Theriva Biologics, Inc. (TOVX) Earnings Call Transcript & Summary

Good morning, and welcome to the Theriva Biologics KOL event. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Theriva website, following the conclusion of the event. I'd now like to turn the call over to Michael Cozart of Lifesci Consulting. Please go ahead, Michael.

Thanks, Tara. Good morning, good afternoon, everyone, and thank you for joining today's KOL event hosted by Theriva Biologics. My name is Michael Cozart, and I'm a managing partner at LifeSci Consulting, a leading life sciences strategy consulting and transaction advisory firm. This morning, Dr. Ricard Mesia from the Catalan Institute of Oncology, is joining us to discuss data that was recently presented at ESMO, highlighting VCN-01's ability to improve outcomes in combo with a checkpoint inhibitor in patients with refractory head and neck cancer. Dr. Mesia will additionally discuss the unmet medical needs in head and neck cancer, current treatment limitations as well as the urgent need for new approaches. To start, Dr. Manel Cascalló, general Director of Theriva, will provide a brief overview of the company, along with insight into the clinical development strategy for VCN-01 based combination approaches to treat challenging cancers. So to start, Dr. Cascalló, over to you.

Okay. Thank you, Mike. Welcome, everybody. Good morning, good afternoon for everybody who's joined us today. I'm Manel Cascalló. I'm the General Director of Theriva Biologics SL, which is the European subsidiary of Theriva Biologics Inc. And we are a company -- my position is also as a founder of the company that has provided this asset VCN-01 to Theriva Biologics portfolio. And as you probably know, VCN-01 is an asset that is being developed in different clinical indications right now. We have a quite extensive program in pancreatic cancer, where we are conducting a Phase II trial right now, in combination with the standard of care gemcitabine Abraxane and we are actively recruiting in Europe and in Spain, in different sites, and we have also different clinical trials in combination with different drugs, because one of the unique characteristics of our product, VCN-01, it's a product that can be systemically delivered, which makes a significant difference with other oncologic virus developments. But also, one of the differentiators of this product is that the product is expressing tumor degrading enzyme called hyaluronidase. And by doing that with our product favor, it's the entry of different chemical entities into the inner part of the tumor. In that way, when wind minister reaching one VCN-01 is able to power the entry of chemotherapy, it's also able to power the entry of antibodies like immune checkpoint inhibitors antibodies, but also the immune system. And that provides a unique product that also is not acting but itself, but it's also powering the action of different compounds. If for that specific reason, we have also initiated a trial combining our product with immune checkpoint inhibitors in head and neck carcinoma, and the efficacy data of this trial has been presented yesterday here at ESMO inventory. And that's why today, I think it's important to just highlight here with Dr. Mesia, the relevance of this data. Dr. Mesia is the Head of the Oncology Department at the Catalan Institute of Oncology in Barcelona in Spain. But moreover, he's a president of the Spanish Society for Head and Neck, that it's a group that is really favoring the development of head and neck treatments in Europe and in general.

