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

Good morning, everyone, and thank you for joining today's KOL webinar. My name is Michael Cozart, and I'm a Managing Partner at LifeSci Consulting, a leading life sciences strategy consulting and transaction advisory firm located in New York City. This morning, we will be discussing Theriva's novel oncolytic virus program, and in particular, the program's potential to treat pancreatic ductal adenocarcinoma, often also known as PDAC. As a background, Theriva Biologics publicly traded on the NYSE as a diversified clinical stage company developing therapeutics designed to treat cancer and related diseases in high areas of unmet medical need. The company's lead program, which we will be discussing today, VCN-01, is an oncolytic adenovirus designed to replicate selectively and aggressively within tumor cells and to degrade the tumor stroma barrier that serves as a significant physical and immunosuppressive barrier to cancer treatment. We are fortunate to have today both Dr. Michael Morse and Arsen Osipov joining me to discuss both the current market dynamics as well as VCN-01's potential within PDAC. Today's call will last approximately 60 minutes, which will include a brief Q&A session at the end. [Operator Instructions]. So to start, perhaps we could have both the physicians introduce themselves, talk about where they practice, as well as perhaps the number of PDAC patients they see on a monthly basis. So perhaps we can start with Dr. Michael Morse.

Mike Morris. Duke GI oncology, of course, at the Duke University Medical Center. Have a translational interest in immune therapies for malignancies, particularly in the GI space, and I developed products in the lab and brought them into Phase I clinical trials and an investigator-initiated approaches predominantly around cancer vaccines, some of which have involved viral vectors. And pancreatic makes about 20% of my practice, so in a year, various stages, mostly advanced stage, probably about 80 or so patients.

Wonderful. Thank you, doctor. Dr. Osipov?

My name is Arsen Osipov, I'm a GI medical oncologist, very much focused on pancreatic adenocarcinoma. I'm the program lead for unique one-day Multidisciplinary Clinic and Precision Medicine Program for pancreatic cancer. I oversee pretty much a majority of our pancreatic cancer clinical trials as well as I run the translational laboratory focused on the tumor microenvironment, immune modulation of pancreatic cancer. We actually have a specific focus on looking at how to modify the stroma in order to synergize with common therapeutics, including chemotherapy, and particularly with the immunotherapy in pancreatic cancer. I would say 95 to -- 95% of my patients have pancreatic adenocarcinoma. I see between 50 to 100 pancreatic cancer patients here, at least on a monthly basis, and probably over 200 to 300 throughout the whole year. We're a large pancreas cancer referral center for the West Coast of the United States.

Wonderful. Thank you so much, both doctors. So just to orient everyone who may not be familiar with PDAC, unfortunately, it is a tumor type that's associated with very low survival rates as well as coupled with ineffective treatment options. It does originate the ducts of the exocrine portion of the pancreas, accounts for the largest portion of pancreatic cancers at approximately 90%. Sadly, PDAC does have a really high mortality rate, accounting for approximately 7% of all cancer deaths, which is projected to be the second leading cause of cancer death by 2030. Some of the risk factors that are associated with pancreatic [ care ] or PDAC: Smoking, of course, 25% of all cases; heavy alcohol use; high BMI or excess weight; and there is some genetic predisposition to PDAC. In terms of the patient dynamics and the patient journey, again, has one of the lowest survival rates among all cancer types with a 5-year survival rate of approximately 10% broadly. Further 3%, unfortunately, in metastatic patient population. There is a fairly low efficacy, with clinical trials actually being recommended as first-line therapy for a lot of patients. The unmet medical need is immense. There really is a lack of targeted therapies. Standard of care have poor efficacy as well as high toxicity. The unmet need is perhaps highest in gemcitabine-relapsed patients who really have, unfortunately, again, no effective treatment option. So Dr. Osipov, perhaps just speaking to a little bit further detail about the patients that you see in your practice, and certainly be interested to hear Dr. Morse' patients as well. Looking at what percent of your patients are diagnosed at "early stage" versus metastatic? What does your patient population look like? And then of those metastatic patients, what is the kind of the performance status of those patients when they come to see you?

Yes, that's a great question. I mean, because my practice is predominantly focused on pancreatic cancer, actually really much simulates what happens in kind of the broader community where I would say about 10% to 20% of patients following that first big bucket of whether it's known as the upfront resectable. Again, it's a small percentage. The next category is probably our borderline or locally advanced patients which have the potential of surgery. This comprise maybe 20% to 30% at most, and unfortunately, the large majority of my patients are in the advanced or metastatic setting. Probably well over 50%, unfortunately, where they -- we are treating generally for palliation with a kind of a limited armament, which is the systemic backbone chemotherapy. Of that, performance status is a big issue, particularly in the patients with advanced pancreatic cancer. There is a fair large majority that still have a reasonable performance that is of ECOG of 0 to 1. But again, this doesn't apply to all patients. We have -- there might be about 20% of patients, even upwards of 30% that sometimes don't have that great of a performance that it might be a ECOG 1 to 2. But most patients at the time of diagnosis are at least amenable to systemic chemotherapy or ideally clinical trial, which is something we advocate for very commonly.

