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

Good day, everyone. I'm Dan Od-Cohen from LifeSci Advisors. Thank you for joining us for Theriva Biologics online event to discuss the top line results of the Phase II VIRAGE trial in pancreatic ductal adenocarcinoma or PDAC. Just a few housekeeping items before we get started. [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 would also ask you to review the full text of the forward-looking statements also available for reference on this morning's press release. As this call could include projections, actual results could differ materially due to several factors, including those outlined in Theriva's latest filings with the SEC. Joining us today to provide context on the PDAC landscape and review the relevance of the VIRAGE clinical data, we are honored to have 2 preeminent clinicians and researchers Manuel Hidalgo Medina, MD PhD, Chief of Hematology and Medical Oncology at Weill Cornell Medical College and attending physician New York Presbyterian Hospital; and Mike Pishvaian, MD PhD, Associate Professor of Oncology and Director of Gastrointestinal Developmental Therapeutics and clinical research programs for the Johns Hopkins Kimmel Cancer Center and Associate Professor at the School of Medicine. I'll now take you through our full agenda for today. Steven Shallcross, Theriva Biologics' Chief Executive and Financial Officer, will provide an introduction to Theriva and its innovative lead asset, VCN-01. Dr. Hidalgo and Pishvaian will comment on the current PDAC treatment landscape. Manel Cascalló, PhD, General Director of Theriva's EU operations will review the top line results from the VIRAGE Phase II trial. And Dr. Hidalgo and Pishvaian will then be available for a live Q&A session along with Theriva Bio management. [Operator Instructions] And with that, I'll turn it over to Theriva's CEO and CFO, Steve Shallcross. Over to you, Steve.

Thanks, Dan, and thanks to everyone for joining us on the call today. We're very excited to welcome our guest speakers, both renowned clinicians and researchers in pancreatic oncology. Today, we're thrilled to present and review the top line data from the VIRAGE Phase II clinical trial, evaluating our oncolytic virus VCN-01 in combination with gemcitabine and nab-paclitaxel, as a potential first-line treatment for metastatic pancreatic ductal adenocarcinoma or PDAC. First, I'd like to take a few minutes to introduce Theriva to anyone new to our story. Theriva is a publicly traded company on the NYC American market, headquartered in Rockville, Maryland with the facility in Barcelona, Spain. At Theriva, we're developing unique oncolytic virus therapeutics to target solid tumors. VCN-01, our lead oncolytic virus just completed the Phase II VIRAGE trial in PDAC but was also tested in Phase I trials in additional indications such as colorectal cancer, head and neck squamous cell carcinoma and retinoblastoma alone and in combination with various cancer therapies like checkpoint inhibitors and cell therapies. We're also leveraging our founders' decades of oncolytic virus experience to advance VCN-X, a discovery engine that enables us to develop a distinct pipeline of oncolytic virus products with alternative mechanisms of killing -- cell killing and potential use as single-agent therapies. Our overall pipeline shown here can be reviewed in more detail on the presentation material submitted with our 8-K. Today's focus, however, is our Phase II clinical trial with our lead product, VCN-01. Our lead product candidate, VCN-01, is our unique stroma-degrading human adenovirus engineered for systemic delivery in very highly selective replication in cancer cells, resulting in cancer cell destruction. The multifaceted antitumor activity of VCN-01 is highlighted in the following animation. VCN-01 is administered systemically, meaning that it targets both primary and metastatic lesions. VCN-01 is selective, replicating only in tumors. It's stroma-degrading expressing the hyaluronic acid degrading enzyme PH20 that the grades the matrix exposing a solid tumor to the immune system in any co-administered therapies. And VCN-01 is immunogenic, turning cold tumors hot and eliciting an extended antitumor immune response. We've seen a lot of success in the clinic thus far with VCN-01, with 142 patients treated to date across several trials in multiple different indications and combinations that speak to the potential we see for broad application of VCN-01 in cancer treatment. Our focus today is on top line data set from the recently successful VIRAGE Phase IIb trial in PDAC. I'm really pleased now to introduce our guest speakers, Dr. Manuel Hidalgo and Dr. Mike Pishvaian, who will discuss the current treatment landscape in pancreatic cancer. Dr. Hidalgo.

