this is from a similar publication in 2013 by [indiscernible] Nature, where they listed on the X-axis a list of different cancers and the Y-axis the prevalence of somatic tumor mutations. You see that -- on the left side, at least my left side of the slide here, you see the acute lymphoid leukemia, you see AML as well right, with low numbers of somatic tumor mutations, whereas on the other side of the slide, highlighted here in green, you see melanoma, really harboring a high number of somatic tumor mutations. Also of note, you'll see that on the same side of the slide, right, with a high number of mutations, you see indications such as lung cancer, bladder cancer and also importantly, head and neck cancer. So whereas we have done Phase I and II to show proof of concept with EVX-01 in melanoma, there are certainly also other indications with a high unmet medical need where we could see a therapy, such as EVX-01 making a big impact for patient outcomes. So now turning to the Phase I trial design. The Phase I trial was conducted out of an expert melanoma site here in Copenhagen, enrolling patients with Stage IIIB, Stage IV melanoma, patients were required to have a performance score of 1 and at least one measurable tumor lesion per RECIST 1.1. Additionally, we did not allow any patients to have active brain metastases when going into the study. If you look here on the slide on the bottom left corner, we have the dosing regime. And when patients were eligible and initiated the study, we initiated checkpoint inhibitor therapy with a dose according to the label. And then we initiated the process of designing the personalized vaccine. This process is projected in the table on the right-hand side of the slide. And what we do is that we obtain material tumor biopsies and also samples from noncancer cells in the patients. These 2 types of tissue are sequenced DNA and RNA sequence, and then we load the data into AI-Immunology. AI-Immunology then selects up to 10 optimal patient-specific targets for the vaccine. The vaccine is a peptide-based vaccine, and this is manufactured, shipped to sites where it is administered to patients. In the Phase I study, we manufactured with a needle-to-needle time of between 6 to 8 weeks and administered EVX-01 for the first time at week 8. This was then followed by administrations at week 10, 12, 14, 16 and 18. If we turn to the results and some of the learnings from the Phase I study, we saw that very importantly, EVX-01 was safe, well tolerated with only Grade 1 and 2 adverse events. These adverse events being mainly injection site reactions, low-grade fever and fatigue. We saw very encouragingly that 8 out of 12 patients showed an objective response to the treatment combination, so an ORR of 67%. However, we also saw that out of these 8 patients, 7 patients eventually relapsed. EVX-01 was found to induce an immune response in all patients, and T-cell responses were observed towards 58% of the EVX-01 peptides administered. Moreover, as I mentioned before, we had efficient manufacturing of the vaccine with a turnaround of 6 to 8 weeks. So 3 key learnings came out of this Phase I trial. First, we selected the high 200-microgram dose as the recommended Phase II dose. Second, we evaluated the tumor relapses, and we found also looking at T-cell -- vaccine-specific T-cells over time that we should include into Phase II EVX-01 booster administration, and Professor Khattak will come more into that, but really to administer these administrations to keep the levels of vaccine-specific T-cells sustained at a high level. And then lastly, we took data here from the Phase I study and additional data and updated AI-Immunology with the ambition of even further improving prediction power of AI-Immunology. So on that, I would like to hand over to Professor Khattak. Professor Khattak serves as Professor of the Edith Cowan University, and he leads the Phase I Trial Unit at the Clinical Research Hollywood Private Hospital in Perth. Moreover, Professor Khattak has served as a primary investigator in this EVX-01 Phase II trial. And also, he recently, this was 5 days ago in Berlin at the European Society of Medical Oncology, Professor Khattak presented the data you'll be seeing now in an oral session. So with that, Professor Khattak, I'll hand over to you for -- to take us through the Phase II data.

Thank you, Benjamin. Can you hear me clearly?

Yes.

Okay. Thank you, everybody, for dialing in from various parts of the world. I'm dialing in from Western Australia. It's 10:40 p.m. at the moment. So -- and the audience is mixed. So I will keep the discussions sort of generic as well rather than going too much into oncology jargon. So may I take control of the talk now, Benjamin?

Yes, please do. Please do, Adnan.

Okay. Can you see my slides?

Indeed.