Thank you, Manel. I'm going to start explaining you what is the current treatment of recurrent/metastatic disease in head and neck cancer and their unmet needs. First of all, I would like to explain to you that recurrent/metastatic disease, those are disease that they're good with metastasis or reoccur in a locally in the head and neck or a distance place and they have not any special treatment locally. So just radiotherapy or surgery that are the treatments who could cure the patient. These are the standard of care in recurrent/metastatic disease. We decided treatment according to tumor characteristics, basically the value of PD-L1 misery CPS, that is an escort or tumor burden. That is because patients with high tumor burden need a fast response, because of they are in danger to have explosion of the tumor and to be very symptomatic. But we use also patients' characteristics, adjust performance scores. Patients with performance scores than 2 or over do not respond to any special treatment, and we are also using comorbidities or edge in order to decide. According to the pivotal clinical trials, we decide in first-line recurrent/metastatic disease if the patient is platinum refractory that those patients who can't resist are platinum in the first line or in the local [indiscernible] disease, and these patients received as a standard durvalumab, that is an anti-PD-1, and then we don't have any specialty treatment in the second line and sometimes the patient response, we use different schedules of chemo. In this particular disease, platinum refactory median progression-free survival is only 2 months, and median overall survival is only 8 months. These are our worst patients in progression-free survival and overall survival. In platinum sensitive, we decide according to the value of the PD-L1. In those patients with a CPS over 1 -- 1 or over 1, we decide according this tumor burden in patients with a high tumor burden, we prefer to combine chemo plus durvalumab. And in these patients without a high tumor burden without symptoms, we prefer durvalumab alone. This is well defined for the first line, but we don't know and we don't have any special treatment in the second or ulterior lines, and that is tended to be defined. But we use any combination with chemo plus or not with cetuximab. In those patients with a CPS less than 1 we use the all scheduled extreme [indiscernible] that is a combination of chemo plus cetuximab that has not moved in the last 15 years. There is no special relevant in this setting for this patient. In second line, we add nivolumab. Important to note, in these patients with platinum-sensitive, medium progression-free survival is 3 months for CPS less than 1 or 5 months, CPS over 1, and median overall survival is only 12 to 14 months, CPS negative, CPS positive. So which are the actual goals of therapy in recurrent/metastatic disease? Before the Axis incorporation to our arsenal, we say that these patients only receive a pagitive intent treatment. So these patients could not be cured. So we try to extend survival -- global survival, by increasing response rate. Here, there is a relation between response rate and survival, with increasing symptom controls and, of course, quality of life. Quality of life is balanced between the response rate and not to have in excess of toxicity. But with the operation of the immune checkpoint inhibitors and pembrolizumab in front-line, we have this curve with well separated curve with this long-term survival that achieved 15% with pembro to 19% onto patients for receive chemo plus pembrolizumab. That is these figures and from this, we have a new challenge that is to improve long survival rate. That is our amend. We want to improve long survival rate. And now we are start to think if we can cure these patients. Possibly, some of these patients are cured even in a recurrent/metastatic disease that were not cure 5 years ago. Our toxicity. Toxicity is very important in our patients and all of the patients who received any special treatment with chemo, cetuximab or immune checkpoint inhibitors have toxicity, but it's not the same according to the treatment. Here, we have a summary of the most important clinical trials in first line or second line with immune checkpoint inhibitors, that sometimes as we compare with combination with cetuximab or with other scales of chemo plus immuno, and we can see that with immuno checkpoints alone, Grade 3, 4 main toxicity was about 9% to 15% -- less than 15%. And everything is immuno related toxicity. When we combine chemo plus immune checkpoint inhibitors, the toxicity is about 35%. And here, we combine immuno related toxicity with kidney toxicity, renal insufficiency and bone marrow toxicity. And when we combine chemo plus cetuximab, cetuximab is an anti-EGFR that is used in some patients if they have menacing first line or in second line, we have exactly the same immune of toxicity, about 35% of Grade 3/4, that is severe toxicity, and we add mucositis or dermatitis instead of kidney malfunction or bone marrow affectation. And what happened after this first line? Here is a summary of the 2 main trials in first-line recurrent/metastatic disease. That is the key note 48 of more than 600 patients included. This is the CheckMate 141 with 940 -- 950 patients included. And we have seen that all the way, 50% to 60%, the patients who received clinical trial in first line have received a second-line therapy. And what's happened in this patient -- happen some of them, probably never recur because they are cured, because they get these 5 years without a disease, but the other are patients that receive a lot of treatment. But some of them do not move to a second line, because they have deteriorated after this first line. So we lost about 20%, 30% of the patients in this first line, because these patients achieved a PS2, and we cannot treat these patients. Here we have a summary of the second line that is only retrospective series. We don't have any special prospective or randomized trial in second line, because the definition of the first line is only from 3 years ago. So we don't have any experience about what happened in the second line. We only have this second line -- it's combining chemo plus/minus cetuximab. And we can see in the second line -- now we can see new response rates that range from 20% to 50%, possibly due to chemo. But with this median progression-free or survival that is extended from 3 to 8 months, but we have increased the median overall survival, but about a 9 to 13 months. That is only in retrospective area. And here is one of my experience presented ESMO last year, and we can see that exactly we have -- exactly the same in second line after immuno checkpoint inhibitors in the first line. Our results are similar of those retrospective series, but we can see that those patients who are PD-L1 positive have an overall response rate higher [ 70% ] instead of -- 17% of those patients were PD-L1 negative. And the median progression-free survival is clearly different in those patients who were PD-L1 negative. So we think that possibly, if we can have a patient with a PD-L1 that better responds to the next generation to the second line chemo or chemo plus cetuximab. I think that is my last slide. Manel?