Good morning, everyone, and thank you for the invitation to join this meeting this morning. And the next few minutes, I will be walking you through the standard of care and the landscape of management of patients with pancreatic cancer today. In this slide, at the top, you see the staging and the frequency of these different stages at presentation. We divide this disease in 4 main groups: resectable, borderline resectable, locally advanced and metastatic recurring and resectable. For patients who have early disease, and this is defined as resectable or borderline resectable, the goal of management is surgery. And we do that by either upfront surgery followed by chemotherapy or by chemotherapy followed by surgery in a neoadjuvant mode. And this -- the selection of these 2 sequences depends on the stage of the cancer. Resectable disease, usually surgery followed by chemo, borderline, we tend to utilize chemo and followed by surgery. And we applied often radiation therapy as well, particularly for patients who have positive margins. On the right side of the slide, you have locally advanced and metastatic recurring disease. These are patients who present with more advanced disease. And unfortunately, as we speak today, they are not curable. For locally advanced disease, the standard of care consists of chemotherapy plus chemo and radiation. And the outcome of these patients, as I said, is they are not curable. We try to reduce the size of the tumor to permit surgery, but this rarely, rarely happens. The majority of patients present with metastatic disease and the management of these patients is mainly chemotherapy. There is a small subset of patients in which doing sequencing and genomic testing, we identified what we call targetable alterations. BRCA1, BRCA2, MSI tumor, RAS12C mutations, those can benefit from more targeted approaches. But the majority of the patients, 90%, don't have any of those alterations. For those, standard of care is chemotherapy. In the first-line setting, we have 2 regimens gemcitabine/nab-paclitaxel, which has been the backbone to which VCN-01 has been added and FOLFIRINOX or NALIRIFOX, the selection of these 2 regimens is made basically on clinical criteria for patients who are very fit, young with good -- very good performance status, we tend to prefer FOLFIRINOX or NALIRIFOX. If the performance status is a little bit reduced of all the patients, we tend to prefer gemcitabine/nab-paclitaxel. The progression-free survival with these regimens is not more than 5 to 7 months or 8 months at the best, and then the patients go to receive second-line chemotherapy, which essentially you use whatever you didn't use in the first line. So 5-FU containing regimens will be followed by the gemcitabine containing regimens, gemcitabine containing regimens will be followed by 5-Fluorouracil-containing regimens. And this summarizes the landscape. Now I'm going to ask Mike if he wants to add any additional comments to this slide.

Thank you, Manuel, and thank you for allowing me to be part of this presentation. I think that this landscape really does lay out well how we manage our patients with pancreatic cancer. And I would emphasize that probably the more important thing than necessarily deciding which regimen to use in the frontline is making sure that we expose the patients to either -- to all of these therapies in the first or second line, and we know that patients who get exposed to gem/nab-pac and FOLFIRINOX, irrespective of the sequence, are those that have the best outcome. But we also know that about 50% of patients actually never get to second-line therapy. And the only other thing I would mention in this landscape is that we are going to see a significant shift in the landscape if and when the KRAS inhibitors become approved, the pan-KRAS inhibitors or the subtype-specific inhibitors. So we'll have to wait and see when that data comes out, but this is definitely the current landscape.

Thank you, Mike. So we -- I pass this now to Manel.

