PDS Biotechnology Corporation (PDSB) Earnings Call Transcript

Good morning, everyone, and welcome to the PDS Biotechnology Virtual KOL event. [Operator Instructions]. As a reminder, this area will be available on the PDS Biotech website following the conclusion of the event. I'd now like to turn the call over to Frank Bedu-Addo, Chief Executive Officer at PDS Biotechnology. Please go ahead, Frank.

Thank you, Tara. Good morning, and welcome to all attending PDS Biotechnologies key opinion leader event this morning. I'm Frank Bedu-Addo Tarasi, Chief Executive Officer of PDS Biotechnology. I would also like to offer a warm welcome to Dr. Jonathan Hernandez, who is Chief of the Surgical Oncology section at the National Cancer Institute and who will be presenting some of the excellent work he has done with his patients. and the compelling clinical research that he and his team continue to perform in metastatic colorectal cancer. Before I start, I will quickly walk through today's agenda. Next slide, please. I will provide a quick introduction to PDS-0301, which will be the subject of discussion today. Dr. Kirk Sheppard, PDS Biotechnologies Chief Medical Officer, will then address the state of affairs in the treatment of metastatic colorectal cancer, and then he will hand over to Dr. Hernandez, who will discuss his ongoing Phase II study of PDS-0301, a second-line and third-line treatment of metastatic colorectal cancer with liver metastasis. The event will conclude with a summary and question-and-answer session. please be aware of the company's forward-looking statements and ensure that you are fully aware of the risk factors associated with the company as filed with the SEC. Next slide, please. Next slide. So let's begin with the introduction to our proprietary immunocytokine PDS-0301. PDS 301 is an antibody conjugated interleukin 12, or IL-12. IL-12 is a broadly studied in naturally occurring immunological protein or cytokine, that is well documented to be a potent activator of our T cells and natural killer cells. IL-12 is also documented to have the ability to promote an effective antitumor immune response. So why then has IL-12 not been successfully commercialized as an anticancer therapy. There are a couple of important reasons. First, IL-12 produces significant inflammatory toxicity when in the circulating blood, therefore, necessitating a low dose. It also has very low presence in the tumors. Now due to these 2 factors, recombinant IL-12, therefore, has a very narrow therapeutic window, which may differ from patient to patient, and these effects have prevented its successful development. Next slide, please. Now PDS-0301 is designed to overcome these specific limitations of IL-12. So with PDS-0301, 2 molecules of IL-12 are fused to the antibody called NHS 76. This antibody binds to free DNA that is released by dying or damaged cells in the body which we will find predominantly within the tumors. This construct therefore, delivers IL-12 into the patient's tumors. Importantly, the binding holds it within the tumor for an extended period of time, as I will show you in the next slide. Now remember, I also said IL-12 is fused to the antibody. This is a unique but very important feature of PDS-0301. So unlike traditional antibody drug conjugates, this fusion is clipping resistant and therefore, does not allow for any free or unconjugated IL-12 to exist in the body. The key takeaway here is that PDS-0301 drives IL-12 into the tumors and retains it within the tumors for a prolonged period. In addition, very importantly, any agent that promotes tumor damage or tumor cell death will create ample binding sites for PDS-0301, therefore, delivering it even more efficiently into the patient's tumor. Next slide, please. So here on this slide, we see pictures from a published study that showed the unique characteristics of PDS 0301. And -- so in this preclinical study, both PDS-0301 in traditional recombinant IL-12 had a fluorescent tag attached to them to allow trafficking and quantification of IL-12 in the tumors. We see the color scale on the right on the right-hand side of the slide, providing a quantitative estimate of the IL-12 in the tumors with time. Now we see that with PDS0301 within 24 hours, there's already a high concentration of PDS-0301 in the tumor, as we can see by the bright red orange florescence in the tumor by 48 hours, the fluorescence intensity in the tumor has increased even further with PDS-0301. Now notably, recombinant IL-12 levels never get that high and PDS 301 remains present in decent quantities even after 72 hours. So now with this study, the key takeaway is this unique feature high concentrations of IL-12 in the tumor and the sustained high concentrations within the tumor over a few days. This sustained presence in this case, provided superior ability to change the tumor's biology or immunology to enable a more effective immune attack on the tumor by the T cells and the natural killer cells. Next slide, please. So let's quickly review here how we use tumor damage with PDS-0301 to promote an antitumor response in the study that we are about to discuss. So chemotherapy, starting with the green, chemotherapy is administered to enhance the initial tumor damage. PDS-0301 is then administered by simple subcutaneous injection, just like taking a flu shot. Next, PDS-0301 then targets the tumor and binds to the free DNA histone complexes within the tumor. IL-12 generates significant local inflammation within the tumor and inhibits immune suppressive cells, such as myeloid-derived suppressor cells and regulatory T cells, which are well documented to block or suppressed antitumor immune response right? So this ability to inhibit the immunosuppressive cells within the tumor is an important feature of PDS-0301. It also causes T cells and natural killer cells to infiltrate into the tumor with IL-12 then activates and expands these immune cells. Now these activated and potent T cells then cause tumor death and expose further binding sites for additional doses of PDS 0301 and this process continues as tumor shrinkage and patient survival continue. Next slide, please. So here, we see a slide from a published preclinical study of M38 colon cancer that shows this effect I described very clearly. So in this study, docetaxel is used to induce the tumor damage and to create the binding sites for PDS-0301. The bar chart on the left shows high necrosis induced with docetaxel administration and higher necrosis when combined with PDS-0301 now the tumor regression plot on the right-hand side shows that administration of docetaxel on its own does not induce any tumor shrinkage. You see this from the red line. recombinant IL-12 does not induce any tumor shrinkage either, as you can see from the gray line. Now when docetaxel is combined with recombinant IL-12 there is, again, no antitumor effect as we see with the green line as IL-12 is not designed to recognize the tumor damage. However, when dose taxable is then administered or combined with PDS-0301, as we can see from the purple line, -- all of a sudden, it drives the IL-12 into the tumors and potent antitumor activity seed. And as we can see here, actually PDS-0301a is even shown to have some antitumor effect in this model, even as a monotherapy, as we can see from the blue line. Next slide, please. So with this introduction to PDS-0301, you may understand why we are so excited about the potential of this investigational therapy to significantly advance the treatment of several solid tumors. We have seen promising results in HPV 16-related cancers in prostate cancer and also in colorectal cancer. Importantly, as seen on the right, the National Cancer Institute has exposed PDS-0301 to almost 400 patients and it has been well tolerated without the high toxicities traditionally seen with IL-12, which is again, very promising for its advancement. With that said, I will hand over to Kirk.