Dr. Morse, comments there?

I agree. I think the -- what constitutes community, first of all, most patients, at least in our area, are treated in the community setting. And so it tends to be a an older, sicker patient population. And I think that reflects we're obviously going to talk a lot about clinical trial data. But our ability to get people on clinical trials, it's a very small percentage are actually able to probably down in the 5%, maybe 10% range because of poor performance status, comorbidities that come along with age or the average age being about 72 for pancreas cancer patient, and the declining -- the rapidly declining performance status. So many people, by the time they actually come to see us, they had to have symptoms often for a while, often including weight loss, increasing fatigue. See the primary care physician, they finally get imaging, they've got a some kind of an advanced disease, they have to get biopsy, sometimes the first biopsy. It's suspicious, but you don't get an answer. And all the while, people are continuing to deteriorate. So the time to deterioration of performance status is actually a critical factor in our thinking about who we can even apply these new and exciting studies to.

Wonderful. Thank you both. This just provides an overview of the U.S. diagnosed PDAC incidents. In 2022, we're looking at approximately 56,000 diagnosed incident PDAC patients in the U.S., of which 29% are metastatic, so roughly 52%. That number is expected to grow, unfortunately to 39,000 by 2035. A CAGR of 2-point compounded annual growth rate, I should say, of 2.3% over that time frame. Again, of that 56,000, 90% of all pancreatic cancers are PDAC. If we look at the segmentation, 29,000 are metastatic, 52%, so that's Stage IV upon diagnosis. According to secondary literature, the performance status, as both physicians were just speaking with, approximately 80% of patients are a good performance status, 20% having poor performance status, although that can decline quite rapidly. The U.S. prevalence, so thinking about the current patients out there who have PDAC, we're looking at approximately 84,000 in 2022. The 5-year recurrence rate is approximately 80%. So just again, setting further context of how many patients are out there, unfortunately, that are diagnosed with PDAC. So looking at 56,000, of which 29,000 in 2022, do have metastatic disease. So this is a point where we really want to focus and kind of dive in deep with both of the physicians and talking about the current treatment paradigm. And effectively, the lack of really treatment options, unfortunately, for these patients. Patients are primarily treated with systemic chemotherapy in both first and second line, at least according to the secondary literature that my group LifeSci Consulting was able to pull. But maybe Dr. Morse, you can speak to your kind of preferred first-line maintenance, if the patient is lucky, and then the second-line treatment options for these patients?

Yes, I'd agree the supplies to most people. The first thing we try to get done if it hasn't been done is some type of molecular testing. You may have your own in-house platform, if you're lucky enough to have that, or send out. But it's certainly -- for the very rare MSI patient, I actually I have one right now, but very rare, they have the immunotherapy option. For the people at the, BRCA Germline or related Germline alterations. Again, we have a potential maintenance option for those people with olaparib. But sadly, most people are not going to have a targeted option. So I see a lot of annihilism around even getting the testing, but we still think it's valuable. And it's not for today, perhaps for tomorrow, because what's not targetable today could be later on, and at least you'll know what somebody can be offered. In terms of systemic therapy, I'd be interested in Dr. Osipov's view on this. I was a much bigger user of gem/nab-paclitaxel, just viewing it is better tolerated by many of these elderly patients. But actually, now that we use modified FOLFIRINOX, much better tolerated than the original regimen in the [ previous ] trial, more people, I think, are actually eligible for that. And you can argue that there's been no direct comparison between them, at least in the metastatic setting, and therefore you can't say for sure, but there's probably a little bit higher response rate with the modified FOLFIRINOX in PFS and OS, so it's become increasingly our outside of clinical trial backbone. But from a clinical trial standpoint, I'm sure we'll get into this more, gem/nab-paclitaxel is certainly more broadly applicable. You don't have to worry about can I enroll this patient, no, I don't think they'll tolerate modified FOLFIRINOX. I think you could say if they're a clinical trial candidate, they can probably tolerate gem/nab-paclitaxel, so it's a nice background for many clinical trials. And then in the second line, it's essentially what you didn't do in the first line. Gem-based -- if you got Gem-based in the first line, though, we generally do not go to a FOLFIRINOX regimen. We used an irinotecan-based. We use a fair amount of ONIVYDE and nanoliposomal irinotecan with 5-FU. But again, some places, just use irinotecan plus 5-FU instead of the ONIVYDE. I'll pass off to Dr. Osipov's thoughts on this.