Okay. Thank you, Mike and Manuel, for your landscape, very useful. And I think it's important to have that in hand to really understand where our development of VCN-01 in pancreatic cancer states. Basically -- sorry, pancreatic cancer, as indicated by our experts, it's highly fatal cancer. But from a biological point of view, it's a tumor that is characterized by a very dense tumor stroma. And this stroma is important because it has an impact on how the tumor cells are reacting to chemotherapy. This stroma protects tumor cells and that impairs that accessibility of most chemotherapy. These metrics, this stroma is basically constituted for several companies, but hyaluronic acid is one of the most adjuvant components of this stroma. And it's also associated with reduced treatment efficacy and poor prognosis. As Steve has already presented you, VCN-01 is onolytic virus that express hyaluronic acid and degrade these metrics. And that's why from the very beginning, pancreatic cancer was the most suitable indication for VCN-01 and for its development. We started VCN-01 development with a Phase I trial that we conducted using different regimens, and this Phase I program allowed us to learn a lot of things that later we take advantage to design our Phase II program. Basically, we learned what's the most adequate regimen for dosing VCN-01 with chemotherapy. In this trial, we tested different regimens, testing the product in combination at the same time or with a sequential approach, and we learned that the sequential approach was by far the most safe and also the most efficacious pathway, basically because if we dose VCN-01 1 week before starting chemotherapy, we allow the virus to modify the metrics from the very beginning. So when we start chemotherapy, the first dose of chemotherapy is much more effective. So in this trial, we have seen that the sequential regimen results in a survival and response rates were much better than what was published in the literature with our combinations with gem/nab-paclitaxel. We also obviously characterized the safety profile of AEs, which was fever, flu-like and reversible and transient increase in liver enzymes. But from our side, what's extremely important is this trial where we could get biopsies from all patients give us a lot of information about the clinical evidence of the proposed mechanism of action of the product. In fact, we have seen in this -- in the biopsies of the patients in the Phase I program that VCN-01 systemically delivered, it's able to reach the tumor to arrive to any metastases in the body, in the liver metastases, in the pancreatic or other metastases, it's able to replicate and we see persistent presence of viral genomes in the blood of the patients. And also, we have seen systemic PH20 also persistent, which is a marker of the active replication of the virus. Additionally, we have also seen analyzing the biopsies of -- tumor biopsies of the patients, a significant increase in different immunomarkers that basically talks about the ability of VCN-01 to enhance accessibilities to CD8 lymphocytes and other molecules to the tumor mass. So with all these data, we decided to move to our Phase IIb program that is the data that we are going to present today. This VIRAGE trial, it's a multicenter open-label randomized controlled trial that has been conducted in newly diagnosed metastatic pancreatic ductal adenocarcinoma patients as a first-line therapy, okay? The trial was a randomized trial. You can see in the bottom of this slide, basically the scheme of the randomization of this trial. In arm 1, patients received the standard therapy with gem/Abraxane, which is cycles of 28 days where gem/Abraxane is administered on day 1, 8 and 15, and there's 1 week off. And that's the classical standard of care treatment for gem/Abraxane. In the control group, the arm 2 -- sorry, in the treatment group, arm 2, that patient received in addition to the chemotherapy, 1 dose of VCN-01 before -- 1 week before the first dose of chemotherapy in cycle 1, as we have conducted in our Phase I program, but we also tested a second dose of VCN-01 that was administered to patients 1 week before starting the cycle # 4 of gem/Abraxane. In that way, our idea was to see if the second dose is effective and can enhance the antitumor effect of the product. And that's one of the aims of our trial. The primary endpoint of this study was overall survival that it's the endpoint that regulatory authorities consider as an approvable endpoint. But we also included the safety profile of the second dose as part of the primary endpoint. But we also include a number of secondary endpoints, including progression-free survival, duration of response and other markers of response that are quite usual. This is the table of enrollment of the patients. The patients are enrolled basically in sites in U.S. -- 7 sites in U.S. and 10 sites in Spain. We have recruited more than 170 patients from those 112 has been randomized. The main reasons for screen failure, it's basically some patients that are not able to fulfill some of the lab parameters that we need for the patients that are very standard for clinical trials and also for some patients who were unwilling to comply with the study treatment. From these 112 patients that were randomized in the treatment -- in the study, sorry, just 96 of them received 1 dose of chemotherapy in the control arm or 1 dose of chemotherapy plus 1 dose of VCN-01 in the treatment group. That's what we define as the full analysis set of the trial, 96 patients, 48 in arm 1, 48 in arm 2. Next slide shows you the demographics of the patients treated in this study. As you can see here in the column for standard of care and the column for VCN-01 plus standard of care, the groups are well balanced in terms of age, in terms of gender, in terms of ECOG and BMI, body mass index. So the analysis could be sound because there's no major differences. But it's interesting to highlight here, taking the note of Dr. Hidalgo about what's the best regimen for patients that the demographics of this population highlights very clearly that we are treating patients that are relatively old in the range of 66 to 68 years old, which is relatively high. And with an ECOG, a percentage of patients with ECOG 1 that it's more than 60%, which is relatively high compared to other trials. And this is, in my view, relevant