Thank you, Frank. First slide. So let's look at our lead indication now as far as our project with PDS-0301 and the challenges and facts about metastatic colorectal cancer. Colorectal cancer ranks third incidents. That's 10% of all cancer cases and second in cancer mortality worldwide. That's about 1.9 million new cases and 900,000 deaths in 2022. And for some unknown reason, the incidents under age 50 is rising in many countries and is now the #1 leading cause of cancer desks in adults under 50, which is why successful treatment of colorectal cancer beyond localized tumors that it's beyond surgery is now a large unmet need. The second point about 95% of the metastatic tumors are MMR and MS. This is a common description of a molecular biomarker classification used to describe how colorectal cancer tumor handles DNA repair. Our target population will be PMR or proficient mismatch repair also referred to as MSS microsatellite stable in advanced third-line metastatic colorectal cancer. This is the most common molecular subtype of colorectal cancer and represents 95% of colorectal cancer and it does not respond to immunotherapy. Only 5% of colorectal cancers are MMR, that's deficient mismatch repair or MSI-H microsatellite and stable. And these do respond to PD-1 blockade, such as pembrolizumab. The third point when compared to patients without liver metastasis, the presence of liver metastasis in colorectal cancer is the main driver of morbidity and mortality in these patients and liver metastasis will occur in approximately 50% of patients with metastatic colorectal cancer. The fourth objective response rates decline with successive treatment lines. Here, you see the 3 columns first line, second line and third line, and you see that it dramatically decreases should go through the lines with 53% to 65% in first line, second line 11% to 20% and then third line 1% to 6%. So these values illustrate trial benchmarks, not pulled estimates and are meant to be direct comparisons above the therapy, but still give you an idea as far as where the treatment is with this disease. Slide 12 so here you see a few controlled trials in metastatic colorectal cancer that in third and fourth line. And even though cross-trial comparisons are descriptive, they're not head-to-head comparisons and populations will vary as far as the prior therapy and eligibility. You can see the mean ORR or the objective response rate and the median overall survival are not very encouraging. The mean ORR in the experimental arms is about 2.5%, and the immediate overall survival is under a year at 7.9 months. Therefore, again, the successful treatment of third-line metastatic colorectal cancer is a large unmet need. And PDS Biotech is fortunate to have an esteemed partner from the inside to work with us with this challenge. Next slide. It is now my pleasure to introduce Dr. Jonathan M. Hernandez, investigator and Chief of Surgical Oncology section at the NCI and Center for Cancer Research. Dr. Hernando has graduated from medical school with Podders from the University of Florida completed general surgery training at the University of South Florida. During his residency, Dr. Hernando spent 2 years the Moffitt Cancer Center and Research Institute studying molecular diagnostic for liver metastasis. Following residency, Dr. Hernandez finished fellowship training in both surgery in oncology and liver and pancreatic surgery and Memorial Sloan Kettering Cancer Center. The Hernandes lab studies now studies hepatic metastasis and has been home to 20 surgical residents since this establishment at the NH in 2016. Dr. Hernandez has authored over 175 peer reviewed publications and contributed book chapters in numerous authority of surgical texts. It's now our privilege to have Dr. Hernandez speak to us on the use of hepatic artery infusion to treat liver metastasis and the effect and impact of PDS 0301 on clinical outcomes. Welcome back to Fernandes.

