Imunon, Inc. (IMNN) Earnings Call Transcript & Summary

All right. Good morning, everyone. I'm Stacy Lindborg. I'm the CEO of Imunon, and it is my true honor to get to welcome you to the 2025 Imunon R&D Day. As I look across the people in the room and certainly have reviewed the -- those that registered online for the live webcast, we have esteemed guests here and investors and partners, which we're delighted by. So we'll be showcasing IMNN-001's progress with our novel immunotherapy, IMNN-001. But what really matters is our goal. And we are in pursuit of the first immunotherapy that will be approved for frontline advanced ovarian cancer. The enthusiasm that I feel and experience as I interact with many of you is also reflected by the registration that we saw for this event, which we're delighted by. And it continues to underscore really the shared urgency that we have and the hope that we have for women that are fighting advanced ovarian cancer. It's a really devastating disease. So thank you for your unwavering support for IMNN-001, our mission and the desire to transform outcomes for ovarian cancer. Today, we'll give an update on our program, our IMNN-001 program, sharing compelling data and the significant potential that this data underlies for IMNN-001 to be a breakthrough treatment for women newly diagnosed with ovarian cancer. Along with the latest milestones and progress on our ongoing Phase III trial, OVATION III, that brings us closer to delivering this transformative therapy to patients. To frame our discussion, it's important to reflect on 2 foundational truths that continue to drive our work. Number one, the standard of care for newly diagnosed ovarian cancer has remained essentially unchanged for 25 years. And no frontline therapy, I'm hearing whispers of longer. They can add that when they come up our esteemed panel. No frontline therapy has ever demonstrated an overall survival benefit in improving this setting, so frontline setting until IMNN-001 until our OVATION 2 data, which will be reminded of today. IMNN-001 in combination with standard chemotherapy represents a potential breakthrough in newly diagnosed ovarian cancer. Our Phase II data showed a remarkable 13-month extension over the standard of care and overall survival with a highly favorable benefit to risk profile. And as I stated before, no other frontline ovarian cancer treatment has achieved an overall survival improvement, making IMNN-001 uniquely positioned to make a meaningful difference in the lives of women facing this disease. We approach this program with great urgency because the unmet need is profound and the opportunity to change the treatment paradigm is within reach. One quick note of housekeeping. We'll hold questions until we finish all of the talks, and then we'll have time for questions. And of course, for those that came to the symposia, we'll have time following with coffee and pastries. But we encourage everyone on the webcast to participate. Please submit questions online. We'll be monitoring the Q&A log. And any questions we don't get to, we'll collect them and we'll make sure that we share them. We find ways to answer questions and follow up after the event. So one last comment before we dive in. I really want to pause and just thank our speakers for making the effort to come here. You all have busy calendars. And I know that even without the government shutdown and the risk of missing surgery tomorrow in clinic, that taking time away from very important and pressing work is a priority that you have to think very carefully about, and we're grateful for you being here and offering the perspective that will be very important to be reflected on today. So thank you for pushing that work aside and joining. Okay. So with that, I'm thrilled to turn to the program and introduce our first speaker, Dr. Premal Thaker. She'll be speaking today on advancing ovarian cancer care, Imunon's potential to transform the microtumor environment from cold to hot. And Dr. Thaker is the David & Lynn Mutch Distinguished Endowed Professor and is Chief of the Gynecologic Oncology Department at Washington University in St. Louis. She's a research member of the Siteman Cancer Center, and she specializes in gynecologic oncology with a background in cancer biology from MD Anderson, focusing in angiogenesis, invasion and the impact of biobehavioral factors like stress on ovarian and endometrial cancers. Dr. Thaker leads clinical trials and novel therapeutics for gynecologic cancers, having served as national PI for several trials, including our OVATION 2 and our ongoing now OVATION 3 trial, in addition to other ongoing trials in platinum-resistant ovarian cancer. She directs clinical research for Washington University's Endometrial Cancer SPORE, and I'm delighted to invite her to the platform.