Thanks, Dr. Morse. I mean, I totally agree. I think to the first point about the sequencing, both somatic and germline are still really relevant. It's a good point that yet unfortunately, we don't have a lot of new targets or it doesn't come up often, probably less than even than 5% at the time. But even sometimes now with contemporary research if you can find both somatic and germline mutations, it does give information about biology and potential ideal clinical trials based on the mutation profile. So I think upfront getting those is important. As it pertains to the systemic therapy part of standard of care, we always advocate for clinical trial. I mean, especially for patients that have good performance status, I can't belabor the point that, as Dr. Morse highlighted, that could change very quickly even before starting or as you go through first line of therapy. So clinical trial is really, really an ideal. I think another good point is that when you're thinking about backbone therapy, when we go back to the [ Cord 11 study ] versus MPAC, yes, with FOLFIRINOX, your overall response rate was somewhere around 31% versus 23% with Gem/Abraxane. But with tolerability, modified FOLFIRINOX is better overall in the clinical trial landscape, the majority of backbone therapy where they add on adjunctive with new reagents is really Gem/Abraxane based, and that's really because of one, tolerability, and the -- there are implications for modifying the tumor microenvironment and for maintaining good immune response, in other words. So FOLFIRINOX is a little bit more immune depleting in that way, and in terms of tolerability, is another issue. I think if they're not a clinical trial candidate and they have excellent performance status, modified FOLFIRINOX is a reasonable option if they're not going to do trial. As an alternative, Gem/Abraxine is still reasonable for those who are not quite the most robust performance status. And similarly, we do use liposomal irinotecan based on the NAPOLI study, particularly for patients that already have [ front ] like Gem/Abraxine. It's really hard to get multi-agent chemotherapy with oxaliplatin in the second line, a lot of patients can't tolerate that. So I truly agree what Dr. Morse have highlighted.

Can I throw in the question here, because I'm actually interested in your thoughts on this. If the landscape in first line may change a little bit, we had the sequence trial at ASCO, Gen/NabPaclitaxel followed by modified FOLFIRINOX in sort of a 6-week regimen that looks superior to Gen/NabPaclitaxel. Do you think that's going to become a backbone in the advance studies?

I'm a little bit hesitant about that because we know about these tumors, particularly developing chemo resistance, right? You want to be able to essentially capitalize as much as you can on that particular agent. Once you start introducing another backbone therapy, you're changing the tumor resistance profile. And we rather keep that for potentially the second line. I think introducing early on, though, maybe there's some data to support that. I think in the overall landscape, it's probably -- I don't think it's going to take over. I think we're going to be keeping it a little bit separate.

And then when we think about the treatment paradigm selecting which treatments patients should use, and this is going to be a common theme today on today's call, thinking about tumor stroma. I know Dr. Osipov, that was something that we had talked previously pretty substantially about. Any thoughts here in terms of tumor stroma as it pertains to PDAC, in particular?

Well, so what we know is that in terms of the stroma and hyaluronan density, if you put all tumors in a line, PDAC is #1. It is the most strong dense in terms of both hyaluronic acid expression as well as the dense extracellular matrix. In terms of what happens to the tumor microenvironment, when you look at even standard of care for FOLFIRINOX or you look at Gem/Abraxine, there are some slight different implications. We have actually shown that you can change PD-L1 expression more with Gem/Abraxine as you can with FOLFIRINOX, which is another implication. And again, in terms of suppressing the immune system, FOLFIRNOX, by and large, we know this just on the patients. It is far more immunosuppressive. So that, I think, is another element, particularly if you're thinking at -- looking at combining immune adjunctive agents, whether it's vaccine, immunotherapy, checkpoint inhibitors or another modality.

Okay Dr. Morris, any comments there?

Well, again, since Dr. Osipov actually does research in the stroma components in this lab, I'm sort of interested in 2 observations that I've had people repeat to me. One is that the stroma and the metastasis is different than the stroma at the primary site. And secondly, when people have tried to classify pancreatic cancers, they frequently, the classification has to take into account, it's an element of the stroma. So Moffitt, for example, has a classification that looks at the tumor cells, basal, non-basal essentially, but also looks at the stroma activated, non-activated. To what extent is it -- what is an activated stroma really mean? And does it vary at the primary site of the metastatic site? Because that would have a lot of bearing on therapies that are designed for metastatic disease versus localized disease.

Interesting. And then when we think about first-line therapy, second line therapy, unfortunately, patients who have poor performance status, at least according to secondary market research, some will just be, again, unfortunately relegated to pallative therapy, right? When we think about first-line therapy failure rate, what does that rate look like on average?

Sadly, it's -- and it's essentially 100%. There are -- that rare person with, again, the MSI high tumor that has a great response to immunotherapy. It's less than 0.5%. There are people that will, of course, have prolongation of their time to progression, progression-free survival with olaparib, that they have germline BRCA alterations, but almost everybody is going to progress. We've had a study going on now for a few years looking at -- trying to actually resect metastatic disease, which is unheard of in pancreatic cancer. But there's a rare -- it's like 1% of people have well-controlled disease for 6 months or more with oligometastatic disease who are actually candidates to do a resection on this. And miraculously, some of those people don't progress afterwards. But I'd say everybody's essentially progressive.

Yes. I mean, Dr. Morse brought up actually some really important points. Unfortunately, that is true, the majority of the patients are going to end up progressing. As it pertains to his last comment, actually, it is important looking at the expression of HA in the primary versus other sites of mets. What's interesting is we actually showed this on a paper we published specifically looking at the expression of HA. We know that in the primary, it's typically higher than all sites of mets but certain sites of mets are less than others. So for example, the liver, we know liver mets had the highest HA expression compared to the other mets. And to the second point about resecting oligometastatic disease, actually, there are large trials being looked at for institutions for very specific subsets. We know that, for example, in patients that have lung-only mets, if you compare it to those with liver mets with pancreatic adenocarcinoma, their survival is on the order of 3x longer. So they have a slightly different biology. So this is another avenue where we look at to be able to select patients that are maybe better responders to certain types of therapies. And to Dr. Morse' other point, it's unfortunately probably less than 5% of the time where you have with our "exceptional responders", that they doubled the overall survival or they doubled the expected response rate from standard of care chemotherapy. A very small subset of patients or about 95% of patients are going to follow the statistics that we see from the studies.

