Good morning, everyone, and welcome to the PDS Biotechnology Virtual KOL event. At this time, all attendees are in a listen-only mode, and a question and answer session will follow the formal presentation. As a reminder, this call and a replay will be made 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 Biotechnology's key opinion leader event this morning. I'm Frank Bedu-Addo, as Tara said, 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 PDS0301, which will be the subject of discussion today.
Dr. Kirk Shepard, PDS Biotechnology's Chief Medical Officer, will then address the state of affairs in the treatment of metastatic colorectal cancer, and he will hand over to Dr. Hernandez, who will discuss his ongoing phase II study of PDS0301, 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. Let's begin with the introduction to our proprietary immunocytokine, PDS0301. PDS0301 is an antibody conjugated interleukin- 12, or IL-12. IL-12 is a broadly studied and 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. 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. Due to these two 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. PDS0301 is designed to overcome these specific limitations of IL-12. With PDS0301, two molecules of IL-12 are fused to the antibody called NHS76. This antibody binds to free DNA that is released by dying or damaged cells in the body, which we will find 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. Remember, I also said IL-12 is fused to the antibody. This is a unique but very important feature of PDS0301. 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 PDS0301 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 PDS0301, therefore delivering it even more efficiently into the patient's tumor. Next slide, please. Here on this slide, we see pictures from a published study that show the unique characteristics of PDS0301.
In this preclinical study, both PDS0301 and 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-hand side of the slide, providing a quantitative estimate of the IL-12 in the tumors with time. We see that with PDS0301, within 24 hours, there's already a high concentration of PDS0301 in the tumor, as we can see by the bright red-orange fluorescence in the tumor. By 48 hours, the fluorescence intensity in the tumor has increased even further with PDS0301. Notably, recombinant IL-12 levels never get that high, and PDS0301 remains present in decent quantities even after 72 hours. 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. Let's quickly review here how we use tumor damage with PDS0301 to promote an anti-tumor response in the study that we are about to discuss. Chemotherapy, starting with the green, chemotherapy is administered to enhance the initial tumor damage. PDS0301 is then administered by simple subcutaneous injection, just like taking a flu shot. Next, PDS0301 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 suppress the anti-tumor immune response. Right?
This ability to inhibit the immune-suppressive cells within the tumor is an important feature of PDS0301. It also causes T cells and natural killer cells to infiltrate into the tumor, where the IL-12 then activates and expands these immune cells. These activated and potent T cells then cause tumor death and expose further binding sites for additional doses of PDS0301. This process continues as tumor shrinkage and patient survival continue. Next slide, please. Here we see a slide from a published preclinical study of MC38 colon cancer that shows this effect I described very clearly. In this study, docetaxel is used to induce the tumor damage and to create the binding sites for PDS0301. The bar chart on the left shows high necrosis induced with docetaxel administration and higher necrosis when combined with PDS0301.
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. When docetaxel is combined with recombinant IL-12, there is again no anti-tumor effect, as we see with the green line, as IL-12 is not designed to recognize the tumor damage. However, when docetaxel is then administered or combined with PDS0301, as we can see from the purple line, all of a sudden, it drives the IL-12 into the tumors and potent anti-tumor activity is seen. As we can see here, actually, PDS0301 is even shown to have some anti-tumor effect in this model, even as a monotherapy, as we can see from the blue line. Next slide, please.