Okay. Excellent. So melanoma is a fairly progressive skin cancer with a fairly high mortality rate, particularly when patients get diagnosed with metastatic disease or Stage IV melanoma. So from 1975, all the way to 2011, so melanoma was considered to be the graveyard of clinical trials, where about 25 to 30 clinical trials were negative. These included trials with chemotherapy, hormonal treatment, biochemotherapy, until 2011 when the first ipilimumab trial came along and immunotherapy was the first treatment to make a significant difference. So roughly about 10, 15 years ago, so maybe somewhere around about 2005, 2010. So the 1-year survival statistic for patient with stage 4 melanoma only used to be about 20%, 25%. I mean only 1 out of 4 patients will see 12-month mark from diagnosis of the Stage 4 melanoma. But since then, significant progress has been made. So we got first-generation immunotherapy drugs. We've got second-generation anti-PD-1 targeting drugs, and then we use them in combination as well. So this is a Kaplan-Meier curve of different clinical trials of targeted therapy and immune therapy in Stage IV advanced melanoma. So if you can see, so these are the months since randomization and along the Y-axis, we got a proportion of patients alive. So if you look at the 5-year survival statistic now, so with the combination treatment, the brown line, so roughly half of your patients could be expected to live for 5 years or even longer. And you can see that the curve starts to plateau around about 3-year mark. If you're doing well at 3 years, now we've got latest data even dragging all the way up to 10 years with survival statistics sort of in a similar range. So that's quite a significant improvement in the last sort of decade. The green line represents targeted therapy, which is the other class of drugs that we use to treat patients with advanced melanoma. Many patients develop secondary resistance. And if you look at the progress through a lot of statistics, they are roughly about 35% to 40%, so inferior compared to immunotherapy. So this -- obviously, the outlook of patients have improved, but you can see 50% of patients benefit, but what about this group of patients who unfortunately die. So how we can help those patients. And obviously, the treatments that we use, for example, the combination of the first and second-generation checkpoint inhibitors, yes, they're efficacious, but they can be quite toxic as well. And none of these immune checkpoint inhibitor treatments here are personalized. So if I get 10 patients, I offer them the same treatment, but they're not specifically designed for an individual patient's melanoma. So I can't be confident. So it works for some. It doesn't work for others. So they are more generic treatments. And then -- so there's ongoing need for coming up with better and safer treatment options that are more personalized as well, so that we can increase the efficacy to try to help rescue those 50% that unfortunately die in the first year and also to come up with more tailored patient-specific treatments so that we can treat the right patient with the right drug. So in the Phase II trial of Evaxion saw building up on the -- and further consolidating the Phase I data that Benjamin presented. In this trial, we included patients with Stage 3 unresectable or Stage IV melanoma. The bulk of the patients were Stage IV melanoma patients, and they were treatment naive and a typical ECOG-01. So this means that they are fairly fit patients. They didn't have any active brain metastasis. The primary endpoint included initially looking at response or in terms of the conversion rate, which is conversion of complete -- sorry, from stable disease to partial response or complete response. So partial response means that you see an objective reduction in the tumor volume by 30% complete response, if you see a 100% reduction in the tumor volume and progressive disease, if you see more than 20% increase in the tumor volume. So these are the different figures that we use. So anything less than a CR and less than in between progressive disease is called stable disease. So the primary endpoint was to see if we can convert stable diseases into a complete response or a partial response, what we call CR or PR or converting a partial response to a complete response to try to see if we can deepen the responses what have been achieved by immunotherapy with checkpoint inhibitor like pembrolizumab, which is one of our mainline treatments that we use. Secondary endpoints included objective response rate, progression-free survival, overall survival and different adverse events and also the neoantigen-specific T-cell response. Exploratory endpoints included a conversion of progressive disease. This means that patients that are not responding to checkpoint inhibitor, can we pull their disease back into either disease stability or response or a complete response. So 2 types of treatments were used as per standard pembrolizumab monotherapy, what we call KEYTRUDA, that was started at week 0 and given all the way for a total period of 2 years, which is the current sort of standard set across a number of clinical trials or more contemporary trials that we generally treat maximum for 2 years and a standard dosing schedule of 400-milligram IV every 6 weeks was used. And then at week 12, so Evaxion's EVX-01 personalized peptide vaccine, as Benjamin told you the mechanism of action and how it's manufactured. So that was started at week 12. Six consecutive doses were given in the priming phase every fortnight, 12, 14 all the way to week 22. And then there was a gap after the priming phase and then leading on to the booster phase and 4 doses were given week 30, 42, 54 and 78. And then patients went into sort of long-term follow-up. More recently, an extension phase has been opened up as well for an additional 2 booster doses because of the preliminary efficacy that we've seen and the benefit that the booster doses are providing to vaccine-specific T-cell responses. So this was the study population. So it's a Phase II, a small Phase II study, 21 patients, 4 screen failed and then 17 patients were enrolled, but 1 patient developed disease progression. So 16 patients went on to the trial. 2/3 of the patients were male and then all patients were Caucasian and with a good ECOG status or their performance -- or their functional status with a vast majority of patients having Stage 4 melanoma PD-L1 expression and BRAF status was sort of 50% of patients had a PD-L1 score more than 5% and then 50% of the patients also had BRAF mutant disease. So generally, we expect 40% to 50% of the patients with Stage IV melanoma to be BRAF positive. So in terms of efficacy -- sorry, in terms of safety, so from what we know now from the personalized cancer vaccine or individualized neoantigen therapies, they've got very classic toxicity profile, which is fairly well tolerated and very well managed. And primarily, we're looking at no toxicities from Grade II or above. So as oncologists, we don't want to see -- so this is a CTCAE grading criteria, Grade 1, which is very minor toxicity. But when it starts to hit Grade 3 and 4, it leads to major morbidity and Grade 5 obviously, mortality. So we don't want to see anything showing up in Grade 3, 4 and 5 territory. So if you look at in the middle of the table, you can see the Evaxion monotherapy. So the vast majority of the adverse events were Grade 1, and this included fatigue, injection site reaction, body aches, muscle aches, feeling tired and flu-like symptoms, which we expect with vaccines. So -- and then a couple of Grade 2 adverse events. And then when they were combined, so again, I think the ones that were attributed to both, so primarily Grade 1s and 2s. And then there was only one Grade 3 and 4 adverse event when a patient develop pancreatitis and secondary diabetic ketoacidosis. But from what we know, that side effect profile is not associated with personalized cancer vaccines. It was driven by an underlying pembrolizumab. So I think very much in line with the data that we have from other personalized cancer vaccines, like the mRNA vaccine. So this is very reassuring. So at week 12, these are the responses that we saw complete, partial stable disease. So the objective response is usually defined as a combination of complete response and partial response, which was roughly about 50% in patients who were treated with pembrolizumab at week 12, means 3 months into treatment. And then once Evaxion was started and then the best objective response rate later on when you combined 15 and 25 was 75%. So generally, with pembrolizumab monotherapy, we expect response rates roughly around about 40%, 45% mark. So seeing the best objective response rate of 75% is fairly encouraging. So it means that you can potentially convert some responses into deeper responses. But obviously, it's a relatively small subset of patients. So we can't