because these 2 parameters, the age and the ECOG put us what type of patients are we treating. And I think that it's the picture from a real-world trial in the sense that I -- my perception is that, that responds to the majority of patients in the clinic. That's something that we can discuss later in the Q&A session. Let's move first to the primary endpoint of the trial associated to safety. This slide summarize the related events associated -- observed in more than 5% of the patients. The profile that we described here, it's very reminiscent to the profile that we have seen in our Phase I program. Basically, the most frequent adverse events are pyrexia, nausea, [indiscernible] vomiting, which is basically under the flu-like symptomatology profile, and that's basically in a percentage very similar to what we have seen in our Phase I program. And we have also seen, again, some patients with an increase of hepatic enzymes, AST, ALP. But again, for the majority of patients, those increases are transient and reversible. These adverse events are very -- last very few days. In fact, flu-like symptomatology normally lasts for 2, 3 days maximum and transaminase increase normally appears by day 3 and normally by day 7 is restored. And without the need for treating patients with any medication, steroids, et cetera, because it's not defined as an immunomediated increase of transaminases. So -- which is exactly the same that we have been in our Phase I program. So overall, it's very reminiscent what we have seen in our Phase I program. And in this slide, we have tried to also separate the adverse events associated to the first dose and also to the second dose because that was one of the new things in our -- in this protocol where we tested the second dose. And if you look at the column for the second dose, you can see that the events that we observed in patients are basically the same, pyrexia, nausea and enzyme increase after the second dose. However, the percentage of incidents is slightly lower after the second dose. And more importantly, the severity of the adverse events are lower also. In fact, for the second dose, we have not practically seen any -- just very few adverse events that could be graded at Grade 3 or Grade 4, we have not seen any of them. So what looks like here is that the second dose looks less toxic than the first dose. This is -- there's some reasons for that, but what we speculate here is that the organism of the patients get used to the virus. In fact, the first dose activates the immune system of the patient. However, as soon as the immune system realized that the virus is not actively replicating in normal cells, the immune system, it's down. And what happens after the second dose is probably the second dose is not detected so as a danger signal as [indiscernible] as the first dose, which probably it's what you expect in that situation. In any case, this safety data has been reviewed twice by an independent data monitoring committee constituted by Dr. Erkut Borazanci from HonorHealth Research Institute and also by Dr. Shubham Pant from MD Anderson and Dr. [ Klarin Durbin ] from the Erasmus Medical Center in the Netherlands. And basically, after the review of the complete safety data of the trial, they concluded that intravenous VCN-01 was well tolerated for all patients treated in the study. The most common VCN-01 adverse events were pyrexia, flu-like, vomiting, nausea and elevated transaminases were transient and reversible. Interestingly, also the AEs observed after the second dose were less frequent and of reduced grade compared to the events registered after the first dose. And the overall conclusion is that the type of the numbers of adverse events in the treatment group was expected for the pancreatic cancer population for the duration of the treatment and for the administration of an oncolytic virus. So no major concern from a safety point of view and reassuring that the safety profile is not a concern for administration of VCN-01. That was part of the primary endpoint. But obviously, we also started to analyze the different endpoints associated to efficacy. And the first endpoint that we analyzed is the progression-free survival of patients. I have to say here that the trial was powered with 80% power to detect differences in the endpoints about -- for one-sided alpha of 0.05 or 2-sided alphas of 0.1. And all the stats that are presented in this presentation are for the 2-sided p-values, okay? You can see here that in the Kaplan-Meier, there's separation between the curves. The curve for the treatment group demonstrate that the progression-free survival -- the median progression-free survival of patients is 7 months, whereas for the control group, the progression-free survival is 4.6 months. The number is statistically significant according to the [indiscernible] analysis and adjusted hazard ratio is 0.55, which is a number quite low. For all of you that are not familiarized with the concept of hazard ratio, basically, hazard ratio can be interpreted as a chance for an event occurring in the treatment arm divided by the change of the event occurring in the control arm. If you have 0.55, it means that if the probability in the control arm to have the event, in that case, to have a progression of the disease is one, the probability to have that event in the treatment group is 0.55. So you have a reduced chance to get the event. Lower is the hazard ratio, more pronounced is your effect. So the hazard ratio allows you to give another analysis of the Kaplan-Meier because obviously, the median is only a cutoff point in the core, but the hazard ratio represents in a single number, the magnitude of the distance between the Kaplan-Meier plots, and that's much more probably informative. So the data for PFS was positive. But importantly, we need to move to the primary endpoint of the study that was overall survival. Again, here, the plots for the Kaplan-Meier curves of the overall survival, you see again the differences between the curves with a bigger separation in the tails of the curves, okay? Specifically for survival, there's a number of patients around between 40% to 30% of the patients that survived for several months, 16, 17, even 18 months, et cetera. The median overall survival for the control group was 8.6. And for the treatment group, it was 10.8 months, which is 2.2 months