With this introduction to PDS0301, 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 HPV16 related cancers, in prostate cancer, and also in colorectal cancer. Importantly, as seen on the right, the National Cancer Institute has exposed PDS0301 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. Let's look at our lead indication now as far as our project with PDS0301 and the challenges and facts about metastatic colorectal cancer. Colorectal cancer ranks third in incidence. 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. For some unknown reason, the incidence under age 50 is rising in many countries and is now the number one leading cause of cancer deaths in adults under 50, which is why successful treatment of colorectal cancer beyond localized tumors, that is beyond surgery, is now a large unmet need. The second point, about 95% of the metastatic tumors are pMMR and MSS. 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 pMMR, 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 dMMR, that's deficient mismatch repair, or MSI-H, microsatellite unstable. These do respond to PD-1 blockades such as pembrolizumab. The third point, when compared to patients without liver metastasis, the presence of liver metastasis in colorectal cancer is a main driver of morbidity and mortality in these patients. Liver metastasis will occur in approximately 50% of patients with metastatic colorectal cancer. The fourth point, objective response rates decline with successive treatment lines.
Here you see the three columns, first line, second line, and third line, and you see that it dramatically decreases as you go through the lines with 53%-65% in first line, second line 11%-20%, and then third line 1%-6%. These values illustrate trial benchmarks, not pooled estimates, and are not meant to be direct comparisons of other therapy, but still give you an idea as far as where the treatment is with this disease. Slide 12. Here you see a few controlled trials in metastatic colorectal cancer, then third and fourth line. Even though cross-trial comparisons are descriptive, they are not head-to-head comparisons, and populations will vary as far as their 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 median 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. PDS Biotechnology is fortunate to have an esteemed partner from the NCI 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. Hernandez graduated from medical school with honors from the University of Florida and completed general surgery training at the University of South Florida. During his residency, Dr. Hernandez spent two years at the Moffitt Cancer Center and Research Institute studying molecular diagnostics for liver metastasis.
Following residency, Dr. Hernandez finished a fellowship training in both surgery and oncology and liver and pancreatic surgery at Memorial Sloan Kettering Cancer Center. The Hernandez Lab, now at the NCI, studies hepatic metastasis and has been the home to 20 surgical residents since its establishment at the NIH in 2016. Dr. Hernandez has authored over 175 peer-reviewed publications and contributed book chapters in numerous authoritative surgical texts. It is 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 PDS0301 on clinical outcomes. Welcome, Dr. Hernandez.
Thanks so much, Kirk. I appreciate that kind introduction. Next slide, please. I just employ. I am not being paid. I am not here to particularly back any sort of company. I am here really to share my data. My sole purpose in all of this is really to move a field forward, and so I am going to speak about what we have done and the results we have seen so far. Next slide, please. Okay, so I think it is 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 is only one drug we currently use. That drug is an antimetabolite called floxuridine. The reason this sort of strategy works is because there are two 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 your intestine. 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's actually kept alive. Those tumors are fed by the artery. 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. This strategy is not new. It's been around for some time. Again, it uses one drug, and the reason that one drug has remained the 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 saline.
We're able to give 400 times the amount of drug through this pump that we could ever give a person systemically. The concept is we're able to give 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. This pump has two sort of mechanisms. I'll draw your attention to the right side. It works based on there's gas in the pump and at body temperature, that Freon gas expands, pushing medicine slowly and continuously into that hepatic artery.
The advantage of this sort of system is that you're able to give medicine continuously over a two-week period of time. That's sort of hard to do in oncology. You basically have to have an oral drug, or you have to bring someone in the hospital for two 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, what does this sort of strategy, putting a lot of chemotherapy into the liver, what does this get us? The data's really quite older. It's from 2006, Dr. Kemeny before she retired at Sloan Kettering. This was a randomized study comparing things that we don't do anymore. We don't give hepatic artery infusion pump alone, and we don't use systemic 5-FU alone.
Both of these are sort of not really used in the way they are now. But when we compared those two, 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 four months of improved overall survival, and this was statistically significant. For patients with liver metastases, this was, at that time, very good. Now, what's changed? We've gotten a lot more systemic drugs. We've gotten the ability to do a lot more systemically. We really haven't moved hepatic artery 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 artery infusion pump therapy, that pump with that one drug added to modern chemotherapy, compared to modern chemotherapy alone in the second line. This is an ECOG study. It's a large randomized study. They want 400 patients. Friends of mine are running the study. There's been slightly over 100 patients randomized to date. 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. I think the questions are, does this make people live longer? If so, how should we position it? Should we put it with first-line chemotherapy?