Thank you, and good morning. Everyone made it. Hopefully, you didn't have as much of a challenging time as myself and Dr. Jazaeri, but here we are. So thank you for the kind introduction. It gives me great pleasure because I've actually been part of this program for quite some time. So I feel very passionate because I've actually seen the science evolve and also making sure that we continue to evolve that. So I hope you'll get as passionate once you see the data as we talk about the unmet need. So as Stacy mentioned, there is such a high unmet need because we really haven't changed the paradigm. We've changed the maintenance strategies in ovarian cancer, but we really have not changed the treatment strategy in terms of chemotherapy and what we can offer our patients. And over 21,000 women actually will be diagnosed closely in the United States this year alone, and we will lose 13,000 women. And really, the reason this happens is because the cancer is so insidious and we actually find most of our patients, over 80% of them at an advanced stage, Stage 3 or 4. So the cancer is widely metastatic at that point. Patients are highly symptomatic and they come and they finally present because we don't have the holy grail of a screening test like we do for some other cancers. And because of that, most patients will have a response, but 70% of our patients will actually recur in the first 2 to 5 years, which makes it quite challenging when someone recurs, as we all know, that's -- we lose our opportunity to cure patients and hopefully give them substantial life. And over 60,000 -- I'm sorry, 60% of our patients will die within 5 years of the diagnosis. So we really do need breakthrough therapies for these women because we haven't really changed the paradigm. And this actually is the first immunotherapy to hopefully give us that opportunity, as you'll hopefully appreciate today. So why do we have so much hope in immunotherapy is mainly because of the cytokine we're really targeting, IL-12. So if you actually have been following the IL-12 story even in the 1990s, early 2000s, there's been over 37 trials that have looked at how to give IL-12 because everyone understands the potential of IL-12 being such a key cytokine for really changing both the innate and the adaptive immune system, which is a really rare thing to actually modulate both sides of the immune system and hopefully give a lasting effect. However, over time, we've not been able to effectively give it because of side effects. So really, what's important is knowing that we give this medication not intravenously, but intraperitoneally into the abdomen itself, which is really where this disease is housed. And so we're changing the tumor microenvironment. And because we're actually giving it into the intraperitoneal cavity, we can give it repetitively, which is the key because we all know that nothing works the first time. If any of you are parents, you know the first time you tell your children something, they don't necessarily do it. It's repetition. I see some smiles. Some people are listening. That's good. Same thing with intraperitoneal chemotherapy. It gives us the opportunity to give it weekly to patients. So really trying to start changing that tumor microenvironment. And also in gynecologic oncology, in 2006, we actually used to give intraperitoneal chemotherapy. So there was an NCI mandate that said this should be a therapy and an option. So now we're giving intraperitoneal immunotherapy, which is really good because of the fact that there's a lot of us, myself and Dr. Jazaeri, who have given intraperitoneal chemotherapy and understand the benefits for our patients. So we can get durable and local expression of IL-12 with this modulation of IMNN-001. And we know it increases really the benefit in the tumor microenvironment without those systemic toxicities that we had seen within -- I'm sorry, recombinant IL-12 previously that really did not allow for the administration effectively. And that's why a lot of companies had given up on IL-12. Fortunately, Imunon had not. So how do we realize that we're really targeting and changing the tumor microenvironment as I'm demonstrating and talking with you today. It's really from our earlier work of looking at both the Phase I where we were looking in more translational samples. And even in OVATION II, we did collect translational samples. And what you can really see on the right-hand side because this doesn't project too well, but is that there's an increase in your dendritic and your myeloid -- I'm sorry, your effector memory T cells. So you can see on the panel all the way on the right in the pretreatment, you really don't see a change. But after you've given actually the intraperitoneal IL-12, you can see post treatment that all of these cells increase. And why is that important? It's actually making the immune system activated in order to fight the cancer. You're really changing a change in terms of making more T cells come and be able to fight this cancer. And we know that's very important because a lot of times these cancers can evade the immune system, and you don't see these sort of increases. Additionally, when we looked at it in patient samples, you can see that we really don't see an increase of IL-12 in the blood. So we really -- that's what helps us limit the toxicities that we see for patients. You see the huge increase in the ascites of these patients because a lot of these patients come not only with a huge disease burden of physical tumor implants, but they're carrying several liters of fluid. And so it's easy for us to aspirate and look at these changes over time. And that's also important. And then what also we know is that interleukin-12 and interferon gamma both collectively work better and help with anti-angiogenesis. So it's not only the immune system that is attacking. And importantly, what you can see is in our higher doses of 100 milligrams per meter square, you can see the sustained improvements of the actual full change of making a difference in the levels. So demonstrating that this really is our dose that we require to use for our Phase III that's ongoing. So what also is important is that this is not new. Immunotherapy is something that ovarian cancer clinicians, physician scientists have been trying to capture how to use the immune system more effectively because we do feel that it is a cold tumor. And if we can change it, the tumor microenvironment, we will have a better success in terms of actually making a difference for these patients. So there's been countless thousands of patients who have gone to immune checkpoint inhibitors and upfront therapy without really seeing the benefits that we were hoping we would see. So why do we think that IMNN-001 works differently? It's really the fact that the microenvironment contains cells which are known to dampen the immune response. So how do we really reverse that? And really, the way we can do this is by increasing the numbers of favorable immune cells from both the innate as well as the adaptive immune systems. So once again, what we did in OVATION 1 is looking at can we really decrease those immunosuppressive biomarkers that we know really make it worse for patients. So what you can see is that we decrease many of the critical immunosuppressive biomarkers such as FOXP3, IDO1, PD-1 and PD-L1, resulting in the CA-125, which is a tumor protein to go down as a way that we can measure how our patients doing. Additionally, what we do is we can see that we're changing the milieu. We're giving an improvement in our CD8+ and CD84 T cells in the tumor. So really changing the dynamic of that tumor microenvironment because we know that, that will make a better sort of immunoresponsive environment for our patients. And so this is how we believe immunologically, we really are changing because we can actually physically measure, and that was by us taking lavages of the patient's abdomen, so we could serially see these improvements, which is really critical because a lot of times, we just say a drug fails without understanding the biology. But here, we really have taken the opportunity to try to understand is our hypothesis working, and it appears to be so. So this is really important because the fact, as Stacy mentioned, we've really not seen any overall survival benefits. And when I'm pointing out these checkpoint inhibitor trials that we have on the top over here with Rucaparib and Nivolumab and below it, you're looking at the use of first, which is the use of Niraparib with Dostarlimab. I want to point out that these are actually trials in patients after we know that they respond. So this was partly in patients who are using a maintenance therapy that we know have responded. IMNN-001, we take patients who really are sort of at the worst, right? They're getting -- they've just started their disease journey. We don't know if they're going to respond to chemotherapy yet. We don't know what the response is going to be. And we start the treatments concurrently with chemotherapy with the immunotherapy intraperitoneally. So that also is super important because we are taking patients at the start of their journey. So we're not self-selecting the patients who may have not made it and then go on to these maintenance therapies. And even though this is not powered the Phase II, it really gives a very strong signal about how patients respond and that we were able to change the tumor microenvironment because it's really important when you talk to a patient to talk about overall survival benefit. People want to know how is it going to impact my life. And when you talk about overall survival, that's meaningful and impactful, especially when you give patients over a year and this data is still maturing. So that's another Christmas, another holiday. It's not just giving them 3 months where it's hit or miss, what quarter of the year you've made it. So patients are also excited to take therapies that they know are going to help them. So then we, of course, looked at our sort of HRD and PARP-treated patients. When the OVATION 2 trial was sort of being developed. I wish we all had like hindsight 2020. We didn't realize that PARP inhibitors were going to become the new standard for patients with a BRCA mutation. So it was not prescribed, but it was definitely considered part of standard of care. So we have patients who did go on to get PARP inhibitors. And what we see is that the response is even more dramatic in patients who are able to get a PARP inhibitor along with IMNN-001. And why do we think it works even better in those patients is that we know that patients who have a homologous recombination deficiency have an impairment in repairing their DNA. And when they do, they're going to have more mutations, more neoantigens, and we know that's how immunotherapy tends to work even better for those patients. So that's why we feel like it even boosts even further immune activation for those patients in particular. And this data, even though it's not -- as I said, it was not prescribed, it definitely shows that this is what we're continuing to see. So I want to tell you that this really can transform care for patients. The impact in overall survival harnesses the patient's own immune system, which is really what we want. We wanted to locally be giving out the IL-12, and Dr. Jazaeri will show some interesting data of how he can see those differences. So we're not just delivering IL-12, but we're activating the patient's own immune system to overcome the barriers that sometimes we've seen with other molecules. It also activates both the innate and the adaptive immune systems to give you more effective, durable responses and memory. That's what we see in a lot of immunotherapy trials across other disease sites is that you'll see overall survival benefits because you have to teach your immune system. It's just like when you get the flu. The first time you might be down and out, but the next time you're exposed to it, hopefully, it's not as severe the side effects because your immune system has learned how to sort of deal with that challenge. And so that's also very key for our patients. And then we're turning the tumor microenvironment from cold to hot. That's a very lovely science way of saying we really are trying to make it more ability for patients to have their immune system, help them complete the therapies as well as potentially even augment future therapies if they recur as well. And then lastly, we do see that we see that the cytokines are induced locally and not systemically. So we do not see cytokine release syndromes. We don't see that patients have barriers because they have high fevers, they can't get the treatments. So that really is also important because you want to be able to do this, as I said, repetitively and giving the durability. So the other part that's really important for OVATION 2, which was presented at ASCO this past year was that the benefit was seen for all of the trial endpoints. And so what you can see is that there was not one endpoint that was not favored for IMNN-001. And so that really is very important because even though some of these were not powered, it does show you that everything is going in the same direction. So this is not like we're just picking out one subset and focusing on them. We really see that it benefits all our patients, whether they've been treated with PARPs, not treated with PARPs, if they're also HRD -- I'm sorry, HR proficient, which is even the hardest group to treat, it's very important. And so it's a highly favorable benefit risk profile that we see for patients. We do see that also when we go in for our surgeries because interval debulking, we do after we give patients their neoadjuvant chemo, so meaning they get chemotherapy with IMNN-001 for 3 cycles and then they get surgery followed by additional therapy. We do see a real biological response in the operating room by more patients having chemotherapy response scores that are favorable that our pathologists can tell us as well as the fact that we're able to get R0 surgical resections, which means we're able to remove all the tumor we can see. So all of this helps us believe that we're really making a difference for these patients, and we don't see many side effects except for abdominal pain, and that's mainly from the distension of infusing a medication into the abdomen. But we've gotten smarter. We've learned how to premedicate patients so they can tolerate this. We also educate better. So we know patients to how to respond when they have these side effects. So they're not suffering, but they're also not just not being proactive about it. And then we do see some nausea and vomiting, but we're able to also help with that with antiemetics. And some of the nausea and vomiting is really because of the disease itself. It sort of coats the entirety of your GI system. So these patients have motility issues and they really do have issues with just sort of absorption and digestion. So this leads us to OVATION 3, which is what we're really excited. It's launched, and it is our Phase III trial that is actually going to randomize patients after either a diagnostic laparoscopy or a biopsy to confirm that they actually have ovarian cancer as well as for us to know about their HRD status ultimately so that we can make sure that when we have the prescribed maintenance therapy at the end of trial that they're well balanced. And you can see that it's really the same as OVATION 2 that patients will get neoadjuvant chemotherapy versus neoadjuvant chemotherapy with IMNN-001 weekly, followed by interval debulking surgery, followed by continuation of their arm and then they'll go on to maintenance therapy only for HRD participants. So this really gives us confidence that we'll be balanced because we now know based on the current state of affairs, where we are in terms of prescribed -- being prescriptive about maintenance therapy. We also will be looking at overall survival because I told you that is the most meaningful. The FDA always wants overall survival and all of us in drug development try to hedge and be like, we'll get you a PFS, and we think it's going to become an OS. But this trial really has benefited and shown an OS benefit in the Phase II, and we're very highly confident that we'll get an OS benefit in the Phase III. Additionally, we hope that because we'll be looking at the HRD subgroup, we might be able to get an accelerated approval because it really does show that it is even extremely more effective in this population. And then we'll be looking at the patient's perspective. So we haven't really done official quality of life measures, but we will in this trial, of course, because we definitely hear from patients, but we will be measuring this at prespecified time points. And then this is an event-driven statistical methodology with an interim analysis for hopefully an early interim approval for the HRD-positive group, but we have statisticians who will explain that much better than I. And so with that, I really hope that you understand that IMNN-001 is really poised to make a difference for patients. Having done this for now close to 20 years, I hate to say my age, but I really would love to leave an indelible mark on this population of patients who really need to have effective medications and therapies and can we do it together to really drive this forward. So I hope you join us and follow us because we really are very optimistic with the sort of prophylactic pain medications that we're going to give, the ability to actually get intraperitoneal therapy to patients because it also makes sense to patients that why are you giving these not only systemic medications, but medications that are treating where the cancer is thriving sadly. So patients also understand and they want immunotherapy. And now we finally have something that's effective. So thank you for your attention, and I'll hand it over to our next speaker.