Yes. And actually, to echo, to add a little bit more. I think you probably agree that population tends to be in the RAS wild type subgroup, which again is only like that 5%.

10%.

Maybe 10%, yes, that have the fusions. Energy on fusion and other unusual molecular findings, at least unusual for pancreatic cancer who seem to have exaggerated responses compared to everybody else.

Absolutely, that's exactly right.

Yes. And I think one of the macro points that you both are driving at is the lack of available therapies, efficacious therapies and safe therapies as well, really just highlights the significant unmet medical need for these patients for sure and I imagine that you both would agree with that. But when we look at next-generation new programs in clinical development, obviously, before the call, we were talking about the Halozyme program. What are, in your opinion, kind of the key areas of unmet medical need within the metastatic PDAC patient population? Perhaps start with you, Dr. Morse?

Unfortunately, every scenario in pancreas represents unmet need, honestly. I mean, if you -- the first-line metastatic patients, it would be great if we had a better maintenance strategy for them. Recognizing they're still going to likely progress, but something low toxicity for the majority of people other than just staying on chemotherapy. Certainly, if we could "downstage " more people to get surgery, I mean, right now, the borderline resectable group that Dr. Osipov mentioned is -- unfortunately, very few of those people end up with curative, truly curative resection. They still relapse at a high rate. So more effective therapies to get the borderline too resectable and then to keep them from relapsing. And obviously, second, third line need very tolerable therapies. Realizing we're probably not going to obviously cure it at that point, the survival is going to be short, but something to offer people. But I can't emphasize enough that even though the majority of people have RAS mutations, we just -- we need to find more targeted therapies. Even in that 10%, that's all a lot of patients that have those RAS wild type that have these unique targets. And I think it's unlikely there will be a lot of drugs developed specifically for those nimotuzumab reported at ASCO in that group of patients, but I think they'll probably be more part of basket trials. So really, we're just trying to get the molecular testing done on patients to make sure that they can either go on those studies or if the drugs are available that their physicians know about them.

No, that's great. I think all this really sets the stage for talking about VCN-01, and really just speaking to what you just talked about Morse-- Dr. Morse, the lack of novel treatment options. I mean, look, I think we would all agree that there is quite severe toxicity with the standard of care, with it being chemo. And unfortunately, the poor patient outcomes, right, given kind of the lack of effective treatments that we have. So what my group did at LifeSci Consulting ahead of this call is we interviewed 7 key opinion leaders, such as the 2 that we have on the call today, to ask them about what a drug like VCN-01 in the PDAC setting, what the advantage is, what it could do in that setting? Certainly, we provided a target product profile to the physicians ahead of the call that talked about the mechanism of action. So it's a systemically administered oncolytic virus which, for those of us who are familiar with the OV space, there are not many systemically-delivered oncolytic viruses out there that selectively replicates and kills tumor cells. Not healthy cells, tumor cells, with very high efficiency. The replicating virus releases a stroma-degrading enzyme to improve intratumoral dissemination and tumor access by concomitant chemotherapy or immunotherapy, again, thinking back of the current treatment paradigm. And then the degradation of tumor stroma by the OV is just really interesting, and want to get the physicians points on this, exposes tumor neoantigens, favoring the infiltration by immune cells and tumor inflammation. What is interesting here, again, reiterating about dosing and administration, it is an intravenous dose administered every 3 months, with each administration 7 days prior to the standard of care, obviously, being chemotherapy, gemcitabine plus nab-paclitaxel. Looking at the primary endpoint, OS greater than 15 months. Standard of care is roughly 8 to 10. Looking at key secondary endpoints of objective response rate, landmark 1-year survival, median time to deterioration. I think, again, thinking about the current standard of care, the safety and tolerability profile of VCN-01, side effects of being transient and reversible, flu-like symptoms, grade 1 or 2. Transient reversible elevations in liver levels so that the safety profile is quite acceptable. So Dr. Osipov, I think we're fortunate that Dr. Osipov and Dr. Morse both have quite extensive familiarity with oncolytic viruses. Dr. Osipov, just thinking about this product, immediate reactions to the proposed target product profile?