make any bold statements, but it's a very good signal. So this is the waterfall plot. So it is 0%. Anything lower than this line is generally good. Anything above this line is bad. So the green lines represent patients who had a complete response. And so there were 4 patients with a complete response. This curve is not reaching 100%, but this patient had a substantial reduction in their target volume to less than 5 millimeter. But obviously, the disease doesn't disappear, but obviously, anything less than 5 millimeter in terms of the nodal disease is classified as a complete responder and can be put down at 0 millimeter. The blue lines represent partial responders. The gray line represents a stable disease, and there are 3 patients with progressive disease. And this patient did have shrinkage of the tumor, but develop new lesions, hence, progressive disease. The responses were measured according to the standard clinical trial evaluation criteria of RECIST 1.1. I like this graph. So it sort of tells us how the responses transformed. So where they started at week 0 and then week 12 and how it sort of tells us how things changed by the introduction of the vaccines. So you can see these are the vaccine priming doses and the booster doses. And I would like to highlight like these patients who -- this patient who started with a partial response first and then transformed into complete response. Then again, these 2 patients also transforming into complete response later on. So the argument is some people put forward is that, obviously, these patients were already responding and you would expect, I think I'll show a graph later on, that these patients were expected to have good response anyway. But I think usually, when patients are responding, they will be responding quite early on in the journey. Generally, in the first 3 to 6 months, you will get quite substantial, or they will achieve their peak response. But here, you can see that some of the complete responders are converting around about week 72, so quite delayed. These are the partial responders that continued and then these are the patients with stable disease that develop a partial response. And particularly if you look at this patient 12, stable disease, stable disease. And by the time the vaccine effect kicked in and the booster doses have been given and there was a spike in the T-cell response, you can see they converted to partial response. So that's what we were hoping to achieve that we can deepen the response on top of the checkpoint inhibitor. And then the overall responses in terms of the conversion rate, so 7 out of 13 patients. So this means that 3 patients transformed from partial response to complete response and 4 patients from stable disease to partial response, leading to conversion rate of 54% and an overall objective response of 75%. The median follow-up was about 2 years. The median progression-free survival and overall survival has not been achieved yet because the vast majority of the responders up to 92%, they continue to respond to treatment at this state. What was more encouraging also was that identifying a neoantigen. So neoantigen is like the fingerprint of the cancer cells. So all of us have got their own fingerprint, which identifies us. Similarly, the neoantigens are the fingerprint of the cancer cells. So identifying neoantigen is important. So quantitative effect is important, but also qualitative as well. So not every antigen is going to lead to a significant anticancer immune response. And what Evaxion's AI-Immunology platform identified was that the neoantigen induced T-cell responses in 81% of the cases, which is very encouraging and further built up on the Phase I data where it was roughly about 65% from memory. This is a very nice graphic representation of how the vaccine-specific T-cell responses happened. So these are both combination of CD8 and CD4 T-cell responses. So this is where the vaccine -- the priming doses started and then the booster doses came along. So if you look at -- this is the pre-vaccination period when pembro was given. This is with the priming phase. You can see the T-cell responses happened quite early on in the priming phase. This means that you start to see an effect because particularly when you're treating a patient, you want to have a therapeutic effect that starts early on because many patients with melanoma were present with high-volume metastatic disease. So you want to generate an anticancer immune response that translates into reduction in the tumor volume so that you can make patients' quality of life better by reducing the tumor burden. So we want a drug that kicks in early. And then what we also saw more interestingly was the boosting phase, where the 4 booster doses are given, where there was further improvement in these T-cell responses, and they were sustained throughout the period, so highlighting the importance of the booster doses. So -- and that's why I think the further couple of booster doses are being rolled out as well. So this is a spider plot. So I'll start off with patients who developed disease progression. So the red line. So this patient experienced disease progression, you can see. But if you look at this patient's T-Cell response. So when they were progressing, I think the vaccine had just been started. And then when the vaccine effect kicked in, there was some reduction, but obviously, after that, it sort of plateaued and then further disease progression. And we don't have any further follow-up sort of T-cell data from it. Then this patient with stable disease, very interesting, one of my patients, you can see the disease volume jumped from 0% to 50%, so almost doubling of their tumor volume at the completion of the first 3-month treatment with pembrolizumab. And then things started to improve when the vaccine was given as well. And you can see how the T-cell responses sort of correlate with that, that when the vaccine has been started, you were seeing increase in tumor volume. And then the vaccine effect kicks in, you see a tumor-specific T-cell response that's going up and the volume of the tumor is going down, down, down, down. And then because this patient had developed disease progression at the beginning, so we can't call them a responder. But we have done a couple of PET scans for this patient now, and they've shown a complete metabolic response, but obviously, as RECIST criteria. So I think we still call them a stable disease. In terms of the deepening of the response, so I think you can see these patients were responding. But then after that plateaued, so the vaccine effect sort of kicked in roughly around about this period, and that's what we start to see these patients coming down, transforming into complete responders. And then the trajectory, if you can see also here, so these patients in the blue line, these were -- this is a 25% line you can draw here. So at 3 months time point, these patients had stable disease. They hadn't crossed the 30% and then they sort of continuing the stable disease up till here and then they start to respond after sort of the 36 weeks time period. Obviously, these are a small number of patients. We need to further study the T-cell vaccine data. And obviously, ideally have a bigger cohort of patients to draw more meaningful and more statistically robust conclusions. And this patient, who developed quite a late complete response, you can see how the tumor volume started to go down when the T-cell response went up and it really spiked, you can see the tumor kinetics hit 0 transforming into complete responder. So in conclusion, I think before we look at the efficacy data, we always want to make sure that whatever treatment we roll out that is safe to use. So this combination was well tolerated with a good safety profile, consistent with the Phase I data, objective response rate is very encouraging. But again, it's a small subset of patients. But what is quite encouraging is that most of the patients, 92% of the responders demonstrated sustained response at 24 months time point. And then more interestingly, the ability of this combination to induce potent and sustained T cell responses. And then the AI platform's ability to recognize the new antigens that will generate anticancer immune responses in 8 out of 10 patients. And the vaccine was successfully manufactured for all of these patients. So we don't want to screen fail. I mean, I'm involved with other personalized cancer vaccines like mRNA vaccine. So we do have a certain vaccine failure rate, particularly the recent clinical trial that we concluded. So this is very encouraging that in this small subset of patients, nobody failed screening because of an inability to make the vaccine. So these findings are very encouraging. They give a very positive signal, and they support the ongoing development of Evaxion in high-risk melanoma and further discussions are ongoing by Evaxion's team. So thank you.