Thanks so much, Kirk. I appreciate that kind introduction. Next slide, please. I just need to say that I'm here in my physical capacity as an NIH employee. I'm not being paid I'm not here particularly back any sort of company. I'm here really to share my data. My sole sort of purpose and all of this is really to move a field forward. And so I'm going to speak about what we've done and the results we've seen so far. Next slide, please. Okay. So I think it's probably necessary to understand what hepatic artery infusion pump therapy is it is a way really to get a lot of chemotherapy into the liver. There's only 1 drug we currently use. That drug is an antimetabolite called fluctuating. . The reason this sort of strategy works is because there are 2 different blood flows into the liver. There's the arterial flow, which is derived from the hepatic artery, and there's the portal venous blood flow, which comes from our intestine. So most of the liver is actually as it happens, kept alive by the portal venous blood flow. But when the liver has a bunch of tumors in it, it's actually kept a lot those tumors are fed by the artery. So we're able to take advantage of this difference and put this special catheter into that artery to basically upload chemotherapy straight to these liver tumors. And so this strategy is not new. It's been around for some time. Again, it uses 1 drug. And the reason that 1 drug has sort of remained to sort of cornerstone or backbone of the therapy is because it never leaves the liver. It's got a very high first pass effect. So the patients don't really know when they're getting drug or sort of sailing -- and so -- and we're able to give 400x the amount of drug through this pump that we could ever give a person systemically. And so the concept is we're able to give a huge mega doses of chemotherapy straight into the liver, and we're able to induce very large responses. What does that do for the patient. Next slide, please. Before we get to the clinical data surrounding what it does, I want to show you a little bit about what this is. It's about the size of a hockey puck. It works this pump has 2 sort of mechanisms. I'll draw your attention to the right side. This is so it works based on there's gas in the pump and that body temperature that freon gas expands, pushing medicine slowly and continuously into that hepatic artery. So the advantage of this sort of system is that you're able to give medicine continuously over a 2-week period of time. that's sort of hard to do in oncology. You basically have to have an oral drug where you have to bring someone in the hospital for 2 weeks at a time. We really don't do that anymore. But this allows us to do this in sort of an outpatient setting. Next slide. Okay. So what is what does this sort of strategy putting a lot of chemotherapy into the liver? What does this get us? So the data is really quite older. It's from 2006, Dr. Kamini before she retired at some tendering. So this was a randomized study comparing comparing things that we don't do anymore. So we don't give hepatic infusion pump alone, and we don't use systemic 5FU alone. So both of these are sort of not really used in the way they are now. But when we compare those 2, what we saw was a very large objective response rate, which I told you expected, because we're giving a huge amount of chemotherapy into that liver. It got us about 4 months of improved overall survival, and this was statistically significant and for patients with liver metastases. -- this was, at that time, very good. Now what's changed? We've gotten a lot more systemic drugs. So we've gotten the ability to do a lot more systemically. We really haven't moved hepatic RD infusion pump therapy forward. Next slide. which brings us to what's happening today? Well, you should be aware that there is a randomized prospective study comparing hepatic or infusion pump therapy, that pump with that 1 drug added to modern chemotherapy compared to modern chemotherapy alone. -- in the second line. This is an e-com study. It's a large randomized study. They want 400 patients Trenaman are running the study. There's been slightly over 100 patients randomized to date but sort of this is the sort of what's going on nationally with that hepatic artery infusion pump. Next slide, please. So I sort of said how should we position this tool. This is a big question for the field. Clearly, we're able to induce these very large responses. I don't think anybody would ever argue that. The questions are, does this make people live longer? And if so, how should we position it should be should we put it with first-line chemotherapy. My feeling is probably going to be really hard to get oncologists to insert this into the first line where you get very big responses just with chemotherapy alone should we put it in the second line. Clearly, I just showed you that's being evaluated nationally position at the NIH really mandates that I sort of try and do something different, not just position a tool in a different sort of line of therapy. And so the DNA the IL-12 drug became very attractive to me because I thought we could utilize the advantages of this pump, which is to induce large amounts of necrosis given huge dose of chemotherapy, and we could bring that IL-12 into the tumor microenvironment, potentially changing things. Next slide. And so our hypothesis was that massive necrosis associated with the hepatic guard infusion pump and delivery of, again, 400x the amount of flow acuity than we could ever give a person systemically will expose those DNA histone complexes allow PDS-0301 to be delivered into those tumors, modulating that tumor microenvironment. This is a very suppressive tumor microenvironment, I should say. You think about we sort of at all the food, all the external environment sort of comes in to your GI tract, gets into that portal circulation gets into that liver. So your liver can't start acting crazy every time it sees something different. And so there has to be some immunosuppressive environment in order for things to be normal. So the liver is very immunosuppressive. And that allows tumors to grow very well there, unfortunately. And so what we think is that by bringing in that IL-12, we could shift the whole sort of immune sort of tolerance and really try and kill tumors get the immune system to kill tumors. So that was the hypothesis moving forward. Next slide. And so what I'm going to show you now is some data about 2 studies that both of which I ran, and I treated every patient on the studies. It was all done with our study team. The first was the hepatic art infusion pump therapy alone patients. So we ran a trial similar to that going through that I showed you before where patients were getting this therapy in second or third line and we did this to establish a program. So this was a number of years ago, but these were sequentially run studies. I should tell you they are not randomized. So this is not randomized data. It's important that you understand that. And so when I'm showing you on the left column here, where it says AIP therapy, there are 20 patients enrolled and