of increase in the survival of patients. Again, the number was statistically significant according to the power of our study and that -- the adjusted hazard ratio for the primary endpoint was 0.57. So meaning that the primary endpoint of the trial was met. Interestingly, this separation between the curves that specifically in the tails of the curve, it's an interesting thing because it has to do basically what happens to the patients in the long term, but has also been observed in other therapies where other -- the immuno mechanism of action has been claimed. And that's why we were interested to analyze also the duration of the response, which is one of the characteristics of immunotherapies. And when you analyze the Kaplan-Meier for the duration of the response, the patients that are responding to the treatment, we see that the duration of the response for the control group was 5.4 months, whereas for the treatment group, we doubled the duration of the response to 11.2 months, which is clearly statistically significant with a hazard ratio very low of 0.22. So again, this talks about an interesting mechanism of action that maybe we can discuss a bit later. As I anticipated to you, this is the first trial where we tested the second dose of VCN-01. And for this reason, we were interested to analyze specifically what happens for that population of patients receiving effectively 2 doses that are the patients that arrived to the cycle 4. That's why we conducted a specific analysis for the population of patients that in the control group has arrived to the cycle 4 of treatment of gem/Abraxane. And for the treatment group, the patient that has arrived to cycle 4, it means that also received the second dose of VCN-01. We wanted to see if the overall survival and the PFS in those patients was different from the global population was higher, was lower because that could talk us about if the second dose has a role in the global efficacy that we are seeing in those population. You see here the demographics of this subgroup of population. This accounts for 60% to 70% of the patients in the trial who were in that situation. But if you look at the demographics for the control or versus the treatment group columns, you see that, again, is well balanced in terms of age, gender, ECOG or BMI. So the analysis could be sound because there's no any major divergence between the groups that could impair a proper analysis. The analysis of the progression-free survival curve in that population of patients receiving 2 doses of VCN-01 is as shown in this Kaplan-Meier. Basically, it's easy to see that the groups are more separated than we have seen in the global population. The progression for survival for the control group was 7.4 and for the treatment group, the PFS was 11.2. So we have much more than 3 months of enlargement on the PFS of the patients. And in that case, again, the number is statistically significant, and the adjusted hazard ratio is 0.48 which is lower than the 0.55 that we have seen in the global population, suggesting that the effect that we have seen in that group of patients is probably higher than the effect in the global population. The same trend was also observed in the overall survival analysis. And where you see here, again, a very good separation between the groups. And in that case, the median overall survival for the control group was 11.6 months versus 14.8 months for the treatment group, which, again, it's an enlargement of survival of more than 3 months. In that case, the increase -- the decrease in the hazard ratio was even more significant from 0.57 in the global population, we passed to 0.44 in that subgroup of population. And as you can see here, that's a result of the curves. And really, in that graph, we see a very, very clear separation in the groups, in the tails of the Kaplan-Meier plots. So really, it means that there's a relatively high number of those patients, more than 40%, that has really long survivals. So this is basically a summary of our data. I have to include here a summary slide basically. This trial is a trial that enrolled a real-world population, probably older and more fragile patients compared to other previous trials in pancreatic cancer, we have an acceptable adverse event profile that has -- is consistent with prior VCN-01 trials in pancreatic cancer, also in other indications. And we have seen increase in the overall survival in the PFS and the duration of the response of VCN-01 when combined with gemcitabine/nab-paclitaxel treatment group compared to the standard of care alone. And hazard ratios that we have got for overall survival, 0.57 for PFS, 0.55 or for duration of respond. 0.22 compared quite favorably to the value reported for other Phase III trials that has been previously reported. Obviously, there's not a lot of positive Phase III trials in pancreatic cancer. Probably the most sound comparison could be in the NALIRIFOX trial in the NAPOLI-3 trial comparing the NALIRIFOX regimen against [indiscernible]. In that specific trial, the hazard ratio for the overall survival was 0.83 that compares quite favorably to the 0.57 in our trial. For the PFS, the hazard ratio was 0.69, which compares against our 0.55. And also specifically for the duration of the response, the hazard ratio for the NAPOLI-3 trial was 0.67 that compares very well against with our 0.22. So in fact, we doubled the duration of the response, whereas in the NAPOLI-3 trial, the duration of response passed from 5 months to 7.1 months, which is much less than in our trial. So I think that the data of our Phase II trial, it's quite positive compared to what has been more recently published for other trials in pancreatic cancer. Also, I think that our analysis of the population receiving 2 doses demonstrate that the second VCN-01 dose appeared to confer additional survival benefit to patients. And with all these data, we have already approached to regulatory authorities in U.S., FDA and also in Europe, European Medicines Agency, and we are just working in a potential pivotal trial design. Also to inform you that this VCN-01 for pancreatic cancer has already received the Orphan drug designation for both regulatory authorities in Europe and U.S. and also the Fast Track designation in U.S. And I think this is basically a summary of the detail of our Phase II trial, VIRAGE. Dan, I -- the floor for you.