Thanks a lot, Dr. Khattak, for this comprehensive overview of the data and running through this. I think this takes us to the Q&A part of the webinar here, and I'm happy to see that we have quite a number of questions here. I think I will start by -- I have so far looked at 3 people who have their hand raised. And maybe we should start with Scott trying to -- we will ensure that you should be able now, Scott to unmute and post your question to Dr. Khattak or myself. You're still muted, I believe, Scott. Maybe -- while we figure this out, I'll go to one of the questions in the chat. This is from Wim, who asked whether EVX-01 -- if EVX-01 was licensed to another company, how dependent would that partner be on the vaccines infrastructure, considering its personalized therapy? How do you see this working in practice? So thanks a lot for this question. This is, of course, something that we're discussing with relevant partners. And without disclosing any of that, I will say that if we break down the designing of the EVX-01 vaccine, the sequencing part is very straightforward in many locations, such can happen decentralized at the site. The predictions AI-Immunology is, of course, the core, as I mentioned, of what we do. This is after being developed, we have a 24-hour turnaround time on this, making it quite really removing any complexity from this. And then I'll also say that the manufacturing of the peptide-based vaccine is using very conventional peptide manufacturing production methods. So in that sense, not complex. However, how this will work when we move forward into our development of EVX-01 with a partner that is really, of course, dependent on discussions between Evaxion and that partner. I hope that suffice. I don't know whether Scott has been able to unmute. If not, then let's try to go to -- I have a RK listed here as having his or her hand up. So maybe RK, if you are able to now unmute and pose your question. Let's give it a shot.