the other the PSO 301 is when we basically took the exact same protocol. We added PDS again, not randomized, but they were run sequentially. This is some of the data they're important to show you and this is so we published this with 9 patients. We've now accrued all of the patients on the study. And so what I'm showing you here is the first 9 patients, but a lot of the patients have received oxaliplatin at rinotecan when we got to the full 22 cohort, -- most of the patients had already seen a rinotecan as well. So this is a very heavily pretreated population of patients. Next slide. And then so 1 of the important things is when you're adding a new therapy that's never been done before you need to understand what toxicity you could be imparting to the patients enrolling on the study. This was very important to us, particularly for 1 reason. I didn't tell you this before, but that hepatic artery is really important because it is the only blood supply to the bile ducts in the liver, the plumbing system, if you will, very cautious not to damage the plumbing system. And so 1 worry I had going forward was would we actually increased damage to the plumbing system to those bile ducts in the liver. It turns out not true. It's actually super well tolerated. The only thing we saw that was significant was some diarrhea, which was, I'll tell you, manageable. Next slide. So this is how the trial works. This is how it looks. So this is the liver of these patients have these tumors all over the liver. I would take a biopsy at the time I was placing that special pump to deliver futurity and patients would then begin cycle 1, where they had fluctuurity in dexamethasone. I'm not going to go into why exameticine is used, but basically is protective of the plumbing system. At the end of that time period, these 2 drugs would be taken out, the PDS-0301 would be administered subcutaneously, and the patients would get heparinize saline for 2 weeks. And then at the end of cycle 1, they would take we would get a biopsy to try and understand what we were doing to that tumor microenvironment. This slide is a bit older. These cohorts are and I'm not going to talk about I'm going to focus on the colorectal cohort, Clearly, we've done the 22. We're almost done with the follow-up time. We instituted these other cohorts because of the results we were seeing with the metastatic colorectal cohort I won't speak about them. These numbers are not accurate, but they are presently accruing in cycle 2, the patients get the same sort of thing, but we add in the systemic therapy. Why do we do that? That's done because that's sort of the way this is done as a standard. Whenever anybody does this hepatic art infusion pump therapy, they do it in a standard way. So we wanted to really mirror really what everybody else does. So we took what other people are doing. We added PDS our PDS 0301, and that's sort of what we did. I'm not going to talk about this, but only to say that we didn't compromise the addition of the study drug did not compromise the amount of luurity we're able to give people. That was really to me because we knew fluctuity really worked at least inducing that tumor necrosis. And so if we were compromising on the amount of drug we were giving that we knew had advantages and that would be problematic but that was not true. We actually didn't change that at all. Next slide. And so I think it's important to see what you get. And so this is when we did the original cohort of 20 patients and the next slide I'm going to show you after this is 22 patients, which is all of the patients accrued to the PDS-0301 EDITION study but when we ran the study initially, here's what we got. We got what the most people show, which is at 3 months, you get great responses. Again, a heavily pretreated population of patients, you're able to induce that tumor necrosis the only problem is it doesn't last super long. For some patients, it lasts a long time, but most patients begin to progress and that starts as early as 6 months. Next slide. The big difference here is when we added in PDS 0301 we see pretty similar things at 3 months, to be honest with you, I really didn't see any difference at 3 months. But what we started to see at 6 months is patients were not progressing. This is extremely important because this basically says that the responses we were getting were more durable when we added in PDS-0301, suggesting we were able to activate the immune system. This is being worked out I'm not exactly sure why we were getting these better responses. Yes, I have, obviously, some ideas about this, but this is ongoing work. Next slide, please. And so this is I apologize for this being slightly blurry. This is the survival data that's already published. It looks very promising, I will say. But we do have updated data. It doesn't look terribly different. This is going to look good. I think next slide, the question for us is why? What we've been able to do so far is looking in people's peripheral blood, we've been able to show naprokiller cell signaling we've been able to show really crucial it's really important that you activate both innate and adaptive portions of the immune system that gives you durability of response when we did this, I won't go into great detail about how this was done, but this is basically looking at a number of a large number of cytokines and immune cells peripherally, not in the tumor, but peripherally, and we've been able to show when you put these sort of analytes through pathway analysis. Importantly, we see communication with both innate and adaptive immune cells, which is important. Next slide. We are actively looking at the tumor tissue biopsies. We have some early data, but we're involved in a large spatial transcript profiling of what exactly we've been able to achieve why we're seeing these better results. And I think this slide summarizes what how I think about this. So first, we're I think we're likely changing the tumor immune microenvironment, although I need to put data behind that, but I think preliminarily, that's what we're seeing. New cells are being brought into that tumor immune microenvironment. I think critically, when you think about this hepatic art infusion pump, what it does differently than surgery or ablation is it doesn't just address what 1 can see. It addresses all of the cells that are probably spread in that lever that we cannot yet see. And I think we're hitting those cells with drugs, and I think we're probably getting antibody to those places. That is my feeling about why this works so well. I'm not sure about that yet that's my feeling. The other thing we did see is patients didn't progress as much outside of the liver as well. I think that peripheral immunity part is that I showed you earlier, is probably really important. This is all very exciting for us. We're trying to sort through the exact mechanism about what we are seeing and why we're seeing better results. But I think that's what we are seeing. We are seeing better results. I think at this point, I'll ask about the data that I plan to share with you today. Thanks for your time