Thank you, Premal. Okay. The next speaker, Dr. Amir Jazaeri, will be speaking on the use of IMNN-001 in combination with chemotherapy to prevent minimal residual disease after frontline therapy. And we'll be really unveiling progress with this trial and safety and tolerability and translational insights. So Dr. Jazaeri is the David Gershenson Distinguished Professor in Ovarian Cancer Research and the Vice Chair for Clinical Research in the Department of Gynecologic Oncology and Reproductive Medicine at the University of Texas MD Anderson Cancer Center. He also serves as the Director for the Gynecologic Cancer Immunotherapy Program and has helped establish a broad range of immuno-oncology programs for gynecologic cancers that include adaptive cell therapies, also focused on intraperitoneal immunotherapies and translational immunobiology. His other areas of research include understanding the basis for minimal residual disease, which you'll hear us refer to frequently as MRD in gynecologic cancers and designing clinical trials to intervene during this phase of the disease. He's the study PI for Imunon's ongoing MRD trial, and he'll share new data today in his presentation from that. So Dr. Jazaeri?

Thanks so much. So it's a pleasure to share with you some of our preliminary findings from this trial. I would think of this trial as kind of a forward-looking kind of what's next. And I really credit Imunon for their dedication to improving outcomes for women with ovarian cancer. And when you're truly dedicated to a purpose, you're never satisfied with your current efforts. You're always thinking what could be better, what could be different. And so I'll share with you sort of how we're thinking that maybe there's a shortcut to accelerate all clinical trials in the frontline setting by focusing on minimal residual disease. I also want to acknowledge funding from Breakthrough Cancer Foundation. So a few years ago, with this trial being the flagship of our ovarian MRD project, we got $15 million in funding and a lot of the clinical and transitional data that I'm going to share with you was directly a result of that. And so if we think about the number of cancer cells in the body, this figure kind of shows that in ovarian cancer, obviously, patients are diagnosed with large number of cancer cells because they have advanced stage disease. Over time, with the standard treatment, this number comes down below this orange line, which is meant to depict limit of clinical detection. But very few patients, as you heard from Dr. Thaker's talk are cured. And what happens is with time, the number of cancer cells rises again. It becomes clinically detectable. And when that happens, what do we do? We still treat them with some of the same chemotherapies. And by the way, when the cancer becomes detectable, basically, it's incurable. And only then after several additional lines of therapy, do we think about trials of novel therapies. And some years ago, we started to sort of think about, well, what if we could overcome this limit of clinical detection, what if we could do a second operation called a second look laparoscopy, which is a minimally invasive operation that's done at the end of frontline therapy. It's an outpatient procedure. And during this operation, we do multiple biopsies. We do washings of peritoneal areas. We aspirate all that fluid and biopsies, we send it all to pathology. And if any of those biopsies or if the fluid contains cancer cells, then we deem that patient as being MRD positive or surgical MRD positive. And so by identifying patients that are MRD positive, as you might imagine, these patients have worse outcomes, and I'm going to share some data on that with you. And so what we hope to achieve is to provide the opportunity to do trials of novel therapies or novel maintenance therapies in this setting. But it also -- this is where I think we can have sort of a shortcut. MRD can also be thought of as an endpoint, surrogate endpoint. And so we hope that by looking after patients are done with frontline treatment and not having to wait until the cancer makes a clinical recurrence, we can accelerate treatment in the frontline setting. And this is exactly the sort of the impetus behind the MRD trial that I'm going to share with you. And that's because currently, frontline trials are hampered by the fact that we have to wait until clinical recurrence, which takes a long time. I think the study rationale is very similar to OVATION 2. So I'm not going to -- Dr. Thaker covered that very well, but I just want to make the point again that frontline treatment is the best opportunity to achieve cures for ovarian cancer. So we think it's the right place to try to have an impactful intervention. You heard that IL-12 promotes inflammation in the tumor microenvironment, making cold tumors hot. And I'll share with you some of our translational data that demonstrates that. You heard again that systemic IL-12 is poorly tolerated. And I think sort of the innovative nanoparticle encapsulated IL-12 that's IMNN-001 has really been an innovation that allows patients to receive this potentially useful cytokine. And of course, the idea of combining with IL-12 and chemotherapy is very attractive. Again, I won't go into OVATION 2 results. You just heard it reviewed. I just want to make the case that our study very much builds on the very attractive PFS and OS advantages that are seen in OVATION 2. But I also want to point out a couple of differences in our study. So we include bevacizumab in both arms, whereas I think in OVATION 2, that wasn't included. And again, I already mentioned that our endpoint is going to be minimal residual disease, and that's shown here in the schema of the trial. Again, patients start with -- patients that are suspected to have advanced stage ovarian cancer, undergo diagnostic laparoscopy. This is just to make sure that they should get neoadjuvant chemotherapy, not primary surgery. This also gives us an opportunity to collect tumor tissue at that pretreatment time point. Patients are then randomized to the control arm, which is neoadjuvant chemotherapy plus bevacizumab for 4 to 6 cycles, depending on their response and/or to the experimental arm and the experimental arm, of course, includes IMNN-001 that's administered intraperitoneally through an IP port. All patients will undergo interval cytoreductive surgery and then get additional chemotherapy. And the other sort of interesting thing about our study, as I mentioned, the primary endpoint is detection of surgical minimal residual disease by second look laparoscopy. But also by the time we initiated our study, we were kind of aware of PARP inhibitors and need for maintenance therapy. And so here, we have a unique sort of maintenance approach where patients that are homologous recombination deficient or HRD positive get bevacizumab plus Olaparib, which is a standard maintenance strategy. And they get that in both arms. So regardless of the arm, if you're HRD-positive, you're going to get PARP inhibitor, and patients that are HR proficient in the control arm get bevacizumab alone, which is, again, the current standard maintenance therapy for these patients. But in the experimental arm, we thought that it would be advantageous to look at extended exposure to IMNN-001. So these patients get bevacizumab plus IMNN-001. The only difference is during the frontline therapy, the frequency of administration is weekly. During the maintenance phase because it's prolonged, we didn't want to expose patients to the need for weekly therapy. So here, the frequency matches that of bevacizumab, which is once every 3 weeks. And then, of course, this allows us to serially collect biospecimens, including tumor, cell-free DNA, microbiome and IP fluid because, again, they have an IP port placed. I'm going to share with you some of the translational data. But for MRD to be useful, it has to correlate with outcomes that we care about. This is a paper that we just published in clinical cancer research and showing surgical. And also, we looked at cell-free DNA or circulating tumor DNA detection of MRD as well. So for those of you who are interested, this has a lot of details on that and how they correlate with outcomes. We also showed that with these serial samples from the tumor microenvironment made possible by the second look operations, we can also do very cool translational stuff. And in fact, one of the pictures of the sort of the -- from our -- one of our figures made the cover for clinical cancer research. And this is really the bottom line. Why do we care about MRD -- because it makes a huge difference. So you can see this is a surgical MRD. So patients that were second look negative, shown here in blue versus positive. You can see the huge median progression-free survival differences. And here on the right-hand side, you can see overall survival is not reached in patients that are MRD negative and 32 months in patients that are -- and again, you can see the hazard ratios and large or small p-values. We saw the same thing with circulating tumor DNA. For time constraints, I'm not going to show that data, but if you're interested, you can see our paper. And this brings me to the MRD study, the current trial. We've assessed 35 patients for eligibility. Some patients did not have high-grade serous ovarian cancer pathology. This trial is limited to patients with that histology. And then you can see some of the other reasons patients did not qualify. 