We've got a few questions already in the queue. The first one is directed to doctors Higaldo, Pishvaian that a lot of Phase II studies in cancer use progression-free survival and response rates as the primary endpoints. Why is it that overall survival was chosen as the primary endpoint in this study?

Thank you. I can start with that. Agree that in this relatively small randomized Phase II studies, response rate, PFS is the most common endpoint, but you can power or design the study to be OS as the primary endpoint. Honestly, while we tend to pay a lot of attention to what is primary, what is secondary. In these small studies, I tend to look at the data in aggregate. And what I like from this trial is that all of these endpoints are consistently improve in the experimental arm compared to the control.

And I would just add that I agree that overall survival doesn't need to be the primary endpoint in a Phase II study. But actually, I think that this is a plus that it was because too many Phase II trials that are successful in pancreatic cancer do not go on to become successful in phase III and having that kind of the hazard ratio in an overall survival analysis, albeit very preliminary in a relatively small study, gives a lot more weight behind and justification for moving into a Phase III trial.

This is an excellent segue into the next question is, can you comment on the significance of the hazard ratios in the study? And how does it compare to other PDAC treatments?

Maybe you're going to start, Mike, with this one, and then I follow.

Sure. I can tell you, and I know Dr. Hidalgo has had the same experience. kind of in designing studies for either cooperative groups or in advising other sponsors. We often want to try and hit a threshold of hazard ratio of less than 0.7. ideally somewhere in the 0.65 range. So the hazard ratio of 0.5-ish is very, very promising. Again, there have been many studies that have not been -- not ended up succeeding in Phase II trial -- in Phase III trials when they looked very promising in earlier phase trials. I do think that some of the real criticisms have been for large or at least medium-sized Phase I studies that were not randomized and just showed a very promising "response rate" that jump straight to a Phase III trial. Those are the ones that are sort of most prone to criticism. But I do think that a randomized Phase II trial that does have a standard of care, concurrent arm with care comparison that shows this level hazard ratio certainly justifies moving forward.

Yes, I agree with that. We'd like to have hazard ratios below 0.7. If you look at the study, the randomized trials that led to approvals, they are both at 0.75, 0.8 in some of them. But the hazard ratio is important because it gives you a magnitude or give you an assessment of the magnitude of the clinical benefit. So one thing is to be statistically significant, the other thing is to be clinically relevant and lower the more relevant. So hazard ratios in the 0.48, 0.55 as we have seen in these studies are very interesting because they have a higher predictability of a positive Phase III on one end. And second, give you -- starts to give you an idea that this can be a clinically important asset.

Okay. So following up, how does the patient population in VIRAGE compared to other studies and the general PDAC patient population?

Yes. That's, I think, a key question in this study. And I think it's a consequence of what we said at the beginning that for the very fit patients, we tend to prefer FOLFIRINOX or NALIRIFOX regimens, which, by the way, given the toxicity profile of this agent, I think one of the next studies to be done is combination with those other regimens, but that's on the side. If you look at the patient characteristics, the age is in the upper side. And what I think is more important, the distribution of ECOG 1 versus 2, it sort of flipped. There are more ECOG -- 1, sorry, there are more ECOG-1s than ECOG 0 as compared to other trials. Interestingly, if you look at the patients that receive more than 4 cycles, that difference is balanced because, of course, the better patients do better, right? That's not a secret. So I think, however, that this is more reflective of the population that now in real world, we manage with GA. So to me -- and for that reason, the control arm, probably the outcome of the control was sort of in the low end of what we would be expecting with GA. So all of this is very consistent in my opinion.

Yes. I would agree. And actually, I had recently coincidentally look back at the median age for some of the pivotal Phase III trials in pancreatic cancer. And for the ACCORD trial in 2011 impact in 2013 and NAPOLI 3 in 2022 or 2023. They were all in the low 60s. So 61, 62 as a median age, and this one with the median age that's gets a little closer to the giant population in a trial that was just presented last year, where the median overall survival was definitely significantly less than what we tend to quote because the patients are older -- so this is -- I agree with Dr. Hidalgo more reflective of our actual population of patients and the fact that there's a benefit demonstrated in the real world, so to the population is very promising.