My feeling is it's 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. My position at the NIH really mandates that I sort of try and do something different, not just position a tool in a different line of therapy. 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, giving huge doses of chemotherapy, and we could bring that IL-12 into the tumor microenvironment, potentially changing things. Next slide.
Our hypothesis was that massive necrosis associated with the hepatic artery infusion pump and delivery of, again, 400 times the amount of fluorouracil than we could ever give a person systemically will expose those DNA-histone complexes, allow PDS0301 to be delivered into those tumors, modulating that tumor microenvironment. This is a very suppressive tumor microenvironment, I should say. You think about it, we sort of eat all the food, all the external environment sort of comes into 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. There has to be some immunosuppressive environment in order for things to be normal. So the liver's very immunosuppressive, and that allows tumors to grow very well there, unfortunately.
What we think is that by bringing in that IL-12, we could shift the whole immune tolerance and really try and kill tumors, get the immune system to kill tumors. So that was the hypothesis moving forward. Next slide. What I'm going to show you now is some data about two studies, 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 artery 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. 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 is important that you understand that. What I am showing you on the left column here where it says HAIP therapy, there are 20 patients enrolled. The PDS0301 is when we basically took the exact same protocol, and we added PDS0301. Again, not randomized, but they were run sequentially. This is some of the data there important to show you. We published this with nine patients. We have now accrued all of the patients on the study. What I am showing you here is the first nine patients, but a lot of the patients have received oxaliplatin and irinotecan. When we got to the full 22 cohort, most of the patients had already seen irinotecan as well. This is a very heavily pre-treated population of patients. Next slide.
One of the important things is when you are adding a new therapy that is 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 one reason. I did not 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. We are very cautious not to damage the plumbing system. One worry I had in going forward was would we actually increase the damage to the plumbing system to those bile ducts in the liver? It turns out it is not true. It is actually super well-tolerated. The only thing we saw that was significant was some diarrhea, which was, I will tell you, manageable. Next slide.
This is how the trial works. This is how it looks. This is the liver. These patients had these tumors all over the liver. I would take a biopsy at the time I was placing that special pump to deliver floxuridine. Patients would then begin cycle 1 where they had floxuridine and dexamethasone. I am not going to go into why dexamethasone is used, but basically it is protective of the plumbing system. At the end of that time period, these two drugs would be taken out. The PDS0301 would be administered subcutaneously, and the patients would get heparinized saline for two weeks. At the end of cycle 1, 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. I am not going to talk about. I am going to focus on the colorectal cohort. Clearly, we have done the 22. We are 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 will not 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 is done because that is sort of the way this is done as a standard. Whenever anybody does this hepatic artery infusion pump therapy, they do it in a standard way. We wanted to really mirror really what everybody else does. We took what other people are doing. We added PDS0301, and that is 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 floxuridine we were able to give people. That was really important to me because we knew floxuridine really worked, at least inducing that tumor necrosis. If we were compromising on the amount of drug we were giving that we knew had advantages, then that would be problematic. But that was not true. We actually didn't change that at all. Next slide. I think it's important to see what you get. This is when we did the original cohort of 20 patients. The next slide I'm going to show you after this is 22 patients, which is all of the patients accrued to the PDS0301 addition study.