Okay. Thank you very much, Ricard. Really interesting and fascinating data. In fact, that's where we are and that's where we were when we started this trial. So basically, with this scenario, when we started our program with VCN-01 in collaboration with Ricard Mesia, we've basically aim to target that population of patients that are refractory to the first line of immune checkpoint inhibitors and needs to receive a second line of treatment. And that's basically the idea of the this trial. So basically, it's a Phase I trial aimed to evaluate the safety, the tolerability and efficacy of the combination of VCN-01 plus an immune checkpoint inhibitor called durvalumab, that is basically an anti-PD-L1 antibody, in patients refractory to immune checkpoint inhibitor that has already received immune checkpoint inhibitor, and has progressed to immune checkpoint inhibitor. In this trial, we tested 2 different arms -- arm when we concomitantly, the virus, VCN-01 plus durvalumab the same day, or that's an arm concomitant, where -- when -- also, we have a second arm, called the sequential arm with those first VCN-01 and 15 days later, we started treating with durvalumab. Basically, because we think that in that way, we let the virus to act during some days before starting with durvalumab. And one of the interesting things of this trial is that we can get the serial biopsies of these patients as in that population, the tumor is more accessible. It's possible to get a biopsy at the screening, also biopsy at Day 8 after administration of our product and also biopsy at Day 28, that allows to get a client of serial evaluation of what's going on in biological terms into the tumor, okay? And that's the trial demographics. We have treated 6 patients in the concomitant arm, all of them at a low dose at 3.3×10^12 dose. And in the sequential arm, we have conducted 2 dose levels, 3.3×10^12 and 1×10^13, because this dose was fully acceptable in that regimen. In the same way, that's the same dose that we are using in our pancreatic trial. The demographics are quite well balanced between both Arms as you can see the ECOG level, it's basically -- it's comparable. The proportion of patients with toxic habit is the same, that is distribution of an anatomical site of the tumor that in that type of tumors it's relevant because there's different relevant obligations that are let's say, different from an anatomical point of view. And also, what's important that the percentage of patients HPV positive, which is a prognosis factor also in head and neck, were well balanced between arms. Also, all of them have received Immune checkpoint inhibitors. Some of them PD-L1 therapy. So PD-L1 antibodies and TNM, so the classification of the state of the tumor at the end of the trial was also well balanced. In terms of -- what we have seen in terms of toxicity, the toxicity was quite reminiscent of what we have seen in our pancreatic trial. So basically, we have seen that the most common adverse event is pyrexia and like symptomatology that includes also asthenia, some fever, but that's normally during the 24 hours after administration that results spontaneously, and some patients has observed increase of transaminitis, but not the hepatic enzymes that are called transaminitis that basically increased by Day 3, and in the sequential arm, as we have observed in the pancreatic trial, they reduced spontaneously. They result spontaneously 2, 3, 4 days later without any need of a subsequent treatment. However, in the concomitant arm, what we have seen is that increase in transaminitis, it's also associated with what is called an [indiscernible] transaminitis that it's a more severe form of transaminitis. And that's why we decided not to increase to the highest level in the concomitant arm. However, basically speaking, it's well tolerated and no major concern of [indiscernible] toxicity. You can see here that we don't have major impact on the renal functions that Dr. Mesia have commented previously or even in the bone marrow is not especially affected in that toxicity profile. What we have presented basically here this year is our data on survival. In this trial, we have evaluated the 3 main efficacy parameters in oncology that is the response rate, the PFS or the progression-free survival and also the overall survival of patients. In terms of the response, we have not -- we have seen very anecdotical response in one patient we have seen a response, but that's not probably the more remarkable thing. In terms of PFS, most patients progress, not very short after administration. However, when you look specifically in the overall survival of those patients, that, as indicated by Ricard, are expected to be in the range of 6 to 8 months, let's say. We see that the overall survival after the trial, specifically in the sequential arm, that is also the most tolerable arm, it's interestingly increased it. So we have seen in the sequential low arm, 15 months. But when we increased the dose, this survival ranks to 17 months that it's quite surprising because for a population that has received a lot of previous lines of treatment. In fact, most of those patients have received multiple lines of treatment. They have received Immune checkpoint inhibitors in the first, the second and the third line. But in fact, when they enter in our trial, they have been treated with previous lines, and the mean of previous line of treatment is 5. So when the patients are really going into our trial, what we are treating is a patient of highly resistant patients that have received a lot of treatment, and you don't expect a major response. So this long-term survival, it's really intriguing, and it's also in line what we have seen in the pancreatic trial. But if you remember our data in pancreatic trial in Phase I, we have seen also an extended survival of all the patients. And in our scientist teams that, that is new because as the product is also inducing a potent immune response by the effect of the replication of the virus, but it's also favoring the entry of different entities, so that any new line of treatment that the patient received after our trial, probably, is really expanding the survival of patients, and that's why probably this patient has a longer survival. So with that hypothesis in our head, what we analyzed here is basically what is the response to subsequent lines of the treatment after our trial? You can see here that, that's the data that we have -- I showed you in a previous slide. In our trial, the response rate is not very high. We have seen one response in the sequential low dose. But what is basically impacted is the median overall survival. But when you look, what happens when these patients receive basically what is a kind of palate therapy or products that -- that -- they are probably previously administered to the patient because they don't have more therapeutic options here. The patients, a significant number of them, respond to the treatment. And you can see here how the response rate