Yes. I mean, there's a lot of important points to kind of go over here. I think first, especially in the pancreatic cancer space, Dr. Morse highlighted this. We -- it's a huge unmet need, right? And we get a lot of patients. I know Dr. Morse, when they come in, they say we heard about immune therapy, and we want to get the new immunotherapy, they're going to get a checkpoint inhibitor. We've had family/friends that have lung cancer or a specific type of colon cancer that they think it's probably MSI and they have this and there are amazing responses. And we know that checkpoint inhibitors by themselves, and we've looked at this as single agents or as combination therapy with targeting with CTLA-4 and PD-1, they don't really work in pancreatic adenocarcinoma. So we want to find novel ways to implement immune therapy with likely chemotherapy backbone. So here, you're actually combining an oncolytic virus, which is adenovirus, which is important because there are other type of viruses that can't be selected. Adenoviruses have a tropism or selection for GI tissues, so that's why it's actually -- it makes rational and scientific sense to do that. And then particularly with nab-paclitaxel and gemcitabine as a backbone, as I alluded to earlier, they're not as immune suppressing. And we know that actually -- it can actually alter the PL-1 expression in the tumor microenvironment. I think the other point that is important is you're looking at an oncolytic virus that actually has a stroma degrading enzyme, which is similar to what we saw with the HALO-301 study or the SWOG-1313. Now those trials did not meet their primary endpoint, they failed and there's reason both clinically and scientifically, we know that why that may have happened. One issue is modifying the stroma just by degrading in shape may not be sufficient. We know that neoantigen exposure within the tumor micron is another critical element to prime the tumor microenvironment and T cells. When you give a PEGylated hyaluronidase, you may be limited to how much you can expose new antigen. But if you're giving a virus that is actually both lysine and killing tumor cells and also making an enzyme to degrade hyaluronic acid, you've got a dual effect. In other words, you're exposing antigen and you're degrading the immunosuppressive stroma. And the antigen exposure, there's a few things. One, it brings in those immune cells that are antitumor. And then it also likely -- the idea is that it will lead to a decrease in immunosuppressive cells like Tregs or MDSCs, so there is a dual effect. And we know that a lot of trials are now looking at synergistic immunotherapy strategies where you don't have only one mechanism, you have dual mechanism. So I think both of those are really important. And typically, you want to decrease immunosuppressive cells, increase the effector T cells, which this can potentially do. And I think that the route of administration and the timing, it's not overburden. There's a lot of clinical trials that will require additional visits on top of your standard of care chemotherapy. This doesn't really have implications of that one additional visit, which will probably be in that week off if you're doing a 3 on 1 week off, would be very reasonable and the side effort profile is not any worse than you would expect even with the most robust chemotherapy, which would be again modified FOLFIRINOX. So I think those are really critical elements that kind of really stand out to me when I first take a look at this kind of synoptic report.

Yes. Dr. Morse?

Yes. I think we'll get into the details of the studies that have been done so far after, so I'll save some of my comments for them. But just in terms of a profile that we're looking for in this patient population that -- unless it's something that we think is going to completely replace chemotherapy, the likelihood is we're going to still be giving chemotherapy to these patients. Certainly first and second line, maybe even third line. So it has to be combinable with it, both from just a general safety standpoint but also it will be nice if there is this potential synergistic effect that Nab-Paclitaxel likely has as far as the stroma. I think the second important point here is that if it's going to be given in addition to other therapies, how much of an incremental benefit do we need to see in the clinic? We've accepted 1-month, 2-month survival benefits in the past, and everybody remembers erlotinib, less than a 1 month median survival benefit when added to gemcitabine, not used much anymore. But at the time, it was considered a big deal, I recall. So to be able to see a 3, 4-plus month improvement over the existing standard, I think, is what we really should be asking for. And also along the way, though, what type of efficacy do we need to see? This is -- which of the pivotal trial eventually show. But just along the way, it's inevitable that the response rates, the PFS, the OS, they're not going to be probably as high as seen in earlier studies. Patient selection, a myriad of reasons. So in earlier studies, we really should be seeing probably substantially more survivals, that could be 50% more progression-free survivals, that could be certainly more than 50% greater. Could be 100% greater to say, we're on to something because it's definitely going to be shorter than that in the final analysis. And then lastly, again, talking about the targetability, it would be ideal if this was -- just somebody that you could do it in all comers. I think it's interesting that the Halozyme experience, we had to ultimately test it and people that had high hyaluronan levels as dictated by -- it would have ultimately been a companion diagnostic, I assume. Here, it would appear that it maybe it doesn't matter what the hyaluronan levels are, and so that would be great because you could apply it to more people instead of having to use some type of test to dictate. Now I think there will be the necessity to look at adenoviral titers, I think those are required in these studies. We've got to have that to a higher or lower than 1 to 350 because if you have a really high titer antibody against adenovirus, I mean, you might clear it before it could have the activity. But broadly speaking, I like the idea that this could really be for a broad group of patients.

Wonderful. And I just want to drill in a little bit more on the mechanism of action, in particular, Dr. Osipov. Just the perceptions, the implications, the importance of the lytic nature of the oncolytic virus. And really, this ability to release neoantigens, and obviously, the subsequent increase in tumor immunogenicity. I mean, how important is kind of that statement there to a product like this in -- ultimately to the patients?