Thank you very much, Dr. Hernandez and I would again like to thank Dr. Hernandez and his team for the excellent and promising work done in these metastatic chorectal cancer patients who participated in the trial gas, you mentioned, very encouraging with the durability. We're also excited about the translational work you're doing to really understand what types of immune cells are infiltrating into the tumor with PDS-0301 that's leading to the durability of these responses. So that will be very interesting work as that becomes available. It's also clear that HIP is rapidly coming to the forefront in the treatment of colorectal cancer with liver metastasis. As you mentioned, Dr. Hernandez, this is demonstrated with a large ECOG trial currently ongoing at some of the top centers in the country such as the Mayo Clinics, loan catering and so forth. So the other thing here that's very interesting. I think the audience will appreciate that is the how clear it is the elegant approach with the HIP hepatic artery infusion pump to generating significant tumor damage within the liver that allows PDS-0301 to target and bind within the liver, therefore driving the immune response into the tumors as we saw very clearly in the preclinical models. This appears to translate really well to the human results, and it will be very exciting, as I mentioned, to really understand the immunology and the types of cells that are infiltrating the tumor. I especially also very highly encouraged by the durability and longevity of the responses seen with PDS-0301, where the responses continue to get deeper and deeper with time. where we go from no complete responses at 3 months to 3 complete responders at 6 months and the shrink tumor shrinkage continues to get deeper and deeper, which is really encouraging as we develop these therapies to treat these patients with these very difficult to treat cancers. So very encouraging data to date and it's really going to inform how we design our Phase III human clinical trial coming up. Very importantly, the data you presented also correlates with the data presented by the National Cancer Institute at the SITC Conference in December, but in November, rather, suggesting that PDS-0301 drives a conversion of T cells to stem-like memory T cells. -- that have the immune memory to continue to drive tumor cell death. So that translational work is all appears to be coming together really nicely, which is very encouraging for the program. Next slide, please. So colorectal cancer, as Kirk mentioned, unfortunately, has become the leading cause of cancer-related death in young adults and continues to be actually severe and rapidly growing unmet medical need. Next slide, please. So PDS-0301 presents a unique opportunity for monotherapy and combination strategies across tumor types where we can use treatment-induced tumor damage as an anchor for our antibody fused IL-12. We found the National Cancer Institute for all the very important clinical research being done with PDS-0301 in multiple cancers and the very encouraging results already reported in HPV 16 positive cancers, including anal cancer, cervical cancer, head and neck, vaginal involve cancers. And also the work being done in prostate cancer and colorectal cancers. The data in all these studies, which have been progressing over the last 3 years at the National Cancer Institute is beginning to mature. We expect to be able to present these maturing results over the next 6 to 18 months. These results thus far have been highly encouraging, and we look forward to progressing some of these studies into pivotal Phase III studies in due course. Thank you very much all again, and we will now move to the question-and-answer session.