25 patients have been randomized. Of these 25 patients, a few withdrew consent, but 7 of them remain in frontline phase. And about 12 of them have made it to the second look laparoscopy time point. I actually think it might be 11 because one of my patients had count issues, so we had to delay the second look laparoscopy. So a total of 11 evaluable patients. And this is -- this just goes through very granularly in terms of what are the outcomes for these patients. So this shows how far patients in the control arm have progressed. On the top, again, you can see the main stages of the study, diagnostic laparoscopy, neoadjuvant chemo, interval cytoreductive surgery, more chemo, second look time point and maintenance and follow-up. And here, you also see the chemotherapy response scores that Dr. Thaker alluded to. So -- and you can see that patients in the control arm, 4 out of the 6 of them that have gone through second look laparoscopy have had positive findings. And then the next slide shows basically the same thing for patients on the experimental arm. And here, you can see only 2 out of the 5 patients. Again, these are small numbers, but you can see sort of the rate. And you see overall better chemotherapy response scores as well in this group. And this information is summarized here where, again, I just want to point out the asterisks. These are only 11 patients. And so this information should be interpreted with caution. But you can see progression-free survival already separation of the curves, which is promising finding. And then here are some of the clinical outcomes. I mentioned the MRD positivity rate. It's 40% in the experimental arm and 2/3 of the patient in the control arm have had MRD positive. Now for positivity rate, we consider anybody who has any biopsy positive. But of course, when we do these operations, we do 10 to 15 biopsies. And one could infer that the number of biopsies that are positive, obviously, if you have more residual cancer, more biopsies are going to be positive. And so if we look at that in the experimental arm, the patients that were positive, it was 1 out of 10 biopsies, 1 out of 11 biopsies. So only 9.5% of patients that were positive in the experimental arm had biopsies that are positive. consider the control arm, those patients that were MRD positive in the control arm, you can see that they were really positive, so a much higher rate of biopsy positive. And again, in the experimental arm, even though we have very small numbers, there is already some indication that the mean chemotherapy response score is higher so that they're more responding to chemotherapy in the experimental arm. So we also, again, had an opportunity with the serial biospecimen collections to ask some key translational questions. The first is, how does IL-12 and chemotherapy reshape the tumor microenvironment and impact immune activation. Can surgical MRD function as a reliable surrogate endpoint for survival outcomes? Again, that's a key sort of aspect of the study. And then does circulating tumor DNA assess and correlate with surgical MRD, providing validation for circulating tumor DNA as a further surrogate endpoint. I'm going to mainly talk about the sort of the tumor microenvironment because some of the other transitional questions are awaiting further data. And so this is just, again, to kind of demonstrate the opportunity here. So at the time of diagnosis, where patients have more tumor, we have the opportunity to collect fluid, tumor samples and blood samples, then patients undergo neoadjuvant and we collect blood samples there. Again, at the time of interval surgery, we collect fluid and tumor and same with second look laparoscopy. And then we're using these biospecimens to do cutting-edge profiling of the tumor microenvironment. From the peritoneal fluid, we can collect single cells and do single-cell RNA sequencing. And on tissues, we can look at protein expression using CODEX and look at RNA expression using Visium HD. And so I'm going to just talk you through some of the early findings based on 3 patients in each arm that have undergone this type of serial analysis. This is single-cell RNA sequencing from, again, IP fluid. So cells collected from the IP fluid. This UMA just is a clustering algorithm that shows the different cell types based on their RNA expression. And what we noticed, which was very exciting and kind of truth -- setting the truth was that when we look at IL-12 expression, so IL-12 is a protein that has 2 subunits, IL-12A and B in terms of the genes that encode for it. And what you can see is among the different cell types, IL-12 is mainly expressed in the macrophages. And this is -- again, these are cells within the peritoneal cavity. And in fact, if we look at individual patient samples, so these are patients from the experimental arm, 3 patients from the experimental arm and 3 patients from the control arm, you can see that baseline levels in the experimental arm are very low. And in all 3 patients, but especially in these first 2 patients, you can see the significant upregulation of IL-12 at the interval cytoreductive surgery and second look time points. So this really shows that the mechanism of action of the treatment is really working, and it's not just random expression of IL-12. This IL-12 nanoparticles are being picked up by macrophages and being controlled. And as you can see in the control arm, you don't see anything like that. And so IL-12 expression is good, but we were interested in does this really impact downstream immunosuppressive aspects of the ovarian cancer tumor microenvironment. And so here, we're showing immunosuppressive gene signature. And you can see in the control arm, if anything, there is an elevation between baseline interval surgery and second look time points, there's elevation, whereas in the experimental arm, there is a decrease in levels of the gene expression. And we just have more time points from the experimental arm. So that's why there's more data because these patients have an IP port and we can interrogate them more frequently. So this was all in the IP fluid, and this was kind of exciting, and we're like, okay, this is working. But what about what's happening in the tissue environment? And to interrogate the tissue environment, we use Visium HD. For those of you who may not be familiar with this technology, basically, Visium HD looks at gene expression, but by preserving the spatial characteristics of tissue sections. So we start with H&Es, and that gives us kind of where the cells are. That information is then digitally collected. And then we look at gene expression and then there are software that put all of this together, so you can see single cell resolution spatial data that preserves areas of tumor and other cells in the immune environment. And I'll just kind of walk you through an example. So this is a patient on the experimental arm. These are the H&E sections from baseline interval cytoreductive surgery and second look laparoscopy time points. And if we overlay the Visium HD data, this -- the white here shows tumor cells, okay? The green is fibroblasts, blue macrophages and then the T and B cells are shown in red. And so what you can see in the baseline, this is before any treatment, there's tons of cancer cells and some fibroblasts. What you don't see is any macrophages, you don't see any immune cells. And by the interval cytoreductive time point, you start to see some macrophages. Again, the blue is macrophages, and you see lymphoid aggregates shown here in red. And then at the second look time point, you see lots of macrophages, immune aggregates and very few cancer cells. And so this is showing in the tumor cells, and again, excitingly, the data that I showed you on macrophages picking up and expressing IL-12 was in the peritoneal fluid. But looking at the tissue, we show that the macrophages that are in the tissue are also expressing IL-12, which is really exciting because that's, of course, where we hope to see the action. And in fact, if you look at macrophage gene expression profile, so these are differentially expressed genes. And on the right-hand side are genes that are higher expressed at the interval cytoreductive surgery. On the left-hand side, it's pretreatment. You can see that 2 genes that are highest -- and on the Y-axis, you see the statistical significance, the higher, the more statistically significant. On the X axis, you see the level of expression. So you see IL-12 and A and B as being the highest, most statistically significant genes that are overexpressed in tumor resident macrophages. The other cool observation is some immunosuppressive molecules like SPP1 and CSF-1 receptor that are known and established markers of immune suppression are lower expressed or higher expressed in the baseline sample. So their expression goes down in the interval tumor reductive surgery. And again, we can show this on a patient level. You can see individual patients in the experimental arm and control arm where IL-12a levels go up, whereas they're flat in the control arm. So that's great. But can we say something about T cell activation and T cell function? So we looked at 2 genes, Granzyme B and granulysin. These genes are usually expressed in cytotoxic T cells that have been antigen experienced and are attacking the tumor. And what you can see is, again, in the experimental arm, the level of these transcripts goes up, whereas in the control arm, if anything, it declines between the baseline and interval cytoreductive surgery time point. And here, you can see cytotoxic T cells are shown in red, and you can see, again, the blue that are IL-12 positive macrophages. You can see them surrounding and activating T cells and supporting their role in killing the cancer cells. So last but not least, one of the first things that happens with T cell activation is that T cells try to turn themselves off by expressing checkpoint molecules. And what we can see is, we see evidence of T cell activation based on checkpoint expression in T cells. Again, that's increasing in the experimental group, but going down in the control arm. This also raises kind of the interesting possibility of in the future, possibly combining IMNN-001 with checkpoint molecules may be an attractive strategy. And we see basically the same thing in peritoneal fluid cells. So this was in the tissue and BATF is basically a transcription factor for many checkpoints. In the peritoneal fluid, the control arm are shown here in the dotted arm. So you can see reduction in interferon stimulated CD8 positive T cells versus we see activation and markers of immune checkpoint activation in the CD8 cells. So last thing, I just want to kind of talk about some of these technologies that I showed you, the Visium HD and the CODEX are novel and they are very informative, but we get nice information out of them. However, they're expensive, time-consuming and they're not really sort of applicable to day-to-day clinical practice. And so one of the things that we want to do with some of this data and are starting to look at is to use AI to get the same segmentation information just from regular H&E samples, which are, of course, routine in pathology, see if we can look at different immune cell and other cell populations just by AI modeling and maybe get similar predictors of outcome. And so I hope that I've been able to show you that the clinical value of MRD trial, we've enrolled 19 out of the planned 30 patients. And notably, there's been no problems with toxicity. No patient has come off due to toxicity due to IMNN-001 and patients have been successfully treated not just during the frontline treatment, but also on the maintenance therapy. I hope that I convinced you of macrophage activation that IMNN-001 induces robust expression of IL-12A and B in both peritoneal tumor and in tissue resident macrophages and that this IL-12 expression is leading to tumor microenvironment remodeling. And so with that, thank you for your attention, and I'll turn it over to the next speaker.