Dr. Khattak, first of all, thank you very much for doing this call and talking to us this late in the night. So a couple of quick questions. The first one being the ORR, which you report 75% in the 16-patient study. Certainly, it looks better than the 40% to 45% that we have seen with the monotherapy. But however, how would you think about this response rate based on not just what has been approved, but other therapies that you have worked with? And what does this say or what should we be expecting as we go into the late-stage studies with the same molecule?

Yes. So I think very, very good question. So I think our current first-line treatment options across Australia and across the globe, obviously, this is a very busy area. A lot of new clinical trials are happening. Different molecules are being added to each other. But unfortunately, they also bring a lot of toxicity as well. So one of the most common regimes that we use is a combination of ipilimumab and nivolumab. So where we expect response rate somewhere around about 50% to 60% with the combination, but it's fairly expensive treatment, number one. Number two, it can lead to substantial toxicity where you got to -- you probably saw that when I mentioned that we do not want to see a high Grade 3 or higher adverse event rate. Now that Grade 3 adverse event rate with this combination hits about 50% to 60%. This means that you expect that 50% to 60% of the patients are going to end up in the hospital in one way or another due to some sort of toxicity. So we got a very good efficacious regime, but it's fairly toxic. And obviously, quite a substantial of our patients are 65-year plus. So we then we tend to shy away from using treatments like this. So certainly, we want to cross that 60%, 70% mark and try to approach more into that territory, 75% plus, but at the same time, not lose the -- in terms of safety. Now tumor-infiltrating lymphocytes are being rolled out as well in the first-line setting. I'm involved with those trials as well. But that's quite a cumbersome process. And at this stage, in the melanoma community field, we're not sort of entirely convinced that the cell therapy has got any striking role in the first-line setting when we got other good efficacious options available that are off the shelf, and we don't have to go through a complex process of cell therapy manufacture. The personalized cancer vaccine field is very interesting that, obviously, we're seeing improvement. So the personalized mRNA vaccine data that presented at ASCO a couple of years ago, that was very encouraging in the Stage II early-stage melanoma setting. And now we're waiting the results for the Phase III from the early-stage melanoma setting. But doing them in the metastatic setting pose a challenge because we need to obviously start treatment, but at the same time, because these are not off-the-shelf treatments, they need to be manufactured. And then we don't want to be in a situation where you start a patient on the standard treatment plus send up the tissue to your central lab to do all the DNA, RNA sequencing and come up with a personalized vaccine and then find out 6, 8 weeks later that we failed to manufacture the vaccine because I've seen it in other clinical trials, vaccine failure, and I've had recent experience in the context of another trial where we waited for a good 6, 8 weeks for a patient to be even randomized because you can't randomize patients till you obviously have the approval or the indication from your lab that the vaccine can be manufactured. And then unfortunately, for those couple of patients, we could not obviously proceed. So you don't want to waste that time. And then at the same time, try to deliver the vaccine as early as possible so that you can start your priming phase early so you can generate your T-cell response. And then at the same time, the data from Evaxion is quite encouraging with the 100% manufacture success rate. Obviously, it's a small population need to be replicated in a bigger, ideally a randomized Phase II study, but this is very encouraging that the toxicity profile goes in its favor, the manufacture and I think the translational response in terms of patient-specific and durable responses are very encouraging.

Can I ask a follow-up?

Yes, maybe a quick follow-up question.

Okay. The follow-up is the 4 patients that did not respond, was there anything unique about these 4 patients either in terms of failure of the vaccine itself or in terms of meaningful T-cell response in these individuals?

Yes. So I think, obviously, the different -- obviously, it becomes hard to drill down to an individual patient's data because they don't have access to each individual patient's data as an investigator. But eventually, obviously, we're looking into those details. But yes, I think I saw the patient where they had disease progression. So we couldn't have the T-cell responses sustained in some of them. I'm not sure if Benjamin, you want to comment on that as well. So the others that progressed, what was their individual T-cell response because I don't have all those curves. Maybe I think the backup slides, you think you have something on that maybe?