No, it's actually very important. We've been studying the tumor microenvironment to great detail, looking at both the stromal profile and the immune profile. And again, we know that when you look even simply at CD8 T cell infiltration. You take a tumor like lung cancer, for example, even the PDAC. You just -- you're staying simply for CD8, PDAC is an immune-barren environment. It's been well described. If you look at other tumor types, whether it's melanoma again or non-small cell lung cancer, the CD8 infiltration is much different. So we know that that's one way that you'll have both an immune response, and then you can provide synergy on top of the cytotoxic effect that comes from chemotherapy. And we've shown that even in pre-clinical models as well as even in clinical translational studies that those patients that have higher CD8 infiltration have better clinical responses. So I think that's one critical element. But how do you get to that increase in CD8, right? So -- and here, we highlight those point as those immunosuppressive cells are also in high abundance and [ BFCs ], Tregs and now we're realizing actually, tumor associated neutrophils was the focus of our lab that they actually have a very critical immune suppressive role. So if you can -- in both degrading the stroma and the density there and as well as altering the or moduling the tumor microenvironment way to increase CD8, that's going to probably provide hopefully and hypothetically a synergy to what we would expect from your standard of care chemotherapy. And Dr. Morse have highlighted very importantly that again, that's still going to be a part of our backbone. We're going to go away from that. I think as we're looking for strategies in order to both prime, which chemotherapy does, it primes the tumor micro environment, and then to synergize ultimately. So I think there's a lot of potential in this type of an approach for this particular vaccine/vector.

Any comments there, Dr. Morse?

No, I agree 100%. I couldn't answer that.

And then looking at that second comment bubble down there, I know both of you have experience with the [ Hollison ] project, and we just recently talked about that. There is -- and just kind of reiterate a huge difference here between administering PEGPH20 or replicating virus, right? There is far less, again, neoantigen exposure that we would have with a product such as what we're proposing here with VCN-01. And one of the things that I also wanted to highlight, right, in today's call, yes, we're talking about VCN-01 in PDAC, but this is a program that can be used in other tumor types. We have one KOL mentioned that it's not only favorable for PDAC, but also many other types of GI cancers as well. Maybe Dr. Morse and Dr. Osipov, you could talk to where such a mechanism would have potential in certain other tumor types?

Yes. I mean, I think we know that, for example, pancreatic cancer, pancreatic adenocarcinoma, there are other tumor types within the biliary treat that actually are fairly similar. Probably a little more immunogenic though. Even if you look at, for example, cholangiocarcinomas or Pancreatobiliary subtype Ampullary cancers, they're similar. And again, not quite as aggressive, but there's a potential there for an immune adjunctive agent. They also, again, have fairly dense stroma where it has implications. Now in general, though pancreas cancer is probably the least immunogenic in terms of responding to checkpoint inhibitors, even if you look at colorectal cancer that is not MSI high, they don't even respond to checkpoint inhibitors, right? So there are implications for looking at immunotherapy adjunctive agents that have tropism to GI tissues, adenovirus as a potential construct that could do that. And again, I think to that second point of when you're looking at neoantigen exposure, we know that when you give PEGPH20, you don't really alter the neoantigen exposure because what you're getting is the same neoantigen exposure you get from cytotoxic chemotherapy lysine in cells. But if you have a virus that has tropism for the specific cell type on top of that, there's a synergistic and likely increasing neoantigen closure.

I think there's also -- the product represents -- if you look at the data on the amount of hyaluronidase that's detected in a circulation, the virus that's detected, there's an initial increase. It decreases and then increases again because of the replication. It's a different pharmacokinetic if you will, of the hyaluronidase, which may be important. I think the stroma can do both good and bad things. I think there's some data that -- my patients often ask us when -- if I talk about the stroma, they were like, well, we shouldn't that keep the cancer from being able to spread? If it's so -- how come the cancer gets out? Well, it does. So maybe there's some benefit to keeping some stoma present may be an on-off approach. It's something -- or just localizing it to where the virus can replicate might be also important here compared to the PEGylated product.

Wonderful. Thank you, doctors, for that. And I wanted to just kind of reemphasize the route of administration. My group has done quite a bit of work in the oncolytic virus space, like both of the KOLs, it will be a little bit different type of work. But looking at the route of administration, and a lot of physicians cited the difficulties with intratumoral administration, which a lot of oncolytic viruses are delivered intratumorally. Perhaps the best known oncolytic virus, because it is approved, being T-VEC from Amgen. Doctors, maybe you can just speak very quickly to how beneficial it is to have a drug like this, an oncolytic virus that is and can be systemically delivered which, from our research, is quite rare out there in the OV space?

Yes, I'll take that. So obviously, you have the technical issues of trying to do intratumoral injections. The T-VEC, I was involved previously when I did melanoma and some of the studies, and just the planning for that is complicated. How much volume should you inject in each lesion and so on? And then this would have to be done by a gastroenterologist or interventional radiologists. It's very hard to get people on their schedules. So obviously, anything that can be done to make it to systemic. Secondly, for all the talk about an abscopal -- abscopal really refers to radiation, but the same concept of abscopal effect. You treat one area, you had an immune response that carries to the rest of the body. It's a nice one. Our lab has shown that with intratumoral gene cytokine delivery and so on. It can work, but with very immunosuppressive tumors like pancreatic cancer, it's very challenging to get that approach so it's nice to be able to deliver the effect as opposed to more diffusely. And I think the last is the -- again, just trying to make this something that's applicable to the average patient, the community. Not the person that's going to one of our centers, it just has to be something that's easy to administer. And now I will say because it's add and add 5, I mean that's -- yes, it's a virus, but it's one that's all about us, so it doesn't create as much consternation in the pharmacy as using some other viral products with as well that are more esoteric.