[Operator Instructions] So our first question comes from Joe Pantginis at H.C. Wainwright.

Everybody. Can you hear me? Okay. Great. I have a few questions more specific to the study moving forward. But first, I'd like to ask Dr. Hernandez if you don't will, if you will, have some in process work that's going on here. So I just wanted to ask a little bit of hand-waving, if you will. So first, in the current study, you include dexamethasone. So I'm just curious impact you see there from a devil's advocate standpoint regarding immune suppression from dexamethasone none. And then number two, you made a comment that there seems to be reduced progression outside of the liver. So I'm just curious as to you and the company's thoughts with regard to the impact of an abscopal immune effect. .

Yes. I think excellent question about the dexamethasone. So it is standard that dexamethasone is included in the pump when you put in luxury. And that was really based off, I would say, okay data from Nancy Kemeny. I think the year was about I don't remember, it's been a long time. But that has become the standard of care. And so I agree with you that there are some concerns that you would be putting an immunosuppressant into the liver. However, when you do that, when you do with the flucturity, that drug's half life is not that long. And so by the time you give the PDS 0301, you have this 2-week into a time where you don't have any dexamethasone. Do you see any residual effects, I don't know. My feeling is I can't really answer it because we didn't do it in both ways. It's always sort of done this way. I will tell you anecdotally that I will add dexamethasone at sometimes later in that second 2 weeks extensively, I don't see any differences. I think this works no matter what does that really make sense? I don't know. It seems like it probably would be counterproductive, but I have not observed that. I think it's probably okay to do it as we did. I think I would be a little nervous to take out the dexamethasone because, again, if you damage those the plumbing, the biliary tree at all, that creates huge issues for people. And you must be cognizant that if you do that, they're never going to get any more therapy, not only this or any other, I mean, it creates huge issues. So I think you have to be I think erring on the side of protecting the biliary tree is important. My feeling is this works the way we did it. I don't know why. I think it's I think your point is well taken, but it seems to be okay.

Fantastic. I appreciate that. So then maybe looking forward and maybe for all of you and talking about the logistics of the upcoming study, Dr. Han, as you mentioned, obviously, with the much more systemic use of drugs that AIP maybe hasn't moved forward as much. So just curious, in these patients with HIP being a great delivery mechanism, how confident are you in the company that you can get adequate sites and patient access now? And then secondly, how does this impact your projections for the time to run the study? .