in the first line and even in the second line is quite remarkable. And especially in the sequential high dose, we have patients with a complete response -- with a complete response after being treated with 5 lines of treatment, and after receiving just what could be Paclitaxel or Palitoetuximab, was this is the standard, non very sophisticated lines of treatment that patients have received previously in the previous lines of treatment, and they have a resulted to be refractory, at least progress into that line. So that again talks about how the virus is not just acting by itself, but it's helping the actions of enabling the action of the different chemotherapy drugs that the patients are receiving, and right now, in that context, probably are much more effective than there was in the past. Obviously, that's an intriguing possibility, and we are trying to think why. Why we can see that? Why that -- what biological data can explain that is happening? Obviously, the most obvious analysis here is going for the immunological environmental of the tumor. Are really the virus changing the immunological environment? And as you know, the immunological environment is quite complex in tumors. Basically, there's different components. We focus it basically on the analysis of probably of the 2 main markers of immune sectors. Also, there's plenty of different immunological markers. And here at ESMO, they have described a lot of them. But probably, as said by Dr. Mesia, in the [indiscernible] head and neck, probably the most relevant, at least up to date, it's status PD-L1. So as you have seen, Dr. Mesia has explained that the first line of patients in head and neck -- in recurrent and metastatic head and neck is decided based on the levels of PD-L1. So the patients with lower PD-L1 or lower than 1 that is considered the threshold, are patients that don't respond too much to the treatment or at least their survival parameters short. So that -- our hypothesis here is if this is true, if our product is really enhancing the survival of patients, it's our product also impacting in the PD-L1 scoring. So it's really increasing the number of PDL positive cell. So -- and that's the data that we have obtained in analyzing the biopsies of our trial in a sequential way. And we have seen that at Day 8, 73% of the patients has increased the CPV -- the PD-L1 staining. So the CP score has increased. And at Day 28, even more patients are still more positive for PD-L1. And that also correlates with -- so it means that the change in the big marker. But obviously, the obvious thing is, it's really then the immune system going into the inner part of the tumor, and for time to solve that question, we also analyzed CD8. CD8, it's a very specific type of immuno population. It's a type of lymphocytes that are characterized by cytolytic properties. The CD8-positive lymphocytes are cytolytic cells that can really kill tumor cells. And you can see here that after administration of our product at Day 8 and Day 28, we see a significant increase in the infiltration by CD8-positive lymphocytes. And you can see here that changes are statistically significant. So when we compare at the screening versus at Day 8 or Day 28, there's a significant increase in the CD8 -- in the CPS score, sorry, in the majority of patients. And you can see here, patient-by-patient, hope the majority of patients are increasing. In green are all the patients that are increasing the CPS score. In black, the patients that are decreasing. And you can see also that, that also correlates with an increase in the infiltration by CD8 positive lymphocyte, which means that really the treatment, it's really enhancing the infiltration. It's really changing the environment. And probably, we are trying we are shifting the tumors from a CPS score quite low, to at least a higher CPS score, and that is eventually explaining why patients are surviving longer. What are -- the question is let's try to identify what is what parts of the treatment -- the VCN-01 of the durvalumab impacting in the increase of CPS score. So that's why we focused our analysis in those samples obtained before treatment with durvalumab that samples at day 8. If you remember, when I explained the design of the trial in the sequential arm, patients received VCN-01 first, and they started receiving durvalumab 15 days later. So the biopsy at Day 8 is the biopsy free of durvalumab, and can give us information if it's the virus alone able to change the CPS score. And that's what we analyzed in that study, and we have seen that a significant number of patients, before receiving durvalumab, they have shifted to an increase at CPS score. And you can see here, a very clear example and a patient in oral cavity that after systemic administration of our product, you can see here how we see a much broader staining. That's a technique called immunohistochemistry that basically the tax expression of a marker in that case, CPL 1, and that gives a brown color. And you can see here that the higher magnification, you can see a significant number of the tumor is sustained by PD-L1, which explains why CPS score is increasing. So the question is, okay, it looks like there's a potential mechanism explaining that increase of survival, at least that's the hypothesis, but it's really true. So what we did next, it was try to analyze from a statistical point of view, if there's a real correlation between the levels that CPS score and the survival of patients. Because it's really that change of CPS score, what it's really driving the increase on survival. And when we analyzed that correlation, we found that the answer is yes. And you can see here how if you -- if we try to correlate the CPS score with the overall survival, there is no correlation. And you can say, but you have said that, that before, that you are selecting patients and probably the patients with higher CPS score has longer survival, that's true. But you have to take into account that, that screening period is when patients has done several lines of treatment. So at that stage, probably we cannot conclude that really there's any corporation between CPS at the entry of the trial with survival. And that's why we don't see any correlation between the survival of patients and the CPS score that they have before going into the trial. However, after treatment with VCN-01, we see a significant shift in the CPS score. As you can see here, there's much more patients with higher CPS score and especially in that scenario, there's a positive statistical correlation between CPS score and overall. So really, those patients that have major changes on the CPS score, increase in the PD-L1 expression and increase in infiltration, are those patients that are surviving longer. So that's basically the data that we have presented at ASCO last week. Sorry, yesterday. And I think that, that's intriguing data. But maybe, Ricard, you can comment a bit based on myself that this data in the context of the current stage of head and neck.