When we ran this study initially, here's what we got. We got what most people show, which is at three months, you get great responses. Again, a heavily pre-treated population of patients. You're able to induce that tumor necrosis. The only problem is it doesn't. Most patients begin to progress, and that starts as early as six months. Next slide. The big difference here is when we added in PDS0301, we saw pretty similar things at three months, to be honest with you. I really didn't see any differences at three months. But what we started to see at six 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 PDS0301, 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 yet. I have obviously some ideas about this. But this is ongoing work. Next slide, please. Yeah. 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. 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 natural killer cell signaling. We've been able to show really crucially, 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 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 the 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 transcriptomic profiling of what exactly we've been able to achieve and why we're seeing these better results. I think this slide summarizes how I think about this. So first, 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 artery infusion pump, what it does differently than surgery or ablation is it doesn't just address what one can see. It addresses all of the cells that are probably spread in that liver that we cannot yet see. 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 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're 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, that's about the data that I planned to share with you today. Thanks for your time.
Thank you very much, Dr. Hernandez. I would again like to thank Dr. Hernandez and his team for the excellent and promising work done in these metastatic colorectal cancer patients who participated in the trial. Again, as 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 PDS0301 that's leading to the durability of these responses. That will be very interesting work as that becomes available. It's also clear that HAIP 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 Clinic, Sloan Kettering, and so forth.
The other thing here that's very interesting, I think the audience will appreciate that, is how clear it is, the elegant approach with the HAIP, hepatic artery infusion pump, to generating significant tumor damage within the liver that allows PDS0301 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 am also very highly encouraged by the durability and longevity of the responses seen with PDS0301, where the responses continue to get deeper and deeper with time. We go from no complete responses at three months to three complete responders at six months.
The 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. 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, or in November rather, suggesting that PDS0301 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 all appears to be coming together really nicely, which is very encouraging for the program. Next slide, please.
Colorectal cancer, as Kirk mentioned, unfortunately, has become the leading cause of cancer-related death in young adults and continues to be actually a severe and rapidly growing unmet medical need. Next slide, please. PDS0301 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 thank the National Cancer Institute for all the very important clinical research being done with PDS0301 in multiple cancers and the very encouraging results already reported in HPV16-positive cancers, including anal cancer, cervical cancer, head and neck, vaginal and vulva 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 three years at the National Cancer Institute, is beginning to mature.
We expect to be able to present these maturing results over the next 6- 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. Thank you very much.
Thank you, Frank. Yes, at this time, we'll be conducting a question and answer session with our speakers. If you'd like to submit a question, please use the written text box at the bottom of the webcast player. Please hold for a brief moment while we poll for questions. Our first question comes from Joe Pantginis at H.C. Wainwright. Please go ahead, Joe.
Hi, everybody. Can you hear me?
Yes, we can.
Okay, great. Thank you. I have a few questions more specific to the study and moving forward. First, I'd like to ask Dr. Hernandez, if you will. You have some in-process work that's going on here. I just wanted to ask a little bit of hand-waving, if you will. First, in the current study, you include dexamethasone. I'm just curious, any impact you see there from a devil's advocate standpoint regarding immune suppression from dexamethasone, number one. Then number two, you made a comment that there seems to be reduced progression outside of the liver. I'm just curious as to you and the company's thoughts with regard to the impact of an abscopal immune effect.
Yeah. Excellent question about the dexamethasone. It is standard that dexamethasone is included in the pump when you put in floxuridine, 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. I agree with you that there's some concerns that you would be putting an immunosuppressant into the liver. However, when you do that, when you do it with the floxuridine, that drug's half-life is not that long. By the time you give the PDS0301, you have this two-week window of 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 is always sort of done this way. I will tell you anecdotally that I will add dexamethasone at some times later in that second two weeks. Ostensibly, I do not see any differences. I think this works no matter what. Does that really make sense? I do not know. It seems like it probably would be counterproductive, but I have not observed that. I think it is 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 the plumbing, the biliary tree at all, that creates huge issues for people. You must be cognizant that if you do that, they are never going to get any more therapy, not only this or any other. It creates huge issues.
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 do not know why. I think your point is well taken, but it seems to be okay.