Yes. So indeed, I can say that we are, of course, drilling down, right? The data presented today is with the data cutoff of end June, right? And we've been cleaning data, getting everything ready for ESMO in this presentation. But over the coming weeks to months, we will, for sure, be evaluating together with Professor Khattak and also our other key opinion leaders that have served as PIs in these studies, whether we can decide for any trajectories in responders and nonresponders. But to Dr. Khattak's point, right, we had 12 out of 16 being responders, right? So they are small numbers, and we see T-cell responses in all patients, all 16 patients. I will go to the next person I have here on my list that is Thomas Flaten. So Thomas, if you are able to unmute, please do so and post your question to Professor Khattak and myself. We may just wait until we get the connection there. Then I have Kevin on my list as well here, who has raised his hand wanting to ask a question. If there's any of you who have a question, but are not able to unmute or whatever for technical reason, feel free, of course, to type in the question in the chat. We will take those after this question from Kevin. Kevin, are you able to unmute and please post your question. Maybe not. If that's the case, please type in your questions in the chat. We will take them in this way.

Benjamin, do you think maybe everybody has been muted by the organizer. Is that the reason because I think Thomas pointed that out.

But we are able hear in the background...

Can you hear me now? Sorry...

Yes.

I think I broke the code. Yes. So listen, it's a wonderful discussion. I just want to -- maybe one follow-up and then a question. I appreciate your responses to RK in the context of what else is out there in terms of other potential new therapies. At ESMO, the primary focus in other tumor types was really sort of the ADC space. Just do you have any comments with regard to ADCs and melanoma? Is there a path in your view? Or can you maybe just add that and then I maybe have a more substantive follow-up.

Yes. So I think, yes, ADCs are very topical. Obviously, there are different bispecific antibodies. There are T-cell engagers that are being used in melanoma. But again, obviously, these are not necessarily patient-specific. There's no proven role of ADCs at this stage, but a number of clinical trials, Phase I and IIs are looking at melanoma subset, particularly in PD-1 refractory patients. Now some of them are purely sort of chemotherapy or put it that way a fancy version of chemotherapy drugs type ADCs, where you use a [indiscernible] inhibitor. But then what we're seeing more promising now is the anti-PD-1 and anti-VEGF bispecific antibody like, for example, ivonescimab, which had some really good results in the lung territory recently. So those type of molecules certainly hold also promising feature in this field moving forward. But again, I think this will be in not a patient-specific, patient tumor-specific territory where we would expect that some patient will respond and then a certain patient population would not respond. So it will be wiser than what we already achieved with other checkpoint inhibitors so far. In terms of clinical trials, I think I've just become aware at this ESMO meeting that some sponsors are looking into this territory in the early phase melanoma setting in the perioperative setting, for example, patient -- not everybody responds in the neoadjuvant setting to the checkpoint inhibitors to see can we rescue the patient who are nonresponders after the neadjuvant treatment? Can you add in an antibody drug conjugate? So this area is going to be explored and quite interesting to monitor moving forward.

And then my sort of question specific to the Evaxion data, which is very interesting. It's just -- do you think we've learned anything in this most recent data set with regard to kind of dose and schedule. I mean, on adverse events, clearly, it looks like if there was a rationale for going with a more intensive regimen either on dose or alternative dosing frequency, it seems to have that flexibility. But when you kind of look at the patient responses and specifically maybe some of the T-cell data in the patients that you've seen, is there -- are there kind of improvements that might be captured through schedule change and improvement?

So do you mean in terms of changing the dosing schedule or starting vaccine early potentially or...

I mean in terms of, for example, a more sort of intensive boosting window or maybe having the option to go to more frequent dosing in the first year and then to a kind of a different sort of taper in year 2 and beyond. I mean, I think that's...

Yes. I think a number of possibilities can be explored. So I think probably somebody posted a written question that, could we start the vaccine earlier? So yes, I think we waited for 3 months. This doesn't mean that we didn't have the vaccine ready for 3 months. So -- but it makes a smaller study like this very cleaner, so that you can tease out difference between what vaccine is contributing compared to what pembrolizumab has done. So if you were to do everything together and somebody gets a response, it becomes hard to tease out how much the PD-1 contributed, how much the vaccine contributed. So ideally, you obviously have a Phase II of the vaccine combined with pembro versus pembro alone. So to tease out this question, what is the vaccine adding? So like what we did in the KEYNOTE-942 trial, it was in the early-stage melanoma setting where a personalized vaccine was given in combination with pembro versus pembro alone to sort of answer a similar question. In terms of the frequency, could we change that? Certainly, yes, we can. But obviously, every dose that you give has got a dollar amount associated with it, unfortunately. So how much that would contribute? I mean, we've got a good schedule. So if you look at, for example, Moderna's mRNA vaccine, all the clinical trials, the INTerpath trial that they're doing in melanoma, RCC, lung trials, perioperative trials, they're giving a total of 9 doses. There's no booster doses involved. So Evaxion is the first trial that I'm involved with, where a boosting dosing schedule was rolled out and has gone through an efficacy and then further extension boosting has been rolled out, very much in alignment to your feedback because we didn't plan the additional booster doses until we stumble on this that when we saw that we're seeing a therapeutic effect and we're seeing a vaccine-specific anticancer T-cell response as well in others. So we're learning as we're going along. And yes, things can be certainly modified and tweaked and this is how we will learn. So -- but obviously, at the same time, I think from a financial perspective as well, I think we just have to make sure we get a good rationale for adding a particular treatment. For example, we saw that there was boosting benefits seen and the boosting effect seen hence further additional 2 booster doses were added. So we'll probably get an idea in terms of the booster doses. Do we need to spread it out more? Or do we need to do it more frequently to begin with? So these things can be certainly explored down the track here.