And another comment, if I may add. I think that we should be expecting a population very similar to this one in Europe and the U.S. in a future randomized Phase III trial. Those are the patients that likely would be offered to participate in these type of studies.

Understood. Next question, VCN-01 features a stroma degrading technology. Is this only useful in PDAC or could it help with other cancers?

Manel, do you want to take that one or has to...

I was having trouble clicking off the mute. So actually, this is something that's relevant in many other cancers. PDAC is the worst and the most notorious for its very, very dense drama. But we do see that level of sort of a dense trauma in multiple other cancers. And so it could be applicable to other disease types. As some of the people on this call may know, there was an attempt to use PH2O in a previous clinical trial, but that was systemically delivered and actually showed some initial promise. And I think to get something that's much more locally delivered with the aid of the adenovirus, if you will, Dan, I think it could hopefully deliver on that promise. But the stroma aggregation to really get immuno affected cell in chemotherapeutics to the actual cancer cells is something that is definitely relevant across disease types.

And another thought, which, of course, is not the topic of discussion today is that because of that ability to modulate the stroma, we should be expecting that there is a rationale to think that this agent will also synergize with other modalities, mainly immunotherapy. We discussed that already. And actually, we saw that the tail of the curve is reminiscence of an immunotherapy type of or immune mediated type of effect in the trial. But other modalities that are now becoming very, very interesting for many tumor types like antibody drug conjugates. We're seeing that one of the limitations of the -- for the efficacy of these drugs is their ability to penetrate in the tumor. So this can be -- should be explored as a more generic mechanism to increase drug delivery and for that reason, efficacy.

Okay. All right. Next question is on the duration of response which stands out in the VIRAGE results. Could you speculate on a mechanism that provides long duration of responses in the VCN-01-treated patients?

I kind of alluded to that in the prior question, which I think is likely immune-mediated. We know from earlier clinical trials that we participated in the past as well as from the preclinical studies that the oncolytic virus by degrading the stroma causes inflammation, causes immune infiltrate. And despite those immune cells probably being sort of not fully activated because the study didn't contain a checkpoint inhibitor, I presume that the reason why we see that tail is because you're causing some sort of immunity. And I think it will be ideal to combine this with at some point. I mean we're throwing a lot of studies there, right, to combine this with the checkpoint inhibitor. So -- but it's a very interesting finding and not common in pancreatic cancer. We tend to see the curve is progressively going down.

Yes, I would agree with that comment.

Okay. Let's move to the next question. Do you think the second VCN-01 dose is providing an additive effect and could additional doses also confer benefit?

I think we're guessing on this one. I think the important thing about the demonstration of the second dose is as much to demonstrate that it was safe to give and there was no sort of additive, negative immune response or negative immune-related adverse events that came with the second dose. I think mechanistically, like with any vaccine or any immunotherapy, the idea that you need to keep the activity within the cells of the virus persistent is just sort of scientifically reasonable. And this second dose study demonstrated that you could do this safely.

Yes, the major limitation for repeated dosages in viral agents is that they thought that the immune system will clear,, will develop immunity against the virus, and then your subsequent dosages will be ineffective. I think this study suggests that, that assumption may not be completely right and that the second dose probably has some efficacy and I think that I agree that continuing dosing is probably a good strategy, but that's a speculation at the moment. Ideally, that should be incorporated or tested in future studies. It is interesting that the second dose was less toxic, which probably also suggest that there may be already an immune protection

The next question directed at Manel. Could you discuss the next steps for the VCN-01 program in PDAC as you've already mentioned feedback from regulators on a potential pivotal study. If you could share any details on your thoughts on study design.

Yes, sure. So basically, our discussions with regulatory bodies obviously has not been with this data because this data is present. We don't have the definitive data when we approach them. However, basically, our discussions concluded with the idea that our pivotal payout should be quite similar to our Phase II trial in terms of -- it should be a randomized trial, also comparing with Gem/Abraxane as a control. And also, they suggested that a blinded study could be probably a next step because to minimize any difference between the groups in the driven that I think it makes a lot of sense. . Another thing that we discussed with them is the idea of this kind of repeated dosing and generating a concept of, let's say, macro cycles of therapy where would be 1 dose of VCN-01 and 3 doses of -- 3 cycles of gem/Abraxane and do as many of these dose cycles as patients -- as long as the patient is still on -- without progression, let's say, to try to maximize the efficacy of VCN-01 as soon as we have not seen any toxicity associated to the second dose, so we don't expect to see a toxicity when we put the third dose, et cetera, et cetera. So that's basically the ideas that we have more or less discussed with regulatory bodies. Obviously, there's other questions about sample size that obviously are not definitive because we have not the definitive data at that moment.