No, fantastic. I appreciate that. Then maybe looking forward and maybe for all of you and talking about the logistics of the upcoming study. Dr. Hernandez, you mentioned obviously with the much more systemic use of drugs that HAIP maybe has not moved forward as much. Just curious, in these patients, with HAIP being a great delivery mechanism, how confident are you and the company that you can get adequate sites and patient access now? Secondly, how does this impact your projections for the time to run the study?
Yeah, I think it is a good question. I think I showed that slide with the ongoing phase in the second-line setting. This is people who had only first-line. Obviously, competing with that trial would be problematic. That trial is accruing slowly. The reasons for that trial accruing slowly probably are the fact that they do not allow any crossover and people are being randomized to no surgery, no pump. Patients generally do not like that. However, when you move this further down the line, I think 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 irinotecan, the options are really not good. No one is really happy about any of those third-line options. They just do not work very well.
I actually think the buy-in will be substantially high once you go past the two efficacious lines. There's always this, can you get oncologists to send you these? Can we do this in a way where the oncologists are agreeable? There's a bit of a fight in the second line. The response rates aren't great with irinotecan, up to 20%. If you look at the data critically, what you'll see is there's some durability to that. But again, once you go past that, I really think you're in this, "God, no one's happy with this." No one likes giving any of those third-line drugs because they just don't work very well.
I actually think 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 PDS0301 had already seen irinotecan oxaliplatin, which probably tells you a lot there. 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. I actually think this is not going to be that big of a deal to accrue.
I'll add to that, Dr. Hernandez and Joe. You talked about the extrahepatic responses. So important to remember that IL-12 PDS0301 is given by a subcutaneous injection, and it binds to necrotic sites. Chemotherapy, as Dr. Hernandez mentioned, in addition to the HAIP pump, systemic chemotherapy is also being given. So it's creating the tumor damage even in those extrahepatic metastatic sites. So we're getting the IL-12 going not only into the liver, but also to those other extrahepatic metastasis also. Right? Dr. Hernandez 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 extrahepatic metastasis sites. Right? So this is, again, very encouraging, consistent with what we've seen with the other studies.
Coming to the clinical sites, I think from what Dr. Hernandez said, 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 HAIP. They're already trained to work with the HAIP. It's well accepted at all these sites where the trial is being run. Since that is 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.
Okay.
On the bright side, again, it's becoming broadly accepted to treat this kind of cancer, liver metastasis. Also the fact that it's becoming more accepted, and 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. Again, basically as 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. Again, we think the timing is right to actually progress rapidly to get the studies going.
That's actually very helpful. I appreciate that. So the study's actually looking to add fuel, as patients to the study, and could potentially reduce enrollment timelines, or is that too much of a-
Exactly. Exactly.
Okay. One more quick question about logistics per se. I guess, is there anything you can comment regarding the cost of this 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. Then number two, manufacturing needs around the asset.
Kirk, do you want to take the clinical study?
Yeah, sure. No, it's a great question, Joe. We're fortunate we had communications with the FDA earlier this year about the study itself. As you said, there's a huge difference as far as the treatment arms. 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 in the hepatic artery infusion therapy, this will not be a huge study. We hope to get this started by around the first quarter of 2027.
Also with the logistics, all the phase III drug is available and ready to go.
Great. Thank you very much, guys.
You are welcome.
Thanks for the questions, Joe. Our next question comes from Mayank Mamtani at B. Riley. Please go ahead, Mayank.
Yes. Good morning, team. Thanks for taking our questions, and appreciate the level of detail here. I was trying to contextualize, Frank, your docetaxel plus PDS0301 preclinical data with obviously a very impressive HAIP plus PDS0301 data that Dr. Hernandez 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. Hernandez pointed to. Could you explore combinations which are not HAIP only in sort of subsequent work? Then obviously a big regulatory question on contribution of components, dose response also. You are moving from instead of doing a phase II-B, now you are doing a phase III. So how much of those questions you feel are already addressed? Maybe that is a Dr. Hernandez question. Then I have a follow-up.