So I see Thomas right, and I apologize for you not being able to speak here, your question, but I'll try to read it through. I think the first one, Dr. Khattak, it's for you, right. Can you comment on any potential read-through from this EVX-01 data into previously treated melanoma patients, particularly in light of the enthusiasm for the Moderna program?

So is this question on the chat?

Yes, this is in the chat.

Any idea speculation to begin with vaccine earlier. So this a question number from.

This is from Thomas Flaten, where it says, although speculative, can you comment on any potential read-through from this study into previously treated melanoma patients? So any read-through from this study into relapsed/refractory...

I think. One, obviously -- so one option is obviously that there will be a group of patients who would respond beautifully to pembrolizumab monotherapy. So not everybody needs doublet treatment. It's just that our understanding that biomarker is not at a level that we're able to tease out and identify. So as a clinician, what I find very frustrating when I was speaking to the patient is that we make it fast, we make a big deal that we got these drugs that people are living a 50% survival rate at 10 years for Stage IV melanoma amazing. But I can't tell that individual patient, are you going to be in the 10% to 50%, who are going to live for 10 years or not. So certainly, our understanding hasn't improved to that level. But I think rescuing patients who have not responded is certainly a good area of exploring further benefit from these vaccines. The other option that I was also thinking was that in the, for example, neoadjuvant treatment or perioperative treatment is very topical and has changed practice. And that's with the rollout of adjuvant and neoadjuvant treatments, we're seeing much less Stage 4 and routine clinics now. And one area particularly that of interest to me and other clinician is that patients who do not respond to preoperative checkpoint inhibitor treatment, what do we do with them, the nonresponders? Do we escalate their care to combination ipilimumab and nivolumab? Do we come up or if they already received the NADINA trial protocol of ipilimumab and nivolumab and they don't respond, where do we go from there? What do we do with those patients? So that's another area where the personalized vaccine could be explored because we'll have access to good quality tissue in the postoperative setting. So yes, that can be certainly explored as well.

Thanks, Dr. Khattak. And Thomas, you have one further question addressed to me. It reads are the boosters the same as the priming doses? And has any thought been given to evolving the boosters to adjust for immunogenicity of the new antigens chosen for the priming doses? And maybe taking the first question first. It is the same dose, right? So when we manufacture EVX-01 based on, as mentioned or described in detail earlier, right, that really gives us one patient-specific vaccine. It's the same vaccine targeting the same neoantigens that we use throughout therapy, and we also use the same dosage throughout therapy. And then has any thought been given to involving the boosters? So what we see and it's not shown here, right? As I said, we're digging into the data and we'll elucidate more is that we see over time, we see more and more of the antigens, the neoantigens in the vaccine eliciting vaccine-specific T-cell responses. So in that sense, I don't know if you're alluding to redoing a biopsy to test whether the neoantigens are the same. However, that is not currently with the response rates and also the duration of responses presented by Dr. Khattak. That is not something we for now at least see is needed to provide an impact on trajectories for these patients. Thanks a lot for the question. I think then I don't know -- I have Kevin still maybe with his hand up here. Kevin, I don't know if you're able to unmute on this, then I'll go up score a little bit up here and see there's a question from Thomas. Thomas Malten saying, how does EVX-01 compare to the IO Biotech plus nivolumab therapy that was also shared here at the recent ESMO? Are regulatory challenges more pronounced for personalized vaccine relative to off-the-shelf vaccine? Are there differences in duration of outcome? Is there room for optimizing EVX-01 during development? And was there any signs of this during the Phase II study? So I'll try to chip away at them, Thomas, right, and then comment if you're missing something, right? So compared to the cancer vaccine developed by IO Biotech, we're very, very different. They have an off-the-shelf vaccine IO-based really targeting regulatory T-cell compartment and off-the-shelf in no way personalized to match personal private neoantigens in these patients. So in that sense, or being a vaccine technology, the concept is very different between IO Biotech's approach and the one we are using at Evaxion. I'll say regarding regulatory challenges, these regulatory interactions is, of course, something we're having on an ongoing basis. When we initiate the Phase II study here, we submitted and discussed with regulators across Australia, Europe and U.S. And without going into too many details, I can say that regulators were very overall positive in regards to allowing us to conduct these studies. And thus, we have not seen major hurdles there. Also, this is an approach where, as mentioned before, we produce the vaccine, we're able to test the vaccines as we should before administering this to patients. Maybe this is so very much in differentiating this from some other cell therapies needing fast infusion. Are there any duration in outcomes? As highlighted here by Professor Khattak, we see 12 patients responding to therapy. One of these patients died from an unrelated intracranial hemorrhage 1.5 years into therapy. Otherwise, all of the responders remain in response. And as Professor Khattak said, this is really encouraging, right, because it's a hint of, that's what we're doing here, right? Do patients live longer? Do they live better? We're seeing these sides of them living longer here with this therapy. So in that sense, we see no differentiation in these patients and room for optimizing EVX-01. I think Dr. Khattak went into that before in regards to dosing, et cetera. I will, however, say that from discussions here at ESMO with key opinion leaders, et cetera, the results are promising and the effect of the boosting vaccinations compared to what we see in the Phase I without boosters is really a tremendous, right, the level of sustained T-cell responses there. Good. I hope that suffices. There's a question from Juhi asking, discussions are underway with regulators. On the last page, means that there will be a possibility to make contracts with your partner companies. And of course, we are in discussions with both relevant partners who find this data interesting and wants to move this forward into further clinical testing. And in regards to the regulatory discussions, as a clinical developer, you know that it's always best to be in close contact to regulators across the world, and we are doing the same by planning for further interactions to discuss this data and possible next steps with the relevant regulatory authorities. Then maybe there's a question for you and Dr. Khattak. Were there any differences in responses based on BRAF or PD-L status?