Thank you, Dr. Jazaeri. So it's my pleasure to now introduce Dr. Giorgio Paulon, who is a statistical scientist at Berry Consultants. He focuses from a research perspective in design and implementation of novel Bayesian adaptive designs, including platform trials. And he has experience in simulation, interim and final analyses of critical studies and presenting results to DSMBs of clinicians and statisticians. His work has really supported high-impact publications, including a pivotal New England Journal of Medicine a trial and a paper published on minimally invasive treatment of intracerebral hemorrhage. Giorgio is passionate about enhancing the reproducibility of clinical research, developing advanced statistical methods and promoting transparent data-driven decisions. His training -- his formal training, he holds a PhD in statistics from University of Texas at Austin, where he developed Bayesian clustering methods for longitudinal data and collaborated on auditory neuroscience projects. He earned 3 other degrees from prestigious universities in Milan, Italy and Paris, France, a bachelors in mathematical engineering and a masters in statistics and a double degree in a top internal managers and engineering program. Importantly, for Imunon and OVATION 3, he is responsible for the statistical simulations that he'll be speaking to today and really the overall framework, which provides the foundation for this pivotal trial. So Giorgio?

Thank you, and thank you, everyone, for being here. So good morning. I'm proud to represent Berry Consultants here, the company that I work for and to kind of showcase our collaboration with Imunon. Berry Consultants is, I would say, a small consulting firm that was created 25 years ago by Scott and Don Berry. Don Berry, you probably know him, especially those of you that are in the oncology space. He was Head of Quantitative Sciences at MD Anderson. And then he decided to create his own company to bring kind of statistical rigor, but also innovation in a real-life trial and push the envelope, especially with regulators, FDA and EMA for bringing innovation and bringing value to patients faster and to the overall community also faster. So today, I will be speaking about a couple of things. The first part of the presentation, I really want to kind of emphasize again the Phase II results that we've had. But I will focus mostly on how we've used this data to kind of drive our assumptions for the Phase III portion of the study. So we've already seen this in the first presentation. So we've had a very robust Phase II study that studied IMNN-001 with a very well robust design, design trial that was randomized and controlled where the 2 arms are clearly defined, and that allows us to interpret very clearly the results of that Phase II trial. It was a very large Phase II trial, I would say, compared to what I'm used to seeing. Obviously, Phase II trials are not necessarily built to be powered to detect statistically significant results. But what we've seen in the previous presentations as well is that we've seen consistent positive results in this Phase II study. So I'm going to focus on a couple of things, the consistency of the effect that we've seen from 2 perspective across the endpoints and also across the subgroup, and that kind of really lays the foundation for our Phase III study. And then I'm going to show you how that data was used to create our assumptions that are very robust for a Phase III study. So we've seen this slide before. What I really want to emphasize here is that this is pretty uncommon for a Phase II study where you see benefit across subgroups. And to the credit of the company, there is not just a focus on a small subset of patients that are even more promising to bring to Phase III, but we go with kind of the overall population where we see a benefit. So all of these primary and secondary endpoints have hazard ratios in the right direction that are favoring the therapeutic intervention. And that's not always the case. Oftentimes, we find a subgroup and then we do a Phase III study in a specific subgroup. And then the second thing that is very striking is that there's a signal both in PFS and OS. Obviously, as I mentioned, there's no really need. The goal of a Phase II study is not to be powered for statistical significance. But there are techniques and in particular, this highlights the totality of effect methodology developed by L.J. Wei at Harvard that combine -- can combine endpoint to see how stronger the effect is when you combine this kind of evidence. So here, you see that we have both PFS and OS estimates. They are in the right direction. None of them on their own are statistically significant. Again, that is beyond the goal of the Phase II study. But then there's techniques where you can combine these 2 endpoints and find even more signal in the data and quantify the benefit to patients, in this case, several months between the experimental arm and the control arm for either of these outcomes. And I will also say these 2 endpoints are very especially OS uncontroversial for FDA. It's actually what is recommended. And so that's what will be brought up to the Phase III portion of the study, the OS endpoint. Okay. So how do we use this, I would consider a large amount of data for the Phase II, larger than usual, at least to build a robust Phase III design. Again, this is the schematic of the trial that was already well described in the first presentation. What I would like to emphasize here, a couple of things are the certification factors, those are very important in this study and the fact that we have a very clinically meaningful primary endpoint that is robust, is very accepted by FDA. It's a so-called hard endpoint. So there's no worry or no notion of biases in assessing the outcomes. This is all-cause mortality. And this trial will target the most responsive subgroup. It still will focus on all comers by the end of the trial. But initially, we'll target the most responsive subgroup, so the HRD positive subgroup and will enable accelerated readout of the data. And I will describe how in a couple of slides. And then even the methodology is very kind of statistically sound. It's an event-driven trial. So in time-to-event outcomes like time to death for this trial, what defines information is the number of events that you observe in this case deaths. And so this trial will have triggers for interim analysis and final analysis that are based on events, and that's kind of the cleanest source of information that you can have in a Phase III trial like this. Okay. So how would this work in practice? I've tried to put together a schematic. So -- the key feature -- there's 2 key adaptive features of this trial. One is that it starts prioritizing HRD patients. So the total number -- the total sample size target enrollment is 500. They are split equally between HRD and HRP. And the HRD patients will be primarily targeted initially because the goal is to allow an early readout in the HRD-positive population and then potentially expand to an overall ITT analysis later on when more data comes in. So the HRD analysis is the one that I will mostly focus on here. And you see that after randomizing 250 subjects, there will be 2 interim analysis before the final analysis. The first one will be targeted by 50% of information. So when 68 events in that HRD cohorts are reached. And then there's a second interim analysis at 101 events in the HRD subgroup and then the final analysis will be at 135 events. So this is a so-called group sequential design. It's, again, very accepted and with precedent by the FDA, especially in oncology. What this means is that if any of these earlier interim looks that are prespecified, there's a signal in the data that is strong enough, then Imunon could file for an accelerated approval or an early BLA in the HRD cohort and then wait and potentially expand once all of the ITT data comes through. And this kind of probability of success that you see here in the middle of the slide, I will describe that further later on, but I just want to emphasize that if our assumptions that I'll show you in a couple of slides are correct, then there is a very substantial chance that this trial will stop early, especially in the HRD population. Okay. So there's quite a bit of regulatory precedent for FDA full approvals that are based on interim overall survival data. So here, I just picked a few from the field of oncology. So we have a couple of examples from triple-negative breast cancer and also non-small cell lung cancer. These are trials that either allowed, so in the first one or actually did stop early for an early filing based on interim OS data, especially the second one is something that mirrors quite closely what we're doing here with the IMNN-001 and OVATION 3. It's a study that allowed prespecified earlier looks by an independent DSMB. And again, if the p-value of the study or the signal was strong enough, the study could stop early for early success. And I will try to quantify later on how earlier that can be. So I have a couple of slides on the assumptions that we've made that are one of the most important things that we make when we design clinical trials. So -- and what I would like to emphasize is that our assumptions are quite conservative. This is the scenario that we expect. So we have on the left here, the OVATION through data stratified by HRD and HRP populations. You see it in the Kaplan-Meier. And then overlaid on it, it's what we are assuming in terms of the ground truth. The ground truth is if we had an infinite amount of data, what would we actually observe. And I think more significantly on the right, I'm showing that in terms of the hazard ratio. So hopefully, you see again, on the x-axis HRD and HRP population separately, you see a 95% credible interval with 2-point estimates. You see one that is denoted by O, that is what was observed in the OVATION 2 study. And then there's an A that is what we are assuming the effect will be in OVATION 3 when we designed the study. So you see that even under what I'm calling expected scenario, this is just one of the scenarios considered, we are assuming something that is slightly weaker than what was observed in OVATION 2. And we do this to give us ourselves a little buffer because obviously, there's still variability out there in the OVATION 2 study. So even under this expected -- what we're calling expected scenario that in reality is slightly weaker than OVATION 2, we see a very large power of 98%. Now we -- what we do when we simulate clinical trials is that we try to be as -- in a way conservative as possible. We try to simulate a wide variety of scenarios because we never know how things will play out in real life. So we also have a so-called weaker scenario where the effect that we're assuming is even weaker than what we were seeing in OVATION 2. And that really is to give us this margin of safety between the observed effect and the assumed effect. And even under this case, we still are adequately powered by what FDA considers acceptable, which is 82%. And again, this is not the target scenario. It's just kind of a dial back weaker scenario just to give us confidence that we could still meet in 82% of the cases, statistical significance. Okay. At this point, you should ask yourselves, how do we come up with these numbers, the 82%, the 98% and also how often the trial stops early. The way we do this, there's generally 2 ways. They're both accepted by FDA and there's guidance. Sometimes we're lucky enough where there's analytical formulas to calculate power for clinical trials. More often, we do simulation, and this is very similar to, I guess, in finances called risk modeling. We have a set of assumptions, simulate the outcomes and then analyze repeatedly across tens of thousands, hundreds of thousands, sometimes virtual trials, what actually happens, and then we characterize the operating characteristics based on that. So this is very much an iterative process that we've been going on with Imunon for about 1.5 years, where we set up the expectations of the trial, where it's accrual rate, dropout rate, hazard rates and the treatment effect profiles. And then we iterate through the design to optimize it and tailor it to the needs of Imunon. And so we do this thousands of times. And then we see kind of an aggregate picture, which is how many of these trials that we've simulated actually win and meet the primary endpoint. This allows us to, on one hand, characterize power, which is probably the most important operating characteristic of a trial, but it also allows us to look at individual trials, example trials, and we've shown many of these to understand if in this case, Imunon was happy with how the trial was performing. So this is kind of the key -- the evidence-based framework that we use to come up with numbers and check the robustness of our assumptions. Okay. The last thing that I would like to really focus on here is how kind of the second level of innovation in this trial, which is the early looks, the early prespecified looks. And here, I wanted to quantify based on our assumptions, how earlier Imunon could file for early success and how often that happens again across our simulation. So in the graph that you see here on the left, what I'm reporting is the probability that the trial will stop at the first interim, the second interim and then the third interim is actually the final analysis for the HRD population. And so as an example, you see a light green here in the second graph -- sorry, in the middle part of the graph, which is the default assumption or the expected assumption. And under this scenario, 93% of the trials will stop either at the first or the second interim. So there's about 50% that stop the first interim and then another 43% that stop at the second interim. So again, this is the expected scenario, which is slightly weaker observed effect than OVATION 2. And those interims, just to give you an idea, occur on average, the first interim about 2 years earlier than the final readout of the data. And then the second interim on average is 1 year earlier than the maximum target of events in the HRD population. So this really can enhance the clinical development and the early filing that translates into a benefit for patients, clinicians, investors and society at large should the effect be observed. Okay. So to summarize, hopefully, I convinced you that we have a very robust design that has some innovation -- some elements of innovation, but it is also very, in a way, statistically sound and very accepted by FDA with a regulatory precedent. The main adaptive feature is that we can look early for signals in the data based on prespecified rules and file for early BLA. And that FDA, we've already gone through several interactions, but this is all framework that aligns with the regulatory precedent and gives us confidence that this trial can be a success. Thank you.