Sure, Mayank. I will start and then I will hand up to Dr. Hernandez. So the first part of the question regarding the translation from the preclinical study to the human clinical studies. Let us go back to the basic principle. The basic principle is induction of tumor damage due to tumor cell death. Right? So any agent that can induce tumor cell death will promote the delivery of PDS0301 into the tumor microenvironment. Right? So for example, in this case, it could be radiation, it could be some kind of immunotherapy. In this case, in this specific study, it is chemotherapy, as Dr. Hernandez described, the different types of chemotherapy that are being administered. Those will essentially induce the initial tumor cell death that allows the PDS0301 to go into the tumors.
You may recall the presentation earlier this year in January at AACR Prostate by Dr. Ravi Madan and his team in metastatic castration-resistant prostate cancer. In that study, they utilized docetaxel as the chemotherapeutic agent to induce tumor cell death.
Right
and tumor damage, very similar to what we showed in the preclinical study. In the preclinical study, very important, the key basic principle of that preclinical study was docetaxel induced huge significant necrosis, right? That was measured. So you could tell that there was necrosis. However, when you deliver regular IL-12, there is no impact, right? The regular IL-12 doesn't bind to the tumors. It doesn't drive the IL-12 into the tumors, and you see absolutely no effect. However, once you add PDS0301, that binds to those sites of tumor damage with the free DNA, you then see the IL-12 going into the tumors, as we showed in those pictures. You can see significant accumulation of the IL-12 in the patient's tumors sustained for a long time, and that drives the immune infiltration into the tumors and subsequent elimination of the cancer.
Now, we don't need chemotherapy to do that. You may recall our triple combination trial in HPV16 positive cancers. We gave PDS0101, which is a highly effective HPV16 targeted immunotherapy. That in its own drives tumor damage. We also gave a checkpoint inhibitor. So between those two, we got significant tumor damage that allowed the IL-12 to also have significant additional impact in driving that anti-tumor response. So again, the principle is you don't necessarily need chemotherapy to do this. Any agent that induces that tumor cell death will create the binding sites for PDS0301 to go into those tumors and facilitate that cycle of driving that anti-tumor immune response and tumor shrinkage, and hopefully, as we saw in Dr. Hernandez's study, survival of the patients. Okay, Mike, I hope that answered the first part of your question.
Yes, it did. Thank you, Frank. If you could comment on the contribution of component.
Okay
dose response that you saw so far.
As Kirk mentioned, we have had some initial feedback from the FDA regarding the trial design. We will include a small third arm that will also measure some of the. To address the contribution of agents that the FDA would always want to see. As Kirk mentioned, even with that, we don't expect a really large study, but that will be addressed, and that is part of the consideration as Kirk and his team with Dr. Hernandez work on finalizing the trial design. That is definitely being taken into consideration.
Okay. The primary endpoint and some of the early signal that you would look to discern activity across maybe different doses or different combination, would that be a response rate, or hepatic PFS, or how would you discern that activity in?
No, I think the team is working on that. As you can see, objective response rates are very clear at six months. You can see very clear differences between the patients who had PDS0301 over 70% objective response rate versus 35% response rates at six months. So we believe that is a very clear potential endpoint that could be utilized. We also talked a little bit about the PFS, progression-free survival. Also, you saw the Kaplan-Meier curve that Dr. Hernandez showed with very clear separation when it comes to survival. So there are a number of endpoints that are being considered, some of which may be primary endpoints, and others may be secondary endpoints. Based upon all those criteria that have been studied today in the current study, we have a number of potential endpoints that could be utilized to get to their studied decision pretty quickly.
Kirk, anything you'd like to add to that?
No. As I mentioned before, especially with objective response rate, the difference is so great as far as our targets that we probably have an interim analysis very soon within the first year. We're very encouraged by that. I think all three of the parameters you mentioned, with PFS also, where we saw also the prolongation with extrahepatic disease, which was really a delight to see with our PDS0301, that it's not just acting on the liver, but it's going to those lesions around the body, is very important. Of course, the FDA always likes to see survival, which we'll also measure, but I think we could have perhaps even accelerated review or some interim analysis before we get to that point.