I don't think. So we evaluated the data specifically based on BRAF status because obviously, 50% of the patients have BRAF mutant disease. So you're looking at 7, 8 patients, so we can't draw any meaningful conclusions from that. And obviously, we don't necessarily use PD-L1 status as a routine biomarker in managing patients with advanced melanoma. And then I think the next question is that based on Slide 20, almost all responses were observed before initiating EVX? So I think it's more looking at the trajectory where they started. Yes, I think there were some responses that were happening, and that's obviously the response rate was 50%. But I think it's more in terms of the deepening of response with time. So those who hit the partial response in the first 12 weeks, if you were to follow their tumor kinetics for a bit longer time. So they were not all going to transform into complete response. So you can see some of the spider plots, this initial response and then the curve is flattened out for some period of time and then before it converts into a complete response. And similarly, those who started as a partial responder and then later on -- so those who started off with stable disease at 2-year time point -- sorry, 12 weeks time point, they transform later on. And I think one of that -- the little BD diagram with the different beads, which I showed. So usually, you would expect in clinical practice that we see patients sometimes have a delayed response, but they usually achieve their peak response within the first sort of 3 to 4 months in the vast majority of cases. And as I showed, I think in that curve, one of the patients who had stable disease and transformed into a partial responders quite like after week 72. And then a couple of patients who were partial responders to begin with, if you look, follow those dots in those slides, so they remain as partial responders up to week 60 and then another one up to week 72. So that's like 1.5 years into your treatment. We generally don't expect partial responders certainly becoming complete responders so far down the track. But again, yes, certainly, this can be by chance. And hence, the need always we look at statistical significance and to put the matter to breast, how much the vaccine is adding. Yes, you do a randomized trial to see how much is contributing. Then you will have your PFS, progression-free survival data, your survival data, your response rate. So you get all those sort of things figured out. But obviously, in a smaller population, we're just looking at more signal generation rather than robust evidence as such.

Thanks a lot. I think we're almost at time. However, there's one -- there's a question from Jan Stenvang here that asks, any ideas or speculation to begin with the vaccine earlier? Any idea to treat only vaccine and not pembro? And I'll say that indeed, right? I think Professor Khattak, you did a good job explaining why we started at week 12, right. For Phase I, we initiated therapy at week 8, right? But indeed, this can also be moved earlier also depending on the trial design and further evaluations of the efficacy EVX-01. And last comment maybe to treat with pembro only, I think this also comes back to one of the aspects raised by Dr. Khattak from earlier, right, that, of course, the combination therapy will also depend on prior lines, which line of therapy you go into, what makes sense for what patients. And those discussions is, of course, discussions we are having with -- we'll be having with Professor Khattak, with partners and of key importance also with regulatory authorities. And then as maybe I think we are at time, and I see maybe there's a few additional questions from Andrew. What's the question? Thank you. So I see a few additional questions. I will reach out to you personally to answer these questions in text with 2 minutes over time. And on that, I will say thanks a lot all of you for attending this webinar, in particular, thanks to you, Adnan Khattak, for staying up late, right, and trying to speak with not too much loudness so that you wake up your girls, right, and we'll be in touch, of course. All the webinar slides here and the recording will be available on the website, right? If you have any further questions, please reach out to the Investors team. On that, have a great evening, day or morning wherever you are, right, and take care. Bye all of you.

Pleasure is mine. Bye-bye.