Yes. So medical oncology is a point of view. Our unmet needs for our patients with recurrent/metastatic disease is now to improve the rate of long-term survival. As in long-term survival is for only 15%, 20% of our patients. We want to increase this figure very rapid. We need to increase it. But we need also to reduce the toxicity of the QoL treatments. And I think the toxicity of the combination of virus plus immune checkpoint inhibitors as lesser than those we have seen with chemo plus immune checkpoint inhibitors. So we can increase the quality of life by reducing this toxicity, but also to achieve adding special response, and we need to define the best sequence of treatment for recurrent/metastatic disease, because as you have seen, we have only treatment for the first-line recurrent/metastatic disease. And the most impressive for us after this clinical trial is to compare with the literature, what happened in those patients who received any line after immune checkpoint inhibitors. We have seen this median overall survival between 9 to 13 months. Now in our -- in same patients at the same moment, after the progression of the immune checkpoint inhibitors, is in our sales prospective area because it's a Phase I trial, we achieved this median overall survival from 22 to 24 months. For us, that is impressive. We have never seen it before. And I think this extends our median survival support, we continue to invest in this investigation in order to improve this long-term survival.

Some questions from my side, Ricard. Here -- I think that the data on survival, it's really intriguing at least, obviously, that's a Phase I trial. We have just a reduced number of patients, and we should take the conclusions a bit carefully. And -- but that's a question from my side. To what extent do you see that this long survival correlates or not with responses. Because that the correlation between overall survival and responses is the kind of debating thing in the field of oncology. What's your feeling? We need to see also response to really confirm the overall survival now?