Thank you, Giorgio. Okay. Our final presentation before we go into Q&A, which is really always fabulous taking the effort to come together as you guys did that are in the room, you have an opportunity to really go deep with a set of phenomenal experts. So Dr. Douglas Faller will be talking about IMNN-001's potential from his perspective and giving an update on the progress of our Phase III trial, OVATION 3. And Dr. Faller is -- I'm delighted to say he's our Chief Medical Officer. He received his MD from Harvard Medical School and has a PhD and a Bachelor’s from the Massachusetts Institute of Technology, so MIT. He was Professor of Medicine at Harvard Medical School and subsequently, he founded and served as the first Director of Boston University's Comprehensive Cancer Center, where he was at Gruenbaum Professor for Cancer Research and Professor of Medicine, Biochemistry, Pediatrics, Microbiology, Pathology and Laboratory medicine. Dr. Faller is the scientific founder of multiple technology and pharmaceutical companies, and we were delighted to have him join largely based on the strength of our data and potential. As you were joining, Douglas, it was really exciting to hear your viewpoint over your career of observing ovarian cancer and really the potential for IMNN-001. So please come and share your thoughts with us.

Thank you, and thank all of you for joining us today. My job is to try to put together some of the things that you've heard. I'll do it very briefly because I certainly can't match the quality of the presentations you've had so far. I think you'll agree that the data that you've seen is exciting, and some of it is really brand new. The information that Dr. Jazaeri presented, I don't think has been presented outside of breakthrough cancer as far as I know. This is the first time it's been presented publicly. As Stacy mentioned, it's this kind of exciting data and this kind of promise that form the reasons why I joined Imunon very happily. I'll mention one other thing, one other reason that I joined Imunon. As you know and you've heard, as you know, -- this is a frontline cancer trial, a frontline trial in ovarian cancer. It's very unusual, as your experience will tell you, for a small company to start their first approval in a frontline setting. It's a gutsy move for a small company. Most companies, including large companies start at the relapsed/refractory setting, an easier path to get approval, but one that would take another 10 years to get into a frontline setting. So Imunon has decided to go where the patient need is the greatest despite the fact it's a bit of a harder path. Although from what you've seen today, I think you -- I hope you will agree that we have great reason for being confident that this is where we'll be successful. So what we've tried to show this morning is a number of things, a number of different parameters that collectively make us confident and optimistic and really enthusiastic about our probability of success and about our probability to provide meaningful benefit to patients over a relatively short term. We have a mechanism of action that's novel and immunotherapy that we can show alters the microenvironment. This is something that people have been trying to do, and I'll get back to this in a later slide. The drug we're using, IL-12 activates both the innate and the adaptive immune systems as both Dr. Thaker and Dr. Jazaeri mentioned. And this gives us sort of a double way of hitting the tumor from both arms of the immune system. You've seen the impressive clinical responses we've had in OVATION 2, and these are further substantiated with the early data from the MRD study. And finally, we've got emerging translational data from both the MRD study, which you've just heard and the OVATION 2 study, which I've had the privilege of presenting at multiple meetings over the last couple of months that continues to support our mechanism of action. You've seen the clinical data. I'm still smiling every time I look at it because of the benefits that we can provide to patients. One of the things that I believe Dr. Thaker mentioned was immunotherapies should have the ability to provide long-term benefit. Chemotherapy, the kind and even targeted therapies, for the most part, provide benefit while you're delivering them. In contrast, Look at the separation of curves and look at the length of time that we're providing benefit to patients. We're only giving our drug over this very short period of time at the beginning, and yet we see long-term benefit, exactly what you hope for if you kickstarted the immune system and the immune system continues to recognize and kill tumor cells. I won't go through all the things that Premal mentioned. But again, the survival data is really unprecedented, as she stated. In fact, after her talk at ASCO, one of the speakers who came up to a microphone said this is a milestone in ovarian cancer. An improvement in survival she implied is something we've been waiting for, for decades. The consistent benefit across other endpoints has been mentioned several times, something that's very reassuring and unusual in a Phase II trial. The fact our safety has been excellent. We've seen no cytokine release syndrome, no adverse events related to immunity, something that has plagued every other approach trying to use interleukin-12. And as I said and several speakers have said, we have clear evidence for an altered tumor environment, cold to hot. I'm sure following biological or biopharma and following cancer, you've been hearing cold to hot forever, mostly in the setting of people saying, we think our drug can turn a cold tumor to hot. I've been involved in many, many BD discussions with companies who say they can do that. We can do that. We have shown that, not in the test tube, not in the mouse, in patients. And I'll show you a little bit more of that data in a moment. And I talked about the long-lasting immune response already. And so just a little bit more data, and this is some of the data, just a tiny bit of it that I've been presenting at scientific conferences over the last couple of months. The data is still emerging. And some of the data Premal showed from OVATION 1, this is some of the data from OVATION 2. We have a whole panel of data. But the idea of turning cold to hot, as I said, has been something of a holy grail and something that everyone has wanted to do. And the inability to do that is, unfortunately, why, as Premal also mentioned, the checkpoint inhibitors have really shown, unfortunately, no benefit in ovarian cancer. You can't get checkpoint inhibitors to work if you don't have T cells in the tumor, activated T cells ready to kill the tumor if you remove the checkpoint. In this case, we can convert the tumor from cold to hot. So as one example, the ratio of -- sorry, I keep hitting the wrong buttons here. The ratio of CD8 cells to T regulatory cells -- I'm losing the pointer -- is quite low as you would expect in a cold tumor. But when we sample the tumor after just 3 cycles of chemotherapy at Imunon, we can see increases in the ratio of CD8 cells to T regulatory cells, both in the tumor and in [indiscernible]. Similarly, we talked -- so this is the adaptive part of the immune system. The [indiscernible] of the immune system, the monocytes and macrophages, M2 macrophages actually promote tumor growth and development. M1 promote anticancer activity. The ratio of M1 to M2 is low in both tumor -- in the cold tumor and cold stroma before we get treatment. After we get treatment, we see a substantial increase in the M1 antitumor macrophages and monocytes compared to [indiscernible]. I'm sorry, I'm too far from the microphone? Okay. I'll just point randomly then. If we look at conversely, so the immunostimulation is substantially increased. And conversely, markers of immune suppression, some of which Premal alluded to in the OVATION 1 study are reversed. We can see T regulatory cells, which just won the Nobel Prize this year for their importance in preventing autoimmune diseases are a terrible thing to have in a tumor because it prevents the immune response in the tumor. We can show decreases in T regulatory cells, both in the tumor and in the stroma, the tumor stroma. And finally, exhausted T cells go down once we stimulate the patient's tumor with the IL-12 with IMNN-001. We have a robust study design, 1:1 randomized treatment control with the endpoint that the FDA wants to see. Very importantly, we have a well-established biomarker, which is driving our study. I suspect you all know, but I'll mention it anyway. It's been well documented, including by a group of my colleagues in the business school at my alma mater that having a biomarker to drive your clinical study increases your chances of success at every phase of clinical development, up to a four fold increase in Phase I, Phase II, Phase III and registration. So the fact that we're using this biomarker that we've identified as a -- which is predictive of response to IMNN-001, we're using it in our trial and our statistical plan to take advantage of this increased probability of success. We have a limited duration of treatment, which is good for patients. And I've already shown you translates into a long benefit for patients, long after our drug has stopped, just what you'd hope for in an immune therapy. Dr. Thaker talked about the quality of life measurements we're going to be doing, including the ones we've already done in OVATION 2. And you've heard already from Giorgio about our confidence in our statistical design resulting from modeling of the design. Our OVATION II trial is successfully underway. We have multiple sites activated. And surprisingly, and unusually in my long experience, our enrollment is already exceeding our internal forecasts. So we're very gratified by that. We haven't mentioned it up to this point, but I think many of you know that we have FDA approval for our CMC plan for drug originating in our own GMP facility. And this is a huge significant cost savings and a strategic advantage. We don't have to rely on others for our drug supply. We've been excited about our kickoff of our trial and about the number of patients we've enrolled. We actually are going personally to visit each of our sites as they come online to talk with the investigators and to share best practices and advice from the trials that have already started and are already enrolling. The favorable benefit to risk ratio that we saw in OVATION 2 with very good safety and really impressive clinical responses and durations of response Have been further strengthened by the data you've heard today from the MRD study. And the other thing that the MRD study has done for us already, it's shown that we can combine safely with bevacizumab, which some gynecologic oncologists like to use in combination with chemotherapy. And as you also heard, we're able to show that we can safely give Imunon in a maintenance setting. So both of these set us up for future studies and future approvals for IMNN-001. We're well positioned to bring on 50 sites by the second half of 2026. I mentioned we've had multiple very successful engagements that we've been invited to attend, including recently ESMO and International Gynecologic Cancer society. I presented at ACR and most recently at SITC, I just came back from the SITC meeting. And several people mentioned that -- SITC is the Society for Immunotherapy in Cancer, the 25, I believe, year-old society in which -- for which nothing was happening for many years. And now the innovations in immunotherapy for cancer have made this one of the most important meeting, international meetings of the year. One of the things that was noted by a number of speakers there was the interest in IL-12. There were many more IL-12 presentations than there had been in previous settings. One person came up to me, one clinical scientist and said, I've been going around and looking at all the posters about the presentations for IL-12. And he said, I've been interested in IL-12 for years. It's the most potent cytokine against cancer. All of these posters, all of these companies, all of these investigators are trying to figure out a way of delivering it safely. You've done it. They're trying to figure out whether they can use it to help patients. You've done it. He said, I'm glad this is the last presentation because this is what I'm going to take home. So in each of these, as I mentioned -- and also, we've had investigator interest. We've had investigators who have come up to me after presentations who have said, can I participate in your Phase III trial? This is something I'd really like to do. So on the basis of what they heard, they were excited enough to want to participate in our trial. So this is the last slide. I'd like to just make the point again, we have really -- our trial -- our Phase III trial is built on unprecedented and clinically compelling overall survival data. We're continuing to get positive safety and efficacy data from Dr. Jazaeri's trial. We've got new translational data that's still emerging from both his trial and our OVATION 2 trial that confirms we have a potent novel mechanism of action and a mechanism of action that we can document is operative in patients. And finally, the biomarker-driven aspects of our trial, we think will even more greatly enhance our probability of success. So thank you very much for your attention, and I'll turn it back to Stacy.