Got it. I guess finally, the dose reductions that were seen in the study, Dr. Hernandez, do you think there's still room for exposures to improve for IL-12 locally, as you kind of learn the dosing for this in the kind of immune environment? Also, if you could comment, Dr. Hernandez, your plan for the updated survival data and the immune profiling work that you're doing. Is there a medical conference or something planned or a publication?
Yeah. The second question is yes, we have updated data. It looks good. It will be presented at the annual meeting of the Society of Surgical Oncology, and so that will be in March. I believe it's in D.C. this year, so it will be sort of a local-ish meeting. It's obviously a national meeting, so that will be updated.
Yep.
We will disclose. We will publish the full results, including all the spatial transcriptomic data and all the really cool scientific endpoints, probably shortly thereafter. It will be not long.
We have most of the follow-up data we need. To address your other question, is there room to go up in the PDS0301 dosing? The answer is yes. The way I designed this was really a path of least resistance with the FDA. We knew the maximum tolerated dose based on studies we had run, single agent studies we had run, and I went a dose level below that just to sort of placate the FDA about safety. Then when we added in the systemic drugs, which had not been used, these specific drugs had not been used, I said we would go down a dose lower. We start, the first dose is 12 mcg/kg . The second dose drops down to 8 mcg/kg, and then we dose reduced based on sort of criteria that we came up with. Could we go up?
We really did not see a lot of toxicity. It is certainly possible. I think that will have to be discussed about what we should do. We have not given it at higher doses, so this seems to work. Should we just go with what works? Should we go with a dose-finding study? I think these things will be discussed.
You would attribute the diarrhea, a third, I think it was not a big issue, but mechanistically, what would you attribute that diarrhea? I think you had a comment on that.
Yeah. You'd say the drug probably only goes where you have some sort of damage, and patients who get irinotecan do get some colitis type symptoms.
It's possible that a small subgroup of those people got exacerbated by the drug. I'm not sure. What I can tell you is it seems to be mostly self-limiting. It wasn't terrible. We just sort of treated it without too much in the way of difficulty. But it can happen. Again, you're looking at where these drugs cause damage. I mean, irinotecan does cause some colitis type, some colon stuff. Could you exacerbate that? Maybe that's what we saw. I'm not entirely sure. I would say I'm pretty happy with the safety profile, though.
Yep. Understood. Thanks again for taking my questions and really appreciate you guys putting this together.
Of course. Thank you. Thank you for the questions.
Yes, thanks for the questions, Mayank. We have time for one more question that came over the webcast. What interaction has the company had to date with the FDA regarding a phase III trial for PDS0301 for the treatment of advanced colorectal cancer with liver metastases?
Kirk, do you want to take that? You can start and I can add if anything.
Yeah. As I mentioned before, we had great communications with them earlier this year regarding the design of the study as well as our planned endpoints. There was nothing there to really stop us from moving ahead, which we're doing right now. Of course, also, we got to fill in the details of the protocol, but we plan to have that protocol to the FDA submitted by this quarter so that the FDA will be able to continue communications with them. That's where it lies right now. Frank?
Yeah. Nothing to add to that. That summarizes it.
Great. Thank you both. Frank, I'll turn it back to you for quick closing remarks.
Thank you very much, Tara. Thank you very much again, Dr. Hernandez. Thank you for all the great work you've done with the patients and also with understanding PDS0301 and how it's working. We really appreciate that, and we strongly believe this is going to significantly advance the treatment of these patients with metastatic colorectal cancer and liver metastasis. I'd also like to thank all the attendees for the time you've taken today to attend this KOL event. Thank you very much to all, and we wish you a great day today. Thanks a lot.
Thank you