Yes. I think it's a good question. I think I showed that slide with the ongoing phase in the second-line setting. So this is people who only first one. So obviously competing with that trial would be problematic. That trial is accruing slowly. The reasons for that trial, including slowly probably are the fact that they don't allow any crossover and people are being randomized to no surgery, no pump. Patients generally don't like that. However, when you move this further down line, I think so that takes us away from competing with that trial ongoing. I think if you talk to most oncologists, if you ask me, once you get past oxaliplatin and arena the options are really not good. No 1 is really happy about any of those third-line options. It's just it's not they don't work very well. And so I actually think the buy-in will be substantially high once you go past the 2 efficacious lines. there's always this can you get oncologists to send you these pit. Can we do this in a way with color agreeable? There's a bit of a fight in the second line. The response rates aren't great with Arena team up to 20%. But if you look at the data critically, what you'll see is there's some durability to that. But once you again, you go past that, I really think you're in this no one's happy with this. No 1 likes giving any of those third-line drugs because they just don't work very well. So I actually think that the bar is not going to the way we've designed this and the way this worked out. It just so happens that a lot of the patients I saw with the PDS-0301 had already seen arena TEQ and oxaliplatin, which probably tells you a lot there. But I think the way this worked out is I think people will be on board with this because you don't have another good option. So I actually think this is not going to be that big a deal to crew.

I'll add to that, Dr. Ads and Joe. You talked about the extrahepatic responses. So important to remember that IL-12-DS-0301 is given by a subcutaneous injection and it binds to necrotic sites. And chemotherapy, as Dr. Hernandez mentioned, has also been in addition to the HIP pump, systemic chemotherapy is also being given. So it's creating those is creating the tumor damage even in those extrahepatic metastatic sites. And so we're getting the IL-12 going not only into the liver but also to those other extrahepatic metastasis also. . Right, in Dr. Anand reported in his publication with a minimum follow-up of 13.1 months, the extrahepatic PFS had not yet been reached. which, again, is very encouraging to show that not only is it working in the liver, it's also working in those extra hepatic metastasis sites. -- right? So this is, again, very encouraging, consistent with what we've seen with the other studies. And then coming to the clinical side, I think from what Dr. Hernandes, which is very important in the way we are looking at this, most of the patients in our study were third line, but it's very important to also recognize the benefit of having this large ECOG study going on in the country. because now these sites are being primed to working with HIP. They are already trained to work with the IP. It's well accepted at all these sites that have been where the trial is being run and since focused on second line and we're looking at third line, these sites will essentially be generating the population that we need for our study. So on the bright side, again, it's been broadly -- becoming broadly accepted to treat this kind of cancer liver metastasis, but also the fact that it's becoming more except in all these sites actually participating in the clinical trial makes it very important for us as we look where to go and how we get these patients. And again, basically, as the second line, these patients going to third line, these sites will ultimately potentially be generating the population that we need to go into our study. So again, we look we think it's the timing is right to actually progress rapidly to get the studies going.

That's actually very helpful. I appreciate that. So the study is actually looking to add fuel as patients to the study and could potentially reduce enrollment time lines? Or is that existing value. exactly. One more quick question about logistics per se. I guess, is there anything you can comment regarding the cost of the study because it seems pretty focused with regard to the potential powering here. It doesn't seem like it's going to be a massive study. And then number two, manufacturing needs around the asset.

Kirk, do you want to take the study? .

Yes, sure. That's a great question, Doug. I mean we're fortunate we had communications with the FDA earlier this year about the study itself. And as you said, there's a huge difference as far as the treatment arms. So I don't want to talk about the exact numbers now or the statistics, but we're very encouraged by the fact because of these large targets and the differences between systemic chemotherapy and then adding the hepatic artery infusion therapy, this will not be a huge study. So we hope to get this started by around the first quarter of 2027.

And also with the logistics all the drug -- the Phase III drug is ready and available and ready to go.

Our next question comes from Mayank Mamtani of B. Riley. .

I appreciate the level of detail here. I was trying to contextualize France docetaxel plus 30 preclinical data with obviously a very impressive IP plus 301 data that Dr. Anand has shown here. Could you help us understand, obviously, the chemo regimen, systemic chemo are different as they are used in the different settings that Dr. Anand has pointed to how like how could you explore combinations which are not HIP only in sort of subsequent work. And then obviously, a big regulatory question on contribution of components, dose response also. You're moving from instead of doing a Phase IIb, now you're doing a Phase II so how much of those questions you feel are already addressed? And maybe that's a Dr. Ananda's question. And then I have a follow-up.