Thank you, Douglas. So we'll open it up for Q&A, and I'm going to get us started actually, Premal, as I was listening to your presentation and thinking about you're one of the sites that's open. You enrolled in OVATION 2. You've now enrolled multiple patients in OVATION 3. How are you finding the interaction with patients with this data? Is it impacting the ability to really help them understand what this trial could mean for them? Yes, we do need to use this.

Thank you for the question. I'll also say I date back to OVATION 1. So I've been a trooper here and believing in this. So it's actually really encouraging and easy to now talk to patients because now we have published articles so patients can actually see it because, as you know, patients are consumers of their health care. And so they are educated. They want to hear what's front and like leading sort of scientific news. So I think it is much easier actually because we have published data, we continue to have data. I'm actually very excited to like present now the MRD data as well to sort of say, here's another trial that shows the benefit and the change. And as I mentioned before, patients have been craving for immunotherapy in all cancers and ovarian cancer is no different. If you watch the news or watch TV, you see a million different ads, right, direct consumer about like medications. And this is finally our opportunity to offer that to patients. And as I mentioned, there's nothing else in upfront ovarian cancer. And when I counsel patients about clinical trials, I tell them that if you want what's the past, that's standard of care. If you want what's the future, come join us in a clinical trial because everything we've done in the past was a clinical trial. And patients really wanted -- they're much more sort of very giving with their time because they know it's going to be a weekly treatment, and they're actually disappointed because they're randomized, right? So I can't guarantee you're going to be on this. However, it's a 1:1 randomization, which is good, too, because sometimes it's not like that. So I definitely do feel that patients are very passionate.

Do you want to add something from the MRD experience? Dr. Jazaeri has been nothing short of a powerhouse with that trial and has enrolled the majority of the patients. So you have a lot of conversations.

Yes. No, our trials open at 3 institutions just recently, a fourth institution is activated. I just want to echo Premal's. We have a patient who comes from Illinois to MD Anderson and she's on the experimental arm. So she comes every week to get this treatment. And I think I'm always -- every time I assume I know what patients are going to do, I've always been kind of humbled that when patients sort of are convinced that something might be in their best interest, they go through extreme lengths to do what they can to advocate for their care. So I just wanted to add that.

Okay. What questions, Tim? You guys want to come up maybe, just come and stand?

Tim Molloy from Alliance Global Partners. I had a couple of questions to Dr Jazaeri. You talked a little about safety [indiscernible].

Okay. I think one of the things that we are learning and getting better of is the administration weekly for these patients because I think also one of the things we didn't touch on as much is that even though not all patients got 17 doses, we are seeing the change in the tumor microenvironment even if patients get lower or less number of doses of the therapy. So it definitely tells you how potent it is. But with the adding of sort of the prophylactic pain medications, being much more aggressive of educating about antiemetics, we really are not seeing patients discontinue, and we improved the tolerability quite substantially. So we aren't seeing patients coming off because of adverse events from this. So we don't see cytokine release syndrome. We don't see interstitial lung disease, things that you commonly hear with immunotherapy. We don't see high fevers because a lot of times, patients when they get sort of these powerful cytokines can get that as part of a cytokine release syndrome. So we're not having patients in ICUs and they can tolerably come to and from every week to get their treatments.

Yes. I would just say that we had, of course, the benefit of Premal's pioneering work as OVATION 1 and 2. So we knew that premedicating patients really resolves any concerns about IP administration. And of course, IP administration resolves all of the previous lack of success with systemic administration. So we really haven't had any issues with tolerability.

One follow-up, Giorgio. You ran the hundreds of thousands of trials, was there a particular thing that came out [indiscernible] trial mostly or [indiscernible] particular things that we should be watching for going forward?

No, we don't necessarily do those to look for things that could derail the trial. I mean, ultimately, what derails the trial is if you don't observe what you are hoping for and you're expecting, right? So the reason for the simulation is more to calibrate, for example, how aggressive you want to be with the interim looks, for example. So we use kind of a conservative approach, which is -- I can go more in details, but it's an O'Brien-Fleming spending function, meaning you do multiple looks to the data, right, first interim, second interim and then the final. How early do you want to start looking? Those are the things that we looked at. We didn't want to look too early because we're expecting a little bit of a delayed effect. So those are the things that we try to mitigate. Don't look too early. have enough evidence that is strong enough that gives you a solid foundation, but it also allows you to save time ultimately. So those are the kind of things that we iterate and we optimize for.

[indiscernible].

Yes. No, I mean I think you raised a really good point. That's why the first thing I pointed out is these are based on 11 observations. But I think what we hope to do is to look at when we have the full complement of the data so that there will be 15 patients in each arm. And of course, I should have maybe mentioned specifically, but all of these patients are going to be also followed to progression-free survival and then overall survival as well. I think FDA has been very clear that they support surrogate endpoints so long as they're tied to traditional endpoints, and they're encouraging more trials to do that in order for us to have a better understanding of what might be a useful surrogate endpoint and what may not. So all of these patients in both arms are going to be followed to traditional endpoints. And I think then we'll see what we'll see. And again, sort of -- that's why I presented the biopsy data because in some ways, MRD positivity as a dichotomous variable may not even fully capture the benefit. But when you look at how many of the biopsies were positive in patients on the experimental arm versus control arm, I think there, again, you're seeing kind of the differences.