Yes. And I think maybe Dr. Osipov, you can speak to the last bullet on this slide, with the vast majority of the KOLs that we interviewed. Talking about, again, the dosing schedule that we highlighted earlier, not meaningfully delaying the start of chemo, right? And thinking about these patients, whether they have good performance status now or unfortunately don't from the onset. That is, and what we heard, that is a pretty big point of differentiation here, right? The last thing that you want to do with a novel therapy is start or delay the start of that backbone therapy.

No, absolutely. And Dr. Morse highlighted a lot of the important points here, so I'm not going to reiterate that. But I'll add 2 things actually that relate to that. I think number one, we do a lot of clinical trials for advanced pancreas cancer. Patients, they bring up a real-world example. They say, hey, I know I can start chemo next week. Why should I do this trial and go through all the additional tests? And we -- there's rationale for it. If there's too much of a delay, it actually detracts patients from doing it, and there's also the implications of the aggressive tumor in its biology. When it comes to doing intratumoral administration versus systemic, we've done studies with this. Each one requires an endoscopic ultrasound and then injection into the tumor. It's an additional procedure. We have biopsies that are part of research studies that that's a swing factor for patients away from clinical trials. So I think having that systemic administration and starting soon within that 1 or 2-week window is an ideal place to be. I think when you start making that window longer, it -- patients themselves don't want to participate in such clinical trials or even be interested in looking at such therapies. I think that's why having a close administration to the onset of chemotherapy in 1 week or 7 days is very reasonable.

Yes, and very, very well said. And then talking about just quickly here, the efficacy endpoints that we highlighted in the target product profile. Looking at overall survival being the preferred end point, we did have 3 KOLs requesting the addition of PFS and duration of response. And looking at KOL stating that the majority is saying that the overall survival endpoint greater than equal to 15 months being the gold standard, and again, putting that into context that Gem plus Nab-Paclitaxel falls around 9 months. Maybe just speak to what that would mean, physicians, perhaps I'll start with Dr. Morse, what an OS of greater than 15 months would mean to these patients?

Well, we have the goals of care. So actually before this, I had a few patients in clinic and everyone, we had to have goals of care talk, and they generally fall around landmarks. When it comes right down to it, it's trying to get to an event that's important with good performance status. So the overall survival is obviously going to be made up of not just first line but presumably second-line therapy, but that amount of time would reflect is that a prolonged period in first line of presumably good performance status, and obviously, survival. And so that allows people to do the things they want to do during that time.

Okay. Dr. Osipov, thinking -- thoughts about the 15 months kind of being gold standard?

Yes. I mean, Dr. Morse gave us a good example actually. In patients, we oftentimes -- patients sometimes come and they say, we want the hard statistics. Tell us the statistics, doc. What if I do this chemo, if I do FOLFIRINOX versus Gem/Abraxane. We always say you're not a statistic, but if we're going to get to the details, we know what the averages are. With Gem/Abraxine, you're looking about 8 months, with FOLFIRNOX, it's 11 months. So those numbers -- so again, Dr. Morse highlights that again, with the second line, patients do -- may do even better. But I think when you compare it to the raw numbers from the clinical trials from a [indiscernible] impact, if you already showed this, that would be meaningful to patients. And I think from a standpoint of those events, as Dr. Morse's highlighting is as an additional important factor for patients. So I think in patients' minds they often compared to the facts they know from the kind of the pivotal studies that got those drugs approved for metastatic pancreas cancer.

Great. And then thinking about in that third bullet, 83% ORR that was seen in Phase I. Obviously, 3 KOLs spoke to that being extremely significant. Thoughts there, Dr. Osipov?

Yes. I mean -- I mean, this is the thing. We know that with Gem/Abraxane, and when you're looking at the mid-20% for an overall response rate with FOLFIRINOX and even modified FOLFIRINOX, you're looking at 30%. So that's a pretty high number and a high benchmark, so I think that number in itself does stand out because we know what we're able to achieve with standard of care chemotherapy.

Wonderful. And again, I wanted to jump to safety as well here in the last 5 minutes before we open it up to Q&A. And I think what is really important, I think both physicians have done a really good job of emphasizing the safety profile that the program VCN-01 has generated to date, and we hypothesize will be going forward. It won't prolong the start of chemotherapy, and I think that is going to be really, really critical here. Again, given that we just can't do that for these patients and kind of delay the start of the backbone chemotherapy. So I don't know, physicians, if you want to -- maybe Dr. Morse, just talk briefly about the safety profile that we proposed?