Just before I see -- before we immune checkpoint inhibitors, we correlate always response rate with prolonging extension of overall survival. But not now. With the clinical trial with immune checkpoint inhibitors, the response rate is less than 15%. And despite this less than 15%, we have an extension in median overall survival in all the trials using immune checkpoint inhibitors alone. So it seems that the correlation depends on the type of the treatment, chemotherapy. But immune checkpoint inhibitors, we have an extension near overall survival despite the response we have as if -- because some of these patients, including this trial, there were response with immune checkpoint inhibitors were progressing.

Yes. That -- I think that's a relevant question, because even from a regulatory point of view, I think that regulatory authorities has been very consistently recommending always to use overall survival as an approval endpoint. Response has been a kind of never been part of the approval process, also can support other endpoints could be PFS. But I think that this kind of relevance to overall survival makes, again, very bold that really the impact of survival of patients is probably the more relevant thing. Because, in fact, also linking with your request for more quality of life of patients, probably that's -- obviously that's something relevant in those patients.

And that's something we can have with this combination, because we avoid chemotherapy by using the combination of [ virus ] plus immune checkpoint inhibitors. We only have a few thin toxicity Immune-related toxicity that is about 15%. And now this 15% is exactly the same recognition of virus plus immune checkpoint inhibitors are these the same that immune checkpoint inhibitors alone. No, I think we don't increase the severity of toxicity of our patient.

And compared to what you are used to see in different treatments, what's your feeling about the toxicity of VCN-01? Do you think that, that's something that it can, in some way, be worrying for the clinical community when treating patients?

With the virus, we only have 2 days toxicity. 2 days after the infusion, we have an elevation of transamination of the hepatic enzymes that is a symptomatic for the patient. Despite it could achieve rate 2 or 3 is totally asymptomatic. And the other is a flu-like symptom that lasted only 1, 2 days at least, very [indiscernible] was antibiotics pain drugs, okay?

Okay, so that's really, really interesting. So I think that my feeling is that, obviously, with this data that I think that in terms of -- even from a toxicity point of view, but also from efficacy, looks promising. Because that's something that has not a subscriber that Dr. Mesia has not been -- he's not very usual to be seen. It makes all the sense of the world going for further development in a Phase II trial, et cetera. And I have discussing with Dr. Mesia, some ideas about who could be the eventual further development of VCN-01 in the current landscape. And if you remember, in the current landscape, basically, it's deciding if the patient received an anti-PD-1 antibody pembrolizumab or not, based on the CPS score. And if they receive first pembroizumab and later, chemotherapy or first, chemotherapy and later, pembrolizumab. But based on this data, obviously, that has been generated in not second line, let's say, fifth or sixth line of treatment for me, makes a lot of sense to try to move the development of VCN-01 to earlier stage of -- in the treatment of the disease. And probably moving to the first line of treatment, just trying to combine with the first line with pembrolizumab. What you're thinking here?

This is our aim. We want to move this team from the hypothesis. She's line to first line. We want to explore what happened using this combination -- combination of the virus with pembrolizumab in first line, because we are seeing these virus that act like a facilitator of any treatment we had at this moment or post argon. So we think we could improve even this survival if we introduce this virus at the beginning of the line of treatment.

That's interesting. How to do it? So in that situation, if we put our buyers in first line, we should include patients CPS higher than 1 and CPS higher than 2? Or you...

I think we can separate to try as one for patients higher than 1, and we compare against the standard. But I think we need to improve the survival of those patients who are CPS less than 1. And even in those patients -- if what we can turn this CPS negative to CPS positive, we can achieve any response with immune checkpoint inhibitors. So I think we need to separate both populations and explore what happened with this combination in both populations.

So probably what makes sense in my way, do a kind of trial and first line in recurrent/metastatic for patients receiving VCN-01 plus immune checkpoint inhibitors versus only immune checkpoint inhibitors, stratifying patients by CPS score. And in a single trial, you get all the development. I think that's our -- probably our ideas for older development in that product could be forward. But Mike, I think that right now, we can probably open that discussion to our audience and see if there's any additional questions that our [indiscernible].