Okay.. And I understand that we have a live question from Jim Molloy at Alliance Global Partners. Could we open Jim's mic, please?

Congrats on the excellent data. Just a quick question on the breakdown of the patients, one of the slide 11, you walk through the 4 stages, 1 through 4. I presume everyone in this trial was stages 2 through 4, but how did it sort of break down amongst the stages? And then I was wondering if you can talk -- can you talk a little bit about sort of the median overall survival in the control group in the trial? It seems to be on the low end of the 8 to 11 months historic. Any thoughts on -- is that driven by the stages of the patients enrolled in the trial?

So the study was a Stage 4 first line. So it's on the right spectrum of the -- that's important, Stage 4, de novo, first line, no prior treatment. And I agree the median survival in the control is in the low end. And the reason is because these patients have worse performance status and older than what we have seen in prior studies. And those differences is what is moving the overall survival to the lower end of the spectrum.

That makes sense. And then could you -- you guys talk a little bit about, obviously, it's early data yet, but certainly seems promising. Can you talk about if this data were to hold up in a Phase III, how clinically meaningful you think it looks? And then how this would -- the potential launch of KRAS the KRAS inhibitors in PDAC, how that might impact the potential treatment algorithm for PDAC?

Yes, I'm happy to chime in on that. So for the first point about the clinical clinically meaningful difference, Unfortunately, in the world of pancreas cancer, we get excited about 2 or 3 months improvement in overall survival. I wish that we had better outcomes in this disease. And so for example, in the NAPOLI 3 trial, that really enabled NALIRIFOX to become a standard first-line regimen. It was only a 2-month overall survival benefit. In the original gem/nab-pac study, it was actually only a little bit less than a 2-month overall survival benefit. So unfortunately, in this disease, even a 2-month overall survival benefit could be impactful for these patients. To your -- the other point, though, that if we're actually truly seeing "a tale of the curve" where these patients -- or some of these patients are able to stay on therapy for a long time and be -- and live for a long time, that could be even more clinically meaningful. To that, I'd point to the recent approval of both durvalumab and pembrolizumab for first-line treatment of cholangiocarcoma in which the survival benefit was basically only 1 month compared to chemotherapy and yet about 20% of patients have long-term control, and we think that, that's an immunotherapy response. And then the last point is, not to hog the discussion, but about KRAS inhibitors. I actually think that there is a significant immune response that's being introduced here in this -- with this agent, there is some really exciting data that the KRAS inhibitors may actually prime a pancreatic tumor to immunotherapy. And so the combination of a KRAS inhibitor with this agent is a sort of a no-brainer thought process.

Yes, I totally agree with the last -- with the prior comment, but I think having the RAS inhibitors and this class of agents available will be an amazing opportunity for patients.

Great. The final question for Manel. And obviously, you're going to look to meet the FDA Phase III meeting date. Any thoughts on timing on that given it's early yet to be figuring that out?

Yes. Obviously, that's contingent to our financing capabilities, obviously. But we are well set for starting the trial in less than -- or around 1 year from now. So mid-2026 could be a date were the trial could start. We are, of course, just finishing this trial. We plan to do an end of Phase II meeting with the FDA to agree with the definitive design of the Phase III and basically, we think that around 1 year from now could be a good time to restart this trial, the development.

Thank you, Jim. And just being mindful of time, we will now go to Steve Shallcross for closing remarks. Steve?

Thanks, Dan. Once again, we'd really like to thank everyone for attending our call today and a special thanks to our guest speakers, Dr. Hidalgo and Pishvaian. . We've seen excellent results with our lead oncolytic virus VCN-01 product in pancreatic cancer patients, which met the primary endpoints for safety efficacy in our Phase II VIRAGE trial. As we've heard today, PDAC is a difficult cancer to treat with a highly fatal solid tumor rate that represents a very, very high met medical need. And we believe VCN-01 has the potential to change the treatment landscape in this indication and to make a real difference for these patients. We're very excited to take VCN-01 forward into a Phase III clinical development program and make our vision for this potential treatment a reality. In ending this call, we'd like to also extend our appreciation to our dedicated and talented team and the brave patients who participated in the VIRAGE trail. Thanks again for attending, and have a great rest of your day.