I'd just like to add one more other point. And obviously, our sophistication of technology has improved greatly if we look over the last decade. But you can also see this is from OVATION 1, OVATION 2 and then MRD study. We're looking at very similar variables, looking at sort of immunosuppressive signatures that are changed by this. So I would say even though the data is small subsets, you're seeing a consistency, which is, I think, really important. It's not like we're showing you just one trial that demonstrated this benefit. We're showing you a body of work.

Yes, it's an important point. And all 4, this is now OVATION 3 is the fourth trial in the frontline patient population and has consistently shown the effects, which from my perspective, when I look at the underlying biology of what's happening in the micro tumor environment and then you look at the clinical data, that's one thing, Emily, to your question of confidence that adds a lot for me. What other questions do we have? [Graham]?

[indiscernible]

I might clarify that -- and I'm realizing I'm not sure on the webcast that you can hear the question, so I'll repeat this question. So you commented on that we are enrolling faster than our expectations, which is true. And you want to know if there is a -- if we can understand what the patients are choosing not to do from in terms of other trials that they might consider. That's correct. I can start and then others can add on. So Premal referenced first in her remarks that it was -- it's a rather bold decision to go after the frontline treatment as we know there are women who don't respond to frontline chemotherapy. And therefore, you're bringing people into the trial that may fail just from the current standard of care. You've been very consistent, I think, in pointing that out. This is one of the things that makes frontline treatment studying the first-line frontline treatment very difficult. But what's -- and then therefore, it's not surprising that when you look at where there's been innovation recently, it's in maintenance or the later lines. And to the best of my knowledge, we don't know any other late-phase trials that are actively -- that are active in this space. So right now, that would mean that really patients would have the standard of care. That would be what they receive in this trial is that we build on with IMNN-001. But there have been other trials that have read out recently. Premal showed a couple of the survival curves, but those very different mechanisms of action and we're unable to show a prolongation of overall survival. So I think right now, those are basically the choices more to add?

Yes. I would echo those thoughts. I think one of the things we also have in this country an increase in neoadjuvant chemotherapy because the bar of trying to get all the cancer out, it has evolved from being less than 2 centimeters, you can leave some larger implants to now you need no gross residual like nothing you can see. So I can definitely say that's really hard to achieve. So a lot of patients now, at least 50% to maybe up to 60% in this country get neoadjuvant. We do the laparoscopies, like Dr. Jazaeri mentioned, to make sure we give every patient that opportunity. The only other upfront trial is really looking at heated intraperitoneal chemotherapy for neoadjuvant patients, only in an HRD population and that, too, you have to sort of go through your 3 cycles of chemo, make sure you're fit and then you get randomized. So patients are opting for options sooner because they are feeling the side effects and realizing that if you're giving a medication in the abdomen, and like I said, a lot of patients like that concept because when you talk about chemotherapy, they're like it goes throughout my whole body, right? So that's why I get my hair loss and other systemic effects. And even though this is causing some systemic effects in the intraperitoneal cavity, it's really changing where the cancer is located. So I think that resonates with patients. And I'd like to say that there's a little less mistrust in science right now, but sadly, there is more based on our current ways of how people are getting information. But I think the patients are really wanting to do the best for themselves, and this is an opportunity. So I think it's easier, as I said, other than when I did OVATION 1, where it's a Phase I and you're sort of hoping that this would work. So it is much easier this time around.

And remind me that the [indiscernible] trial that's ongoing, do you have to actually have partial or complete remission from chemo. Is that right?

We should have a response.

Response, yes, response. Other questions?

It's not an all [indiscernible].

Graham, do you have another question?

There was a reference earlier to use of AI [indiscernible].

Yes. So this, I think, falls under the umbrella of research and investigational aspects. And basically, I showed a lot of sophisticated ways you can interrogate the tumor environment, but these are expensive, time-consuming. And so where we see, hopefully, in the future, AI playing a role is to take the routine H&E section that all pathologists create when they receive tissue from surgeries and be able to see something and say something predictive at that level that doesn't require weeks of analysis and bioinformatics and things like that. So that's kind of a future direction that we have.

Other questions? Okay.

I was just curious about -- so the average numbers of [indiscernible].

I don't know that that's the average, but we shoot for 10 to 15 roughly. Yes.

[indiscernible].

So what we want to do is, we want to do systematic biopsies. So we do several areas in the pelvis, several areas next to the bowel, several areas in the upper abdomen plus anything that looks suspicious, any scar. What we've learned is that when we look with surgery, we can't -- very rarely can we tell obvious areas of cancer. So we have to do biopsies of suspicious areas, biopsies of where ovarian cancer likes to hide, for example, in fatty tissues near the diaphragm. And then because you can only biopsy so many areas, we also do the washings where we put in sterile saline, we swish that around and we aspirate that and the cells that are collected through that washing are also submitted to pathology. So that's kind of the way we have to -- but surgery is not perfect either. Unfortunately, many patients that have negative surgery, as you saw from the Kaplan-Meier curve, still progress. However, the time to progression is clearly different. And again, we're also sort of thinking that with ctDNA technologies becoming more and more sensitive than, and something that we can check repeatedly unlike surgery that you can only do once. I think that's going to be probably the preferred way to look at MRD. And there's pros and cons to both, but happy to discuss at the break.

Great question. Certainly, all of these markers and advancing technology for any of us that have lived through cancer with loved ones, you're always wanting markers that give you a sign of hope and success and that the treatment is working. So it's very powerful to see what all the work that Dr. Jazaeri that you continue to do. Any other remaining questions? Otherwise, we have coffee. I'm going to make a couple of just closing remarks, if you guys can have a seat if you'd like. So I hope that you guys enjoy it. I think it definitely, I know for everybody takes time away and to come to the Harvard Club for those of you here in New York ahead of your -- going to your day job and your office. It means a lot to be able just to allow the conversations to go deeper. So enjoyed the conversation before this, we'll enjoy it after. I found it certainly engaging, and I learn every time I hear discussions of really what you're facing on a day-to-day as you treat patients. We heard a lot of really interesting ideas. I think certainly, it was important, and we've gotten a couple of -- we've gotten questions as we've met with investors in the non-deal capacity about the trial design. Giorgio did a really great job of showing the conservative nature of the assumptions, which is, of course, what you want going in. The value of the grid that he showed with even the more robust efficacy. Obviously, if you have larger efficacy than you expect, you know that the chances of a successful trial increase. But when you look even at a weaker assumption, which we don't expect, based on the data, we still see that we have a trial that we would expect to read out positive. So very high probability of success estimate. So very great insight. It was certainly wonderful seeing the new data from the MRD study. It's a trial that has been going and really an important partnership with Break Through Cancer Foundation and their commitment to ovarian cancer. And of course, just hearing the viewpoints on our trial and the Phase III trial and really the properties of it. And so we are really -- we believe we have a very clear path going forward. I would hope that even the most skeptical of individuals that might be watching this or really just as a nature of being critical of evidence, I really think that it would be hard to deny that we're knocking on the door of something incredibly powerful and that this really does represent a true potential for a breakthrough. And I would say as being not only a novel therapeutic, it is a platform therapy. So when we think about IMNN-001, we know from preclinical research and really the literature that this really has potential not just for ovarian cancer, but other solid tumors. And then, of course, the ability to modify with through the platform to different targets. As we learn in science, we have an ability to play to that. So what's next? You've heard OVATION 3, we're actively enrolling. We have great momentum heading towards the end of this year. We've been very careful with spend as we're very carefully navigating our cash runway. And so we started with 4 sites. They are exceeding our expectations, and we are prepared. We actually should double the number of sites before the end of the year. We have 4 more that are either fully negotiated. We're waiting on IRB to give the final go. So we will be bringing a new wave on board, and then we've pulled forward the identification of the sites you saw reference to up to 50. So you're going to see a real infusion that's going to happen in the new year, which will be very exciting. Our regulatory strategy, we've shared, it's always been a strength. We are continuing to have dialogue. In fact, we're advancing our CMC as we do development work, and we're preparing for commercialization. It's really important that we're producing product, of course, for the Phase III trial, but ultimately thinking about a bigger scale. And that is all advancing and moving very well. And then for those of you, the investors, in particular, that we're having more and more conversations with that really don't just care about the returns, but care about what we're able to do for patients. I think everybody appreciates that when we look at the U.S. market alone has -- is valued at about $1 billion using conservative estimates from checkpoint inhibitor pricing and looking at the market with a significantly higher potential, obviously, globally. So we are executing with urgency, women who have ovarian cancer deserve that and really can't thank you enough for coming and for your partnership as we step through these important steps and this registration trial with the goal of bringing forward the first immunotherapy for ovarian cancer. So thank you for your time today. We should still have coffee and pastry so we can go out and I know all of the speakers are able to be here for a little while, so we can have some dialogue there. Thank you.