Yes. Wonderful. And I know we have one question from one of the analysts. So Jim Malloy if he wants to go ahead and ask the question. Maybe not quite yet. Okay. Apologies. I thought he did have a question. So not a problem. Now let's pivot to another one of the questions. So maybe just talk a little bit about -- given the data that we have that's been presented at ESMO, Dr. Mesia, what kind of is the potential for VCN-01 in combo with a checkpoint inhibitor to move perhaps upwards in the treatment paradigm for these patients. Thoughts there?

[indiscernible] disease?

Yes.

Probably yes, but I think we need to explore before in the first-line recurrent/metastatic disease. Because now we have different type of treatments that we can sequence after this treatment, and we can have a lot of information using in different line, because we have first line, second line, third line, fourth line. And here, we kind of summarize a lot of information in order then to translate to the recurrent/metastatic disease, of course, and we can include -- use this virus in the new advanced [indiscernible] before the local treatment with radiotherapy or surgery, in combination with immuno [indiscernible]. Because there are a lot of clinical trials now in this setting -- new advance setting to reduce the disease just before a local treatment.

Got it. And Dr. Mesia, give the audience an idea of kind of the FE, the market size, these types of things, in particular for the investors. I mean, how large is that patient population that patients with recurrent/metastatic head and neck cancer?

In size?

Yes.

It's -- well, it depends on if they are HPV negative or HPV positive. Usually patients with HPV negative that is related with tobacco and alcohol, they have high tumor burden. In these patients, the majority of them need for a combination of chemo from the beginning, because we cannot use immune checkpoint inhibitors alone, because they have a risk to have any special complication and death, but very fast. And the amount of the disease in HPV positive is clearly less and they progressed slowly. For example, 50 of our patients are at risk of having problems with breathe, because the larynx is just here to [indiscernible] because bleeding because the current arteria is just in the neck. The neck is a very narrow structure and any special movement in only millimeters of the borrowings of the tumor could provoke a fatal death. Even problem with as well because we have the esophagus just inside. In only 5, 6, 7 centimeters, we have all these special structures that are very sensitive to any growing of the tumor. So despite the tumor is only 3, 4, 5 centimeters, we'll have a lot of complication, because if the tumor is growing 2, 3 millimeter. That's the reason because we need responses.

Understood. No, that's wonderful. One of the questions and looking at the data and the poster that was presented at ESMO, perhaps maybe this is a question for you as well, Manel. I mean, would you recommend, would you suggest testing kind of a higher viral particle dose, given the data that you've seen?

So I would say not. I think the trial was the signs dose escalation trial, okay? And it's sure that we have not identified a dose in type in ranking toxicity in the sequential arm. So eventually, we could increase the dose of virus in the first dose. However, first, that could be kind of limiting from a manufacturing point of view. But for me, what makes much more sense, it's probably start re-dosing patients. And that's a very interesting discussion. As some of you could know in our pancreatic trial, we are already starting to test the re-dosing of our product. Because with that long survival, the data that we have presented here is basically obtained with a single dose of VCN-01. A single dose that patients received on Day 1, and that's all. And later, the patient is treated with standard treatments and he likes for several months. So -- could make much more sense to reduce the product maybe after 3 months, et cetera. In our pancreatic trial, we are right now testing if re-dosing at 3 months makes sense. And if that is true, then we can extend to redose at several points. And one interesting thing for testing that hypothesis is that because in clinical pharmacology, it's not always easy to know if a second dose works or not works. Because it's a standard thing that everybody is doing with DUCs, as long as toxicity is not affected. However, in our specific case, as you remember, our product, it's a product that contains a [indiscernible] that, obviously, it's modifying thematics, but can also be used as a self-reporting cargo in a way that when the virus replicate and produces [ yellow rebase ], part of this [ yellow rebase ] is secreted to the bloodstream. And the detection is the bloodstream. It's a kind of surrogate marker of what's happening in the tumor, if the virus is really replicating in the tumor or not. So we can use that biomarker, but also the levels of viral genomes in block is a [indiscernible] marker if the virus is replicating, because we know that if the virus is not replicating, the clearance is quite fast. So in our Phase I trial right now, we are collecting data from all the patients that have received a second dose. And we have analyzing in the sera and a lot of those patients if there's a second peak of PH20, a second peak of viral genomes in blood. And if that's the case, that's something that we are testing right now. But if that's the case, that opens the door for the re-administration of the product. That could be very interesting in those patients that in the long term, you -- after some period, you can redose and then you even order extend the survival of patients.

No, super helpful, Manel. Dr. Mesia, anything to add there?

Well, I have received a lot of questions about these resequences of the virus. Many medical oncologists want to know if we can repeat these dose in order to extend more this effect of the virus. And even if we can do it at any line of treatment in order to extend. But in order to facilitate the response to the next lines of treatment that we have done to our patient.

I can just put a question for you from the business point of view, how large is the market of head and neck? How many patients are using normally in head and neck? Normally -- I don't know. Do you have an idea?

For example, in Spain with 48 million people, which have 12,000 patients every year. That is the relation.

And who ranks in terms of incidents?

In many instances, in women it's the 6th. So it's 5th, 6th depending on, but the 5th or 6th run in of all cancers. It's quite common, quite common. And is related to tobacco and related to HPV, and now HPV-related tumors are growing very fast.

Yes. No. And certainly, that's unfortunate. One of the questions from the audience is more surrounding kind of pricing and market access considerations. And look, I know it's a little bit, perhaps early to be thinking about a lot of these things, but the cost -- sorry, the question is are the cost of the new technology within the possibility of the patients and their insurance companies? So perhaps reframing it a bit different, Dr. Mesia. For these patients with head and neck cancer, look, polypharmacy is something that is very common within the oncology space. Are the vast majority of these patients in head and neck, are they on multiple therapies? Or kind of what does that treatment regimen look like?

They have a lot of drugs during all the disease, because they need to control different symptoms they have during the disease. But according to the number of lines of treatment, we have changed just from 2 years ago. Before, we only have 1 line or 2 lines of treatment, no more. Now we have more lines of treatment, just because in immune checkpoint inhibitors have been introduced in our parameter of treatment in our we bonds.

Yes. No, exactly. I know that's something that is obviously a very commonplace across a lot of different tumor types and something that the insurance companies, the payer organizations are very familiar with. So with that, Manel, that was the last question that we have. So maybe what I'll do is turn it over to you for some closing comments.

Okay. Perfect. Thank you very much. So thank you, everybody, for hearing us. And I think that the data we have presented here, as you can hear from the [indiscernible], et cetera, has generated certain interest for people, because that's something that is not usual to extend right now, the life of patients in that way, especially in a population that it's practically in the -- assume it to be in the last line of treatment. So that's something that I think that demonstrate, again, how VCN-01 behaves different than other products. And in first, obviously, in the [indiscernible] with respect to the current standard of care for head and neck, also for pancreatic, however, it introduces a new mechanism can be -- can impact not only in the tumor sites, but also enabling the access to and enhancing the action of any subsequent treatment, which is, I think it's relevant. That's something that we have seen in head and neck, but also in pancreatic cancer, where we have seen an enhancement of the action of gemcitabine. But these mechanism of action, it's a different mechanism of action, but also comparing in the field of oncolytic viruses, the oncotic viruses have generated a lot of waves of interest, hype and -- but I think that our product, it's really a new generation of products that really demonstrating something that not has been demonstrated in the clinic with patients previously. That is basically due to the unique characteristics of the product, the fact that can be systemically delivered, that it's really, really safe, and that allows those at very high doses, it means that really you get the virus into the tumor in an effective way and you can really modify the tumor, and also this ability of the product to really change the market. So we are fully convinced that VCN-01 is really a changer in different diseases. It is in head and neck. We think that could be in pancreatic, and that's why we are just putting all our efforts to move ahead our pancreatic program as soon as possible. But also in other more minority diseases that could be, for instance, retinoblastoma. As you know, we have also an active program in retinoblastoma, where we are just treating patients -- pediatric patients that are really in a situation that can lose the visual capacity, and I think that all that makes us really comfortable that all these clinical evidence that we are getting in the different programs, over in a general idea that VCN is really a different product that can really provide new mechanism of action in the benefit of patients. Thank you very much. And I hope that, that's been helpful for you. Obviously, all our team in our company is more than happy that we see more questions if you know or obviously, you can approach us as well as when [indiscernible] indicated for you. Thank you very much to everybody for joining this meeting.

Thank you, everyone. Thank you.