Yes. Well, the key is it can't increase or can't overlap with the other drugs you're giving because it would mean you then would have to reduce the dose of the other drugs, which could make them less effective. The second issue is, obviously, it's nice not to have a some unusual toxicity that now requires a whole new management strategy and one that doesn't slow up the development of the drug. With the Halozyme, there were the blood clots that were an issue, DVTs, PEs, and we had to put people on anticoagulation. That took some time to figure that whole issue out, and it remains an issue. Interestingly, that doesn't seem to be a problem here, so that's a nice advantage. The other point is that you are giving a -- I mean, the -- as a viral vector, you're going to expect some sort of fevers and so on. There are certain things that lots of prepare people for so they -- it will take a little bit of a knowledge upswing, the learning curve here because anytime somebody gets chemotherapy and then they have a fever, we immediately send them to the emergency room because they may have febrile neutropenia. So I think we're going to have to learn how to manage some of the expected side effects here, but at least they're expected. They're not unusual.

Got it. Dr. Osipov, any comments on the safety profile that's proposed?

No. I mean Dr. Morse highlighted all the important points. I think we were talking before this about how you had to actually implement blood thinners during the HALO studies, so I think that's one very important point. I think transient effect versus long duration effects are importing in combinatorial strategies in pancreas cancer, because chemotherapy as it is one of the big complaints is long-term tolerability from fatigue. So I think if patients are more willing to accept transient side effects versus those that are additive and prolonged. So I think that's another important point that we have to just be mindful of and make sure, again, it doesn't interfere with chemotherapy because I think that you never want to compromise the kind of standard of care that patients explore.

Sure. And I guess before I turn it over back to Tara for Q&A, looking at, again, assuming everything goes to plan, as this drug gets ultimately approved. I mean, what kind of utility are we talking about, you're doctors in the PDAC patient population, first-line, second-line patients? Is this something that would be again, given what we're proposing here in the TPP, something that would be really widely used? Is that fair?

I think that's a great question because what you're getting at is, is this going to be the drug to give throughout first line, second line, third line? Because it enhances chemotherapy delivery, improves the immune response, will it be possible to give it with chemotherapies and immune therapies and targeted therapies? And I mean, that's a lot of studies that will have to be done. But it does open up the possibility that's a widely utilizable therapy. Again, you'll have to get over the idea that it's a virus we're giving to people. I think explaining that to patients and their caregivers. But with all the viral vaccines we're getting for COVID and other stuff, I mean, I guess the public is getting more used to that now.

Dr. Osipov?

Yes, I totally agree. I think the last one is important. We live in a post-COVID era, you can think of it now, right? So the implications of -- when people talk about viruses and particularly in the context of cancer, because we often get patients that come and ask us. We heard about the mRNA vaccine and the clinical trials with this or similar type have approaches. And that's why things like this have promised in it. In that sense, also, I would say that transient effects, particularly those that are more immunogenic, it really is still reserved for patients that -- you want to have a reasonably good performance status. You have to be mindful as we enter the realm with patients that may not have a great ECOG because of the ability to tolerate even a viral vector as such. But I think there's still a large amount of patients that still could be applied to, should it prove to be efficacious.

Wonderful. Well, thank you, physicians. Tara, I know I wanted to turn it back over to you for perhaps a couple of questions?

Yes, sounds great. [Operator Instructions] So our first question comes from Jim Molloy from AGP.

I'm good, thank you very much.

Great. So I'll turn it over to you, Michael, to read the remainder of the questions. Michael, you're on mure.

Sorry. The other question that we -- one of the questions that we got from the audience, I know we touched on it very briefly. But perhaps doctors, just reiterating, other tumor types outside of PDAC that this might have utility in? Any comments there, if you could just reiterate what you said, I believe, Dr. Morse...

I think we touched a little bit briefly on this, was -- if you look at immunotherapy as a general category, even though there's been increasing approval since the approval of ipilimumab in 2011 and [indiscernible]. In the GI cancer space, it has been increasing. There are more -- tumors that are a little bit more immunogenic, [ ATC ] is an example of that. But again, there are tumors, small bowel cancer, cholangiocarcinoma, the ampullary adenocarcinoma, which are somewhat -- can have similar behaviors to PDAC, MSS, colorectal cancer. There are implications of finding immune adjunctive agents. We know that in general, these tumor types aren't as immunogenic. Now again, probably pancreas cancer is the poster child, unfortunately, of that, but there are implications in other tumor types. And that's why actually if you look at the oncolytic virus space, there's -- it's not just in pancreas cancer. It's being looked at in multiple other tumor types within GI cancers.

Yes. I think that's a good point that one of the nice additions here is the hyaluronidase. There's also been a modification to enhance targeting to tumors, integrant targeting as opposed to the usual receptors for adenovirus. But fundamentally, this is an oncolytic virus, and so there are lots of them out there. But I think at a minimum, even in cancers where hyaluronan maybe isn't as critical, it still should have the effects that oncolytic virus would in the combined ability with other immunotherapies. So I think it probably could be broadly used across cancers, although there is some that make more sense that have this more of a stroma component.

Sure. Sure. Well, look, doctors, I really appreciate the time today. That was the last question. I really, again, want to thank you for the time, the insight that you provided. Thank you, everyone for attending today. If there are any questions, please feel free to reach out to the Theriva management or the relationship manager at LifeSci Advisors. Be happy to address any additional questions. Again physicians, thank you so much for your time today. Hope you have a wonderful afternoon.

Okay